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Bactericidal versus bacteriostatic antibacterials: clinical significance, differences and synergistic potential in clinical practice

Bactericidal versus bacteriostatic antibacterials: clinical significance, differences and... J Antimicrob Chemother 2025; 80: 1–17 https://doi.org/10.1093/jac/dkae380 Advance Access publication 29 October 2024 Bactericidal versus bacteriostatic antibacterials: clinical significance, differences and synergistic potential in clinical practice 1 2 3,4 5,6 Angela Ishak , Nikolaos Mazonakis , Nikolaos Spernovasilis , Karolina Akinosoglou and Constantinos Tsioutis * 1 2 Department of Internal Medicine, 48202 Henry Ford Hospital, Detroit, MI, USA; Department of Internal Medicine, Thoracic Diseases General Hospital Sotiria, 11527 Athens, Greece; Department of Infectious Diseases, German Oncology Centre, 4108 Limassol, Cyprus; 4 5 School of Medicine, University of Crete, 71500 Heraklion, Greece; School of Medicine, University of Patras, 26504 Rio, Greece; 6 7 Department of Internal Medicine and Infectious Diseases, University General Hospital of Patras, 26504 Rio, Greece; School of Medicine, European University Cyprus, 6 Diogenes str, Nicosia 2404, Cyprus *Corresponding author. E-mail: k.tsioutis@euc.ac.cy; kostsioutis@gmail.com @TsioutisC Antibacterial activity can be classified as either bactericidal or bacteriostatic, using methods such as the MBC/ MIC ratio and time–kill curves. However, such categorization has proven challenging in clinical practice, as these definitions only apply under specific laboratory conditions, which may differ from clinical settings. Several fac - tors, such as the specific bacteria or infectious medium, can affect the action of antibiotics, with many antibac - terials exerting both activities. These definitions have also led to the belief that bactericidal antibacterials are superior to bacteriostatic, especially in more severe cases, such as endocarditis, neutropenia and bacteraemia. Additionally, current dogma dictates against the combination of bactericidal and bacteriostatic antibacterials in clinical practice, due to potential antagonism. This review aimed to assess the differences in antibacterial activ- ity of bactericidal and bacteriostatic antibacterials based on in vitro and in vivo studies and examine their antag- onistic or synergistic effects. Our findings show that specific bacteriostatic agents, such as linezolid and tigecycline, are clinically non-inferior to bactericidals in multiple infections, including pneumonia, intra- abdominal infections, and skin and soft tissue infections. Studies also support using several bacteriostatic agents as salvage therapies in severe infections, such as neutropenic fever and endocarditis. Additionally, not all combinations of bacteriostatic and bactericidal agents appear to be antagonistic, with many combinations, such as linezolid and rifampicin, already being used. The findings should be interpreted with caution, as most evidence is from observational studies and there is a need for randomized controlled trials to assess their effect- iveness and combinations, especially within the context of rising antimicrobial resistance. at 24 h of growth in specific media, whereas the MBC is the min - Introduction imum concentration of antimicrobial required to give a 3-log The introduction of antimicrobial agents in clinical practice has (≥99.9% killing) reduction in surviving bacteria (cfu/mL) com- played a significant role in reducing the morbidity and mortality pared with the initial inoculum at 24 h of growth. To define associated with infections. As antimicrobial discovery rapidly whether an antibacterial agent is bactericidal or bacteriostatic evolved, various antibacterials with diverse mechanisms of ac- 4 in vitro, the MBC/MIC ratio can be used. If the MBC/MIC ratio is tion were introduced in clinical use and different classification ≤4, the effect is considered bactericidal, and if the MBC/MIC ratio systems were used to group them according to their function. is >4, the effect is defined as bacteriostatic. There are, however, One classification is based on their mode of action—either bac - certain limitations to this definition. Firstly, this definition is tericidal or bacteriostatic. In simple terms, bacteriostatic antibac- laboratory-based, and many of the techniques used to calculate terials are defined as those that prevent the growth of the this ratio differ between laboratories; moreover, some studies bacteria; bactericidal antibacterials are those that kill bacteria have used non-standardized methods. Additionally, these tests (Table 1). However, it is crucial to remember that even bacterio- are usually done in a specified time frame and against specific static antibacterials do kill bacteria, although they do not reach bacterial strains, thus providing data on antibacterial agent activ- specific laboratory thresholds to be termed as bactericidal. ity against specific strains only. Finally, these tests are per- The MIC is defined as the lowest concentration of the anti - microbial that will inhibit the visible growth of a microorganism formed in vitro and do not necessarily mimic in vivo conditions; © The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/ by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Review Table 1. Commonly used antibacterials categorized by their activity antibacterials that have demonstrated both bactericidal and bac- teriostatic activity in in vitro studies. Bactericidal agents Bacteriostatic agents The aim of this review is to further clarify the terms bacteri- cidal and bacteriostatic, especially in clinical settings, and de- Aminoglycosides Tetracyclines scribe the differences in applications of these agents based on β-Lactams Macrolides recent data from in vitro and in vivo studies. Furthermore, this re- Fluoroquinolones Oxazolidinones view will examine the antagonistic or synergistic effect of com- Glycopeptides Sulfonamides bining bactericidal and bacteriostatic antibacterials. Rifampicin Lincosamides Nitroimidazoles Trimethoprim Antibacterial combinations Lipopeptides Chloramphenicol Polymyxins Nitrofurantoin Combination therapy involving different antibacterials has been Fosfomycin Fusidic acid increasingly used to address the emergence of MDR bacterial in- fections. However, when choosing combinations it is paramount to understand which antibacterials act synergistically and which they do not consider the host’s immune system capability and its antagonistically to optimize treatment strategies. It is generally interaction with bacteria and antibacterial agents. believed that combinations of bacteriostatic and bactericidal The MIC and MBC of antimicrobials constitute measures of in antibacterials should not be used, as in vitro studies have shown 18–20 vitro efficacy against bacteria, whereas in vivo efficacy and, them to be antagonistic. It is hypothesized that antagonism correspondingly, the optimal antimicrobial dose depend on phar- results because bacteriostatic drugs slow the growth of macokinetic and pharmacodynamic (PK/PD) indices. For bacteria, hence reducing the efficiency of bactericidal drugs, as concentration-dependent antimicrobials, the ratio of the free the latter are most potent against actively growing cells. maximal concentration to MIC (fC /MIC) is critical, whereas Antagonism between bactericidal and bacteriostatic agents max time-dependent antimicrobials rely on the time above the MIC may also be explained by the balance in synthesis of the different expressed as a percentage of the dosing interval ( fT > MIC). For compartments of the bacterial cell (i.e. DNA and proteins), which co-dependent antimicrobials, the ratio of the (unbound) 24 h occurs due to the combination of the agents. More specifically, in AUC to MIC ( fAUC /MIC) is used. Moreover, calculation of the the presence of a DNA replication inhibitor (e.g. ciprofloxacin), dose administered is based on body clearance, targeted plasma protein synthesis is not affected and as a result, proteins are pro- concentration and drug bioavailability. duced more rapidly than DNA, leading the bacterial cell to a state Another in vitro model that can be used for the characterization of imbalance. When a translation-inhibiting drug (e.g. tetracyc- of an antibacterial as bactericidal or bacteriostatic is by use of line) is added, protein synthesis is suppressed, reinstating the time–kill curves. Even though these curves are not routinely used ratio of DNA to protein and rendering bacterial growth faster. for this purpose, they can aid in determining the kinetics of bacter- Moreover, some antibiotics (e.g. nitrofurantoin) induce polysac- ial killing and whether it is time-dependent or concentration- charide synthesis by bacterial cells. These molecules act as dependent. Time–kill curves are important to understand, as anti-adhesive agents and impede the cellular entry of other many of the studies discussed in this review use these curves drugs (e.g. ciprofloxacin), thereby developing an antagonistic 22,23 when expanding on antibacterial activity. Typically, they depict interaction. However, in clinical practice, several such combi- that the bacterial concentration stabilizes or is maintained (i.e. nations have proved to be synergistic, such as trimethoprim and growth is halted) when exposed to bacteriostatic agents, whereas streptomycin. An important study that tested this hypothesis there is a steady or rapid reduction in the bacterial concentration was by Ocampo et al., who combined five different drugs (nali - 6–8 when exposed to bactericidal agents. dixic acid, streptomycin, tetracycline, erythromycin and tri- In reality, the activity of antibacterials and whether they will ex- methoprim) at clinically relevant inhibitory concentrations and hibit bactericidal or bacteriostatic in vitro activity can be affected assessed their interaction using time–kill curves; they then ex- by multiple factors, such as the environmental conditions in the tended to assess combinations of 21 different antibiotics at sub- medium or tissue, the number of bacteria, the type of bacteria, inhibitory concentrations. Their results confirmed the hypothesis the duration of the treatment, the dose of the agent and its mech- that in the presence of a bacteriostatic agent, the killing rate of 1,9 anism of action. Prominent examples of these phenomena are bactericidal drugs declined, highlighting that antagonism was linezolid, eravacycline, ciprofloxacin and some aminoglycosides. present; however, it did differ according to the bactericidal drug Multiple in vitro studies have showed that linezolid exhibits bacteri- used. For example, there were higher degrees of antagonism be- cidal activity against Streptococcus spp. and is bacteriostatic tween nalidixic acid and tetracycline than between trimethoprim 10–12 24 against Gram-positive cocci such as enterococci and MRSA. and streptomycin. More importantly, their assessment of the Eravacylcine is another antibacterial that is generally bacteriostat- 21 different drug interactions using screening methods revealed ic against Gram-positive cocci such as staphylococci; however, it more information about antagonism among antibiotics using dif- has also demonstrated bactericidal activity in in vitro studies ferent mechanisms of action. Their results further proved that against certain strains of Acinetobacter baumannii, Escherichia antagonism among bactericidal and bacteriostatic drugs was coli and Klebsiella pneumoniae. Another example is ciprofloxacin, highly prevalent and that specific combinations such as tetracy - which exhibits bacteriostatic activity when DNA replication is ham- clines and aminoglycosides with β-lactams, macrolides with pered, by inhibiting DNA gyrase, whereas it is bactericidal through fluoroquinolones, and β-lactams with folic acid synthesis inhibi- 14 24 bacterial DNA fragmentation. Table 2 summarizes some of the tors, frequently showed antagonism. However, it is important 2 Review Table 2. Bacteriostatic antibacterial agents with dual bacteriostatic and bactericidal activity Antibacterial agent Bactericidal activity Bacteriostatic activity 10–12 Linezolid Streptococcus pneumoniae MRSA Bacteroides fragilis VRE Clostridium perfringens Chloramphenicol Haemophilus influenzae Enterobacterales Streptococcus pneumoniae Staphylococcus aureus Neisseria meningitidis Eravacycline Acinetobacter baumannii Staphylococcus aureus Escherichia coli Enterococcus faecalis Klebsiella pneumoniae 16,17 a Tigecycline MRSA Enterococcus faecalis MSSA VRE Penicillin-resistant Streptococcus pneumoniae Escherichia coli Klebsiella pneumoniae Streptococcus pneumoniae In prolonged therapy. to understand that these results came only from studies on E. coli Enterococcus faecium and E. faecalis and showed both were syn- and these combinations could act differently against different ergistic, which could aid in suppressing the selection of resistant bacteria and in in vivo environments, where many different fac- strains of enterococci against both antibiotics. tors can affect drug behaviour. Another bacteriostatic agent that has been used in combina- In clinical studies, many combinations of bacteriostatic and tions with bactericidal drugs in clinical practice is clindamycin. An bactericidal antibacterials have been used, even though many interesting combination used is clindamycin/rifampicin; many in in vitro studies showed antagonistic effects. A landmark study vitro studies have shown their synergistic activity and therefore for the treatment of endocarditis was the Partial Oral it has been extensively studied in clinical settings in several infec- Treatment of Endocarditis (POET) study that compared partial tions. A 2017 retrospective cohort study in the Netherlands as- oral antibiotic regimens with IV antibiotic regimens for the treat- sessed this combination (orally) in treating periprosthetic hip or ment of left-sided endocarditis. A closer look at the antibiotic knee infection by S. aureus or coagulase-negative staphylococci combinations used for many cases of bacterial endocarditis re- in 36 patients following surgical debridement for an early infec- vealed that combinations of bacteriostatic and bactericidal anti- tion or those who underwent aseptic revision of loose compo- biotics were frequently used. These combinations included nents that were later found to be culture-positive. Their amoxicillin plus fusidic acid, linezolid plus rifampicin, and dicloxa- results showed a cure rate of 86%; 78% (14/18) in the surgical de- cillin plus fusidic acid for Staphylococcus aureus, coagulase- bridement group and 94% (17/18) in the revision group. negative staphylococci (methicillin-resistant or sensitive) or Another retrospective cohort study in France showed a cure streptococcal endocarditis. Furthermore, a linezolid plus moxi- rate of 64.7% by intention to treat and 84.6% by per protocol floxacin combination was recommended for Enterococcus faeca- analysis, using an oral combination of clindamycin/rifampicin in lis endocarditis, whereas moxifloxacin and clindamycin were 37 cases of erythromycin-resistant and lincosamide-susceptible 25 30 recommended for streptococcal endocarditis. bone and joint infections due to Staphylococcus spp. In studies It appears that linezolid was commonly used in combinations that also assessed this combination in hidradenitis suppurativa, with other bactericidal drugs and is expected to continue to be where cases have been associated with Staphylococcus spp. in- used, especially against resistant Gram-positive infections. An fection, the reported success rate for oral clindamycin with rifam- in vitro study assessed the combination of linezolid with other picin ranged between 63.6% and 85.7%. bactericidal drugs using time–kill curves. It showed that the add- Tigecycline with colistin is another combination that has been ex- ition of linezolid to gentamicin and vancomycin resulted in reduc- tensively studied, especially against resistant Enterobacteriaceae. A tion of their antibacterial activity and was therefore deemed 2012 in vitro study assessed the interaction between tigecycline and antagonistic. However, linezolid with rifampicin resulted in an colistin against eight NDM-1-producing Enterobacteriaceae using additive interaction against susceptible S. aureus strains and in- time–kill curves, and showed that the addition of tigecycline to co- hibited rifampicin-resistant variants. Another study also re- listin sulphate and colistin methanesulfonate did not increase bac- vealed that linezolid was synergistic with imipenem, doripenem terial killing and in low concentration was antagonistic. However, a and plazomicin against MRSA and methicillin-resistant strains more recent in vitro study showed that this combination was effect- of Staphylococcus epidermidis. These studies suggest that not ive against five carbapenem-resistant NDM-producing E. coli strains, all bacteriostatic/bactericidal combinations are antagonistic, with colistin allowing increased uptake of tigecycline. These results and many can prove synergistic and could aid in reducing resist- were reproducible in an in vitro study that evaluated this combin- ance. For example, a recent in vitro study has examined the com- ation against MDR A. baumannii, with tigecycline increasing the bac- bination of linezolid and fosfomycin against 34 clinical isolates of tericidal effects of colistin. There is also a limited number of studies 3 Review that assessed this combination in clinical settings. A retrospective for treatment of hospitalized patients with CAP, indicating similar cohort study from Thailand assessed the use of IV colistin and tige- clinical response rates for the two drugs. This agent constitutes cycline compared with IV tigecycline monotherapy in the treatment an effective oral alternative option to fluoroquinolones in patients of 28 patients with post-surgical non-bacteraemic intra-abdominal with CAP and pneumonia severity index (PSI) risk class II/III and at infections (IAIs) due to carbapenem-resistant A. baumannii (CRAB), least one comorbidity. Additional subgroup analyses of the and showed that 14 day, 30 day and in-hospital mortality rates, the OPTIC study based on disease severity risk scores and presence rate of breakthrough bacteraemia and the rate of bacterial eradica- of COPD/asthma or bacteraemia, demonstrated that omadacy- tion, were not significantly different between the two groups, with cline was inferior to moxiflox acin only in the context of bacter- the combination therapy associated with more severe renal impair- aemia, exhibiting lower success rates at early clinical response. ment and higher costs. Additionally, a larger cohort study from Finally, with regard to aspiration pneumonia in elderly patients, Spain with 118 patients with bacteraemia due to CRAB showed simi- IV clindamycin as monotherapy was compared with ampicillin/ lar results, where the 30 day crude mortality was not significantly sulbactam and panipenem/betamiprom during a randomized different in the combination therapy as compared with colistin prospective study in Japan. Researchers observed that clindamy- monotherapy. These results highlight that, even though the ma- cin was cost-effective and had results similar to the two other jority of in vitro studies demonstrated synergy among both antibio- agents regarding cure and adverse event rates, concluding that tics, this does not necessarily translate to increased effectiveness in clindamycin monotherapy is an effective therapeutic option clinical settings, as patient factors such as severity of illness and co- against aspiration pneumonia. morbidities also play an important role in response to treatment. With respect to nosocomial pneumonia, a multicentre, rando- mized, double-blind study was carried out at 138 sites in 31 countries, comparing tigecycline with imipenem/cilastatin in Head-to-head comparison of bactericidal 945 patients with HAP. Patients received either tigecycline (100 versus bacteriostatic antibacterials in mg daily) plus an optional adjunctive therapy with ceftazidime for Pseudomonas aeruginosa coverage (and addition of an amino- common infections glycoside in some cases for double coverage) or imipenem/cilas- Pneumonia tatin plus an optional adjunctive treatment with vancomycin for Bacterial pneumonia remains a significant cause of mortality, es- MRSA coverage. Overall mortality was similar between the two pecially in older patients with comorbidities. Current guidelines groups of patients; however, death rates were higher in the sub- on management of community-acquired pneumonia (CAP), group of VAP patients treated with tigecycline. Nevertheless, in hospital-acquired pneumonia (HAP) and ventilator-associated a following study investigating the same topic, researchers used pneumonia (VAP), offer all necessary information to healthcare higher doses of tigecycline and observed a numerically higher 38,39 52 professionals. To this end, a head-to-head comparison be- clinical response with the use of 200 mg of tigecycline daily. tween bactericidal and bacteriostatic antibacterials in the treat- Direct comparison of linezolid with vancomycin in the treat- ment of bacterial pneumonia is of interest. ment of suspected MRSA nosocomial pneumonia has also In a study performed nearly 30 years ago in the Netherlands, grabbed the attention of researchers. A systematic review and the effect of oral azithromycin was compared with IV benzylpeni- meta-analysis including nine randomized controlled trials cillin in 104 hospitalized patients with suspected pneumococcal (RCTs), compared linezolid with vancomycin in the treatment of CAP, demonstrating higher clinical and radiological success 2618 patients with suspected MRSA pneumonia, and showed rates with azithromycin, although statistical significance was not that the overall clinical cure rate, the clinical cure rate for patients reached. Two years later, an open prospective randomized study with culture-confirmed MRSA pneumonia, and the MRSA eradica- contrasted IV clarithromycin with amoxicillin/clavulanic acid in 112 tion rate were similar for the two antimicrobials. A subsequent hospitalized patients with CAP in Switzerland. The rate of clinical systematic review and comparative meta-analysis including se- improvement was similar for the two administered drugs. In a ven RCTs with 1239 patients and eight retrospective cohort or subsequent study azithromycin was compared with cefuroxime case-control studies with 6125 patients, analysed the effect of in the treatment of 180 patients with CAP, demonstrating similar linezolid versus vancomycin against proven MRSA pneumonia. clinical efficacy and a shorter duration of therapy. The clinical cure rate and the microbiological eradication rate In the context of antibacterial management of CAP, direct com- were significantly lower in the vancomycin-treated subgroup of parison of tigecycline with levoflo xacin has been a matter of inter- patients in the RCTs. Mortality rates were indistinguishable for est in multiple studies, indicating non-inferiority of tigecycline and the two treatments in both RCTs and cohort or case-control stud- revealing comparable cure rates for the two antimicrobial ies. These results may reflect the better accessibility of linezolid 43–45 agents. Furthermore, doxycycline, another tetracycline de- compared with vancomycin in the epithelial lining fluid, rendering rivative, was studied side by side with levofl oxacin in the treatment this agent an effective treatment against MRSA pneumonia. of patients with CAP requiring hospitalization in a teaching hospital Overall, a systematic review and meta-analysis, published 46 55 in Cleveland, Ohio. According to the results of this prospective in 2015 by Nemeth et al., included 33 RCTs and compared double-blinded trial the therapeutic efficacy was not significantly bacteriostatic with bactericidal antibiotics in the management different between the two drugs. More recently, omadacycline, of severe infections. Subgroup analysis of 13 studies that covered a newer tetracycline, has been approved in the USA for the treat- pneumonia showed no significant difference in clinical cure, mor- ment of CAP, based on the results of the Omadacycline for tality and relapse rates between patients treated with bacterio- Pneumonia Treatment in the Community (OPTIC) trial, an inter- static or bactericidal antibiotics. These results were compatible national clinical trial that contrasted this agent with moxiflox acin with the findings of a subsequent systematic literature review 4 Review by Wald-Dickler et al., which also investigated bactericidal versus infections. Constituting a leading cause for antimicrobial pre- bacteriostatic antibiotics in the treatment of bacterial infections, scriptions, SSTIs contribute to approximately 10% of hospital ad- 65,66 including 56 RCTs. In 19 trials on pneumonia and additional trials missions in the USA. SSTIs can range from erysipelas and that included pneumonia in specific subgroup analyses, non- common cellulitis to more serious conditions, such as necrotizing inferiority of bacteriostatic agents regarding clinical efficacy was fasciitis or abscesses, which warrant meticulous wound care and observed, except for the aforementioned study of tigecycline ver- surgical interventions in severe cases. sus imipenem/cilastatin in HAP patients, which demonstrated in- In 2014, the IDSA released guidelines outlining the treatment 51 67 feriority of tigecycline in patients with VAP. Finally, a systematic of SSTIs. In brief, management of SSTIs is dependent on the se- review and meta-analysis of 43 RCTs contrasting bactericidal with verity, nature and type of infection. Purulent SSTIs, whether mild, bacteriostatic antibiotics in the treatment of pneumonia indicated moderate or severe, are recommended to be treated with incision no statistically significant difference with respect to clinical cure, and drainage followed by empirical treatment with one of vanco- mortality, microbiological eradication and treatment failure rates mycin, daptomycin, linezolid, telavancin or ceftaroline in severe, between the subgroups of patients treated either with bacteri- purulent infections. Moderate purulent infections, following inci- cidal or with bacteriostatic agents. This meta-analysis included sion and drainage, are empirically treated with trimethoprim/ RCTs with patients having CAP and HAP, and trials that compared sulfamethoxazole or doxycycline. Severe, non-purulent SSTIs multiple categories of antibacterials, such as oxazolidinones with are managed with aggressive surgical debridement to remove glycopeptides, macrolides with fluoroquinolones, and macrolides any necrotizing processes and empirically treated with vancomy- 56 68 with β-lactam antibacterials. cin plus piperacillin/tazobactam. Moderate non-purulent SSTIs are managed with IV penicillin, ceftriaxone, cefazolin or clindamy- cin. Finally, mild and non-purulent SSTIs are treated with oral Intra-abdominal infections penicillin, cephalosporin, dicloxacillin or clindamycin. Tigecycline, a broad-spectrum glycylcycline, has been used for the Numerous studies have compared the efficacy of linezolid, a treatment of complicated intra-abdominal infections (cIAIs) be- bacteriostatic, with vancomycin, a bactericidal, as monotherapy. cause of its activity against multiple microorganisms, such as Itani et al. conducted an open-label multicentre study in the Enterobacteriaceae, E. faecalis, E. faecium and anaerobes, consti- USA and found linezolid to be statistically superior to vancomycin tuting a suitable antibacterial option in polymicrobial infections. in the treatment of complicated SSTIs caused by MRSA, revealing A double-blind, multinational study comparing tigecycline with that hospitalized patients with linezolid had a significantly short- imipenem/cilastatin for treating patients with cIAIs exhibited er length of stay and duration of IV therapy. Several other studies similar clinical cure rates. comparing the two antibiotics found no statistical superiority in Two randomized studies of patients with cIAIs comparing tige- clinical outcomes and microbiological eradication in hospitalized cycline with a combination regimen of ceftriaxone plus metronida- patients with MRSA and other complicated SSTIs involving 59,60 zole have shown non-inferiority of tigecycline. The first study 70,71 72 73 Gram-positives. Other RCTs from Taiwan and India have was conducted in the USA, Canada and Latin America, evaluated compared tigecycline, a bacteriostatic, with vancomycin alone clinically 376 patients, and exhibited similar clinical response rates or with aztreonam in complicated SSTIs in hospitalized patients, between the two treatment arms. The second study was an inter- and revealed that tigecycline monotherapy is statistically non- national trial that evaluated 387 patients clinically and 227 patients inferior to the combination of vancomycin and aztreonam; how- microbiologically. Similar clinical and microbiological response rates ever, tigecycline use was associated with higher rates of nausea, were revealed between tigecycline and comparators. dyspepsia and anorexia, whereas vancomycin and aztreonam In the age of MDR, eravacycline, a newer tetracycline derivative, 72,73 combination led to pruritus and rash. In 2007 Cenizal represents an additional weapon in the therapeutic arsenal against et al. reported a prospective randomized trial in the USA, com- resistant bacteria, even CRAB. This agent has been recently ap- paring the efficacy of doxycycline monotherapy with trimetho- proved for use in the treatment of cIAIs, as it demonstrated non- prim/sulfamethoxazole for outpatient treatment of SSTIs and inferiority compared with ertapenem and meropenem in cIAIs in revealed no statistical difference in clinical outcomes. Similarly, two double-blind clinical trials, IGNITE (the Investigating Gram- linezolid monotherapy compared with teicoplanin monotherapy, Negative Infections Treated With Eravacycline) trial 1 and trimethoprim/sulfamethoxazole combined with rifampicin, or 62,63 IGNITE4. In terms of real-world evidence, according to the re- dalbavancin monotherapy, showed no statistical difference of sults from a Bayesian network meta-analysis including 25 RCTs and clinical outcomes in treatment of MRSA SSTIs in hospitalized pa- 9372 adult patients, it was indicated that eravacycline had similar 75–77 55 tients. A meta-analysis conducted by Nemeth et al. re- clinical efficacy and safety in patients with cIAIs, compared with vealed that linezolid demonstrated statistically significantly common bactericidal antibacterials, such as meropenem, ertapen- higher clinical cure rates when compared with its bactericidal em, ceftazidime/avivactam plus metronidazole, piperacillin/tazo- comparators and reported near-significant association of in- bactam, imipenem/cilastatin, and ceftriaxone plus meronidazole. creased mortality in patients treated with tigecycline. Moreover, eravacycline proved significantly better than tigecycline with respect to microbiological response rates. Osteomyelitis and prosthetic joint infections Skin and soft tissue infections Linezolid constitutes a reasonable antimicrobial therapeutic choice Skin and soft tissue infections (SSTIs) represent a spectrum of mi- for bone infections, when a Gram-positive microorganism is the crobial invasion involving the epidermis, dermis and underlying causative factor, including MRSA. The oral bioavailability of linezolid soft tissues, and are among the most frequent bacterial and its sufficient concentrations inside bone tissue render this 5 Review agent an attractive option against this type of infection, which re- microbiologically equally effective to ciproflo xacin, when adminis- quires prolonged treatment. Limited data exist regarding direct tered for a 7 day treatment course of adult patients with uncom- comparison of linezolid with bactericidal antibacterials in the treat- plicated disease. ment of bone infections. In a case-control study in Greece, linezolid Another bacteriostatic agent, chloramphenicol, was com- was administered to 34 patients with osteomyelitis or prosthetic pared with ceftriaxone in a randomized trial for treatment joint infections (PJIs), and results concerning efficacy and safety of 46 adults and children who had positive blood cultures for were compared with a group of well-matched controls, who re- S. enterica serotype Typhi or S. enterica serotype Paratyphi, dem- ceived monotherapy or combination regimen, including at least onstrating similar cure rates. Chloramphenicol has also been one bactericidal agent. Although initial treatment success rates compared with fluor oquinolones, such as ciproflo xacin and gati- were similar for the two subgroups, relapse rates were higher, flo xacin, for the treatment of enteric fever, revealing equivalent and discontinuation of antimicrobial therapy was more prevalent clinical efficacy, although requiring longer treatment duration. in the linezolid group. Poor tolerability occurred mostly due to mye- Despite these findings, the decision about the optimal anti- losuppression. Moreover, a retrospective study in China compared microbial option should not be based on the bacteriostatic or linezolid and vancomycin regimens combined with one-stage sur- bactericidal action of the agent. It should be guided by the re- gery, followed by implantation of a vancomycin-loaded calcium gional rates of antimicrobial resistance, as MDR and XDR S. enter- sulphate artificial bone in 64 patients with traumatic osteomyelitis ica serotype Typhi isolates are increasing worldwide, rendering of the limbs caused by MRSA. This showed that both antimicrobials the understanding of patterns and trends of antimicrobial resist- had satisfactory clinical outcomes, yet linezolid-treated patients ance essential to avoid treatment failure. had fewer adverse events, a shorter duration of antimicrobial ther- With respect to plague, a disease considered extinct in Europe, apy and a shorter hospital stay. Regarding PJIs, a retrospective anecdotal evidence exists regarding direct comparisons of bac- cohort study in Japan compared linezolid with daptomycin in 82 tericidal with bacteriostatic antimicrobials in the treatment of patients with PJIs caused by Gram-positive microorganisms, reveal- this infectious disease. Plague is caused by Yersinia pestis, re- ing comparable success rates for the two drugs. Nonetheless, lower mains a public health concern in countries of sub-Saharan c-reactive protein (CRP) values and fewer adverse events were ob- Africa, Asia and the Americas, and can be treated with various served in the daptomycin-treated subset of patients. Finally, in a classes of antibacterials, such as fluor oquinolones, aminoglyco- randomized non-inferiority trial in Switzerland of osteoarticular in- sides, tetracyclines and chloramphenicol. In a randomized clin- fections comparing linezolid monotherapy versus trimethoprim/ ical trial in Tanzania, 65 adult or paediatric patients with bubonic, sulfamethoxazole combined with rifampicin against various types septicaemic or pneumonic plague were enrolled, who received of MRSA infections, higher relapse rates were observed in the line- treatment with either gentamicin or doxycycline for 7 days. zolid group. Nevertheless, a major limitation of this trial was the Results were similar with high success rates for both regimens. small sample size. Conclusively, linezolid, a bacteriostatic agent, is a valuable Role of bacteriostatic antibacterials compared therapeutic option in bone infections caused by Gram-positive with bactericidal antibacterials in severe microorganisms, including MRSA, especially in terms of treat- ment completion in outpatient settings, because of its high oral infections bioavailability. However, caution is required in detecting adverse It is a long-held strategy in treatment of infections such as endo- effects, such as haematological toxicity, peripheral neuropathy carditis, meningitis, bacteraemia or infections in immunocom- and lactic acidosis, during prolonged treatment courses. promised patients including febrile neutropenia, to use a Tedizolid, a more recent oxazolidinone, may feature a more fa- bactericidal antibacterial in order to increase the odds of cure. vourable safety profile than linezolid in case of lengthy treatment However, with the rise of resistance to several bactericidal of osteoarticular infections, yet clinical data are still scarce. agents, use of bacteriostatic agents could prove useful, if not im- Clindamycin also constitutes a bacteriostatic agent that can perative. In this section, the recent literature evaluating the use be used for the treatment of Gram-positive bone infections. of bacteriostatic agents in severe infections is summarized. However, data are lacking regarding head-to-head comparisons Table 3 summarizes the studies that have assessed bacteriostatic of this agent with bactericidal drugs. It is usually used in combin- antibacterials in patients with neutropenic fever, endocarditis, ation with other bactericidal antibacterials, such as rifampicin, Gram-positive bacteraemia and meningitis. fusidic acid or trimethoprim/sulfamethoxazole. Neutropenia Other infections A 2009 systematic review of the role of linezolid in infections For treatment of enteric (typhoid and paratyphoid) fever, a disease caused by Gram-positives, including VRE in neutropenic patients, caused by Salmonella enterica serotype Typhi and S. enterica sero- included five studies (two of which were prospective comparative type Paratyphi, bacteriostatic antibacterials have been compared studies) and eight case studies where linezolid was used on a with bactericidal antibacterials in several studies. Azithromycin compassionate basis (i.e. after all available treatment options has been compared with third-generation cephalosporins, such failed) in 438 neutropenic patients. The overall cure rate ranged as ceftriaxone and cefixime, exhibiting non-inferiority regarding from 57% to 87%. Interestingly, in the prospective studies there clinical outcomes in children with uncomplicated typhoid was a 100% microbiological cure rate against VRE. Moreover, 82,83 fever. Moreover, a randomized trial conducted in Egypt more only 0.02% of bacterial isolates developed resistance to linezo- than 20 years ago revealed that azithromycin was clinically and lid. Of note, one of the included trials (a double-blinded, 6 Review Table 3. Summary of the characteristics and results of studies that have assessed the use of bacteriostatic antibacterials in severe infections such as febrile neutropenia, meningitis, bacteraemia and infective endocarditis Bacteriostatic Bactericidal antibiotic antibiotic Author (number of (number of (year) Type of study Patient characteristics Disease patients) patients) Main pathogen Main results Bucaneve RCT (open label) Hospitalized adults with Neutropenic Tigecycline + Piperacillin/ Multiple (Gram-negatives Clinical success rate was et al. 2004 neutropenic fever fever piperacillin/ tazobactam and Gram-positives 67.9% of patients in the secondary to tazobactam (n (n = 205) including MRSA) combination group, haematological = 187) compared with 44.3% of malignancy patients in the monotherapy group (P < 0.001). The combination regimen had a higher clinical success than monotherapy in bacteraemia (0.5%, compared with 27.7%; P < 0.001) Jaksic et al. RCT (double-blind) Hospitalized adults with Neutropenic Linezolid (n = 304) Vancomycin (n = Gram-positive including No statistically significant 2006 neutropenic fever fever 301) MRSA difference in clinical secondary to success [linezolid group malignancy 219 (87.3%) of 251; vancomycin group 202 (85.2%) of 237]; microbiological success rates [linezolid group, 41 (58%) of 71 patients; vancomycin group, 29 (50%) of 58 patients]; and mortality rate [linezolid group, 17 (5.6%) of 304; vancomycin group 23 (7.6%) of 301 vancomycin-treated patients]. Drug-related adverse events (24.0% vs 17.2%; P = 0.04) and renal failure (2.3% vs 0.3%; P = 0.04) were higher in the vancomycin group. No difference in haematological adverse effects Continued Review Table 3. Continued Bacteriostatic Bactericidal antibiotic antibiotic Author (number of (number of (year) Type of study Patient characteristics Disease patients) patients) Main pathogen Main results Faella et al. Case series Patients with Meningitis Linezolid N/A Penicillin-resistant 5/7 patients treated with the (2006) pneumococcal combined with Streptococcus combination of ceftriaxone meningitis ceftriaxone pneumoniae and linezolid survived (n = 7) Munoz et al. Case series Adult patients with Gram-positive Linezolid (n = 9), in N/A Staphylococcus aureus Clinical and microbiological (2007) Gram-positive endocarditis combination (including MRSA; n = 6), cure with no adverse endocarditis and with rifampicin Streptococcus mutans effects or relapses for all 9 refractory disease, in one case (n = 1), cases intolerance to other Corynebacterium drugs or need for oral striatum (n = 1), consolidation coagulase-negative treatment staphylococci (n = 1) Lauridsen Retrospective cohort Patients with infective Infective Linezolid (n = 38) N/A Gram-positive cocci No statistically significant et al. study endocarditis that endocarditis (including some cases differences in cure rate (2012) failed first-line of culture-negative (74% vs 71%, P > 0.05), treatment endocarditis) in-hospital mortality (13% vs 14%, P > 0.05) or post-discharge mortality at 1 year follow-up (26% vs 26%, P > 0.05) for patients receiving treatment with linezolid compared with patients without such treatment Sipahi et al. Case series Patients with MRSA Meningitis Linezolid (n = 9) Vancomycin MRSA Patients’ treatment with (2013) meningitis (n = 8) linezolid had a greater rate of MRSA clearance from CSF on Day 5 (7/9 vs 2/8; P = 0.044). One-month survival of the patients with microbiological cure was 2/ 2 in the vancomycin group and 4/7 in the linezolid group Balli et al. Systematic review Adult patients with VRE VRE Linezolid (n = 538) Daptomycin VRE Higher 30 day all-cause (2014) and bacteraemia bacteraemia (n = 429), mortality (OR, 1.61; 95% CI, meta-analysis heterogeneity 1.08–2.40) and (including 10 in daptomycin infection-related mortality retrospective dosage (OR, 3.61; 95% CI, 1.42– studies) 9.20) for patients treated with daptomycin. Overall Review mortality was also significantly increased among patients treated with daptomycin (OR, 1.41; 95% CI, 1.06–1.89). Relapse rates were higher in the daptomycin group of patients (not statistically significant), and adverse events did not demonstrate a statistically significant difference between the two subgroups of patients Chuang Systematic review Patients with VRE VRE Linezolid (n = 656) Daptomycin VRE Mortality was higher in et al. and bacteraemia bacteraemia (n = 532), patients receiving (2014) meta-analysis heterogeneity daptomycin (OR, 1.43; 95% (including 13 in daptomycin CI, 1.09–1.86; P = 0.009) retrospective dosage and subgroup analysis of studies) studies that reported adjusted ORs indicated that daptomycin was associated with higher mortality (OR, 1.59; 95% CI, 1.02–2.50; P = 0.04) Zhao et al. Systematic review Patients with VRE VRE Linezolid (n = 894) Daptomycin VRE Similar overall crude mortality (2016) and bacteraemia bacteraemia (n = 445), (RR = 1.07; 95% CI, 0.83– meta-analysis standard or 1.37), clinical cure (RR = (including 11 high dose 1.11; 95% CI, 0.88–1.42), retrospective microbiological cure (RR = studies) 0.99; 95% CI, 0.90–1.09) and relapse (RR = 1.08; 95% CI, 0.76–1.52) rates between daptomycin- and linezolid-treated patients. No statistically significant difference regarding adverse events between the two groups Continued Review Table 3. Continued Bacteriostatic Bactericidal antibiotic antibiotic Author (number of (number of (year) Type of study Patient characteristics Disease patients) patients) Main pathogen Main results Zhou et al. Prospective Hospitalized adults with Neutropenic Tigecycline N/A Gram-negative Clinical success rate was (2018) observational neutropenic fever that fever (n = 125) organisms 68.0% (85/125) and study failed first-line mortality rate was 18% treatment (23/125). Clinical success rate in patients with pneumonia as cause of neutropenic fever was 73.1% (49/67). Clinical success in patients with bacteraemia was 35.3% (6/ 17), with the 30 day mortality rate of 64.7% (11/ 17) Sipahi et al. Case series Patient with Meningitis Linezolid (n = 17) N/A Methicillin-resistant 15/17 patients achieved (2018) post-neurosurgical staphylococcal spp. microbiological cure with meningitis linezolid and 1 reported death due to treatment failure without documented relapse of meningitis due to methicillin-resistant Staphylococcus spp. Shi et al. Systematic review Patients with VRE VRE Linezolid (n = Daptomycin (n = VRE There was a trend towards (2019) and bacteraemia bacteraemia 2053) 1934), increased mortality for meta-analysis heterogeneity those in the daptomycin (including 21 in daptomycin arm vs those in the linezolid retrospective dosage arm, although this trend did observational not reach statistical studies and 1 significance (OR, 1.27; 95% prospective CI, 0.99–1.63; I = 42.9%). cohort study) In the subset of studies focusing on high-dose daptomycin, comparable mortality associated with daptomycin and linezolid treatment was observed (OR, 0.92; 95% CI, 0.46– 1.84; I = 49.4%). Overall, clinical response, microbiological cure, recurrence of bacteraemia Review and risk of CPK elevation were similar for the two agents. Finally, risk of thrombocytopenia was significantly lower in the daptomycin group of patients Munoz et al. Retrospective cohort Patients with infective Infective Linezolid (n = N/A S. aureus, Patients treated with linezolid (2021) study endocarditis treated endocarditis 295), only 11 coagulase-negative presented higher with linezolid patients were staphylococci, in-hospital mortality in included for Streptococcus spp. contrast to matched comparison controls not treated with with patients linezolid (54.5% vs 18.2%, not treated P = 0.04) with linezolid Modemann Retrospective Hospitalized adults with Neutropenic Tigecycline ± Carbapenem, MDR pathogens (including No statistically significant et al. observational neutropenic fever fever carbapenem, vancomycin or MRSA and VRE) difference in response rate; (2022) study with unknown origin vancomycin or linezolid (n = however, in patients secondary to AML/ALL linezolid (n = 30) receiving tigecycline there 43) was lower absolute sepsis (33% vs 47%, P = 0.235) and infection-associated mortality rates (5% vs 13%, P = 0.221) Kawasuji Systematic review Patients with MRSA MRSA Linezolid (n = 293) Daptomycin (n = MRSA All-cause mortality, clinical et al. and bacteraemia bacteraemia 114), and microbiological cure, (2023) meta-analysis vancomycin hospital length of stay, [including 2 RCTs, (n = 4894), recurrence, 90 day 1 pooled analysis teicoplanin (n readmission and adverse of 5 RCTs, 1 = 27) event rates were similar subgroup analysis between patients treated (1 RCT) and 5 with linezolid vs those case-control and treated with vancomycin, cohort studies] teicoplanin or daptomycin ALL, acute lymphocytic leukaemia; AML, acute myeloid leukaemia; CPK, creatine kinase; RR, relative risk. Review prospective RCT) compared vancomycin with linezolid in approxi- bactericidal agents in treating endocarditis. However, due to mately 600 neutropenic patients and showed no statistically sig- the increase in drug-resistant cases and the development of nificant difference in clinical success rates (linezolid, 87.3%; newer bacteriostatic agents that can reach desirable levels in vancomycin, 85.2%; P = 0.52) and mortality rates (linezolid, the bloodstream, there have been some published studies that 5.6%; vancomycin 7.6%). Moreover, linezolid was associated assess bacteriostatic agents in endocarditis. with fewer drug-related adverse events and drug-induced renal One example is linezolid, which was also regarded by the POET failure. One of the concerns of using linezolid in neutropenic pa- study as optimal for oral consolidation in endocarditis in combin- tients for Gram-positive coverage is the reported myelosuppres- ation with bactericidal drugs. A case series from 2007 described sion when used for longer than 14 days. Interestingly though, nine patients who were diagnosed with Gram-positive endocarditis the above-mentioned trial showed that blood count recovery and were treated with linezolid due to failure of previous therapies or was comparable among patients who received vancomycin and due to allergies to first-line therapies. All nine patients achieved clin- 91 95 those who received linezolid. ical and microbiological cure with no adverse effects or relapses. Another bacteriostatic agent studied in neutropenic patients Additionally, several published case reports document the success- is tigecycline. An open-label trial in 2014 from Italy compared ful treatment of endocarditis caused by MRSA, Corynebacterium spp. 96–100 monotherapy with piperacillin/tazobactam (a bactericidal agent) and VRE, using linezolid. Interestingly, in two cases, linezolid with a combination of piperacillin/tazobactam plus tigecycline (a was combined with bactericidal drugs, such as daptomycin and ci- 98,99 bacteriostatic agent) in 300 cancer patients with febrile neutro- proflox acin. In all these cases, linezolid was used either due to penia. The intention-to-treat analysis showed that there was vancomycin resistance, gentamicin resistance or failure of other a 23.6% risk difference in favour of combination therapy in first-line treatments to achieve microbiological cure. achieving a clinical cure. This was significant for neutropenic pa- The largest study to date describing the use of linezolid in tients with bacteraemia and clinically documented infections. endocarditis is a 2021 retrospective cohort study from Spain Another prospective cohort study from China assessed the use that compared in-hospital and 1 year mortality among patients of salvage tigecycline (i.e. following treatment failure with first- who received linezolid for endocarditis treatment (n = 295) versus line therapies) in 125 neutropenic patients with haematological patients who did not (n = 3172). When the authors were trying malignancies and showed a 68.0% treatment success. In this to assess the true impact of linezolid, only 11 cases fulfilled the study, tigecycline was not compared with other agents; however, criteria and were considered to have been administered linezolid it was used after bactericidal combination therapies such as car- as a definite treatment for endocarditis. Thus, only these 11 bapenems with vancomycin had failed. The use of another cases were used for comparison. Their results showed that pa- antibacterial in combination with tigecycline was not restricted tients treated with linezolid had higher in-hospital mortality and, of note, the most common combinations were with bacteri- (54.5% versus 18.2%, P = 0.04); however, it is important to note cidal agents, such as carbapenems and cephalosporins. In both that patients receiving linezolid were affected by a larger number studies mentioned above, the majority of isolated bacteria were of comorbidities and endocarditis complications, which could those that tigecycline is known to have bacteriostatic activity have affected the mortality rate. Another retrospective study against, such as VRE, K. pneumoniae and other Gram-negative from Denmark also compared linezolid (n = 38) with other treat- 92,93 bacteria. A more recent retrospective single-centre study ments (n = 512) in left-sided Gram-positive endocarditis. Their re- conducted in 2022 in Germany assessed tigecycline as salvage sults showed that there were no significant differences in the therapy in 73 neutropenic patients with leukaemia, either as cure rate, in-hospital mortality or mortality at 12 months be- monotherapy (n = 30) or in combination with a carbapenem tween linezolid and other treatments. These studies show (n = 43). Response rates and mortality rates were similar among that linezolid could prove to be an effective and well-tolerated both groups. It is important to note that in studies where com- treatment for endocarditis caused by Gram-positive organisms, bination therapies were used, the role of the bactericidal drug especially MRSA and VRE; however, larger studies are needed to 93,94 was to provide coverage against Pseudomonas spp. Overall, draw more concrete conclusions. these studies show that bacteriostatic agents can be effective and safe in neutropenic patients and their combination with bac- VRE and MRSA bacteraemia tericidal agents to broaden antimicrobial coverage is possible and can achieve significant clinical improvement. The dogma that rapid killing of bacteria in bloodstream infec- tions, by use of antibacterials traditionally considered bacteri- cidal, is also not clinically relevant in the case of linezolid use in Infective endocarditis bacteraemia caused by resistant Gram-positive microorganisms. It is widely believed that bacteriostatic agents are ineffective in In a systematic review and meta-analysis published in 2014 in- the treatment of infective endocarditis, and that bactericidal cluding 10 retrospective studies and 967 patients with VRE bac- antibacterials are the management hallmark. This is partly due teraemia, treatment with linezolid compared with daptomycin to older studies that have shown poor outcomes when using bac- exhibited lower 30 day all-cause, infection-related and overall teriostatic agents in endocarditis. Additionally, due to the large mortality, as well as comparable adverse event rates. These concentration of bacteria that can grow on cardiac valves and results were compatible with mortality outcomes presented in the poor accessibility of phagocytic cells, it is accepted that non- another meta-analysis, which included 13 retrospective cohort phagocytic killing by bactericidal agents is crucial to achieving a studies and 1188 patients with VRE bacteraemia, and compared 1,2 microbicidal cure. There are no current clinical trials that com- linezolid with daptomycin, showing higher mortality rates in the pare the effectiveness of specific bacteriostatic agents with daptomycin subgroup. However, it is of utmost importance 12 Review to emphasize the heterogeneity in daptomycin dosage used in first-line antibacterial for acute bacterial meningitis due to the above-mentioned studies. In several of them, daptomycin Haemophilus influenzae and Streptococcus pneumoniae. dosage was approximately 6 mg/kg/day, whereas some studies However, due to its toxicity, such as bone marrow suppression 103,104 did not mention dosage. Bactericidal activity of daptomy- and emergence of bacterial resistance, as well as studies show- cin is dose-dependent, and the safety and efficacy of high-dose ing better results with β-lactams, it is rarely used in developed daptomycin (>6 mg/kg/day) in difficult-to-treat Gram-positive in- countries. Nevertheless, data on its success in treating bacterial fections have been well established. meningitis highlight that bacteriostatic antibacterials have the 106 1 Another meta-analysis published by Zhao et al. in 2016, in- potential to result in cure of CNS infections. cluded 11 retrospective cohort studies and 1339 patients, and There are newer small studies that highlight the use of other compared the efficacy of linezolid versus standard- or high-dose bacteriostatic drugs in treating bacterial meningitis. Linezolid is daptomycin in VRE bacteraemia, observing similar overall mortal- one such drug that has also shown good CSF penetration, with 111,112 ity, clinical cure, microbiological cure, relapse and adverse event drug levels reaching 30%–70% of its serum levels. A small rates between the two agents. More recently, Shi et al. con- number of studies have assessed the effectiveness of linezolid in ducted a meta-analysis on the same topic and compared the treating meningitis caused by Gram-positive bacteria in combin- above-mentioned drugs in treatment of VRE bacteraemia. The ation with other bactericidal antibacterials or as salvage therapy. researchers included 22 observational studies involving 3987 pa- A case series of 17 patients from Turkey studied the use of tients and found a non-significant higher mortality rate and a sig- linezolid either as primary therapy or as salvage therapy in the nificantly lower risk of thrombocytopenia in patients treated with treatment of meningitis by MRSA and methicillin-resistant daptomycin. In the daptomycin-treated subgroup, a trend to- coagulase-negative staphylococci in post-neurosurgical pa- wards higher clinical response and microbiological cure as well as tients, after failure of first-line treatment with vancomycin and lower risk for bacteraemia relapse was observed, though without third-generation cephalosporin. Fifteen of the 17 patients statistical significance. Moreover, a subgroup analysis of studies had microbiological clearance of infection by Day 5 (88% micro- using high-dose daptomycin revealed similar mortality rates be- biological cure rate), and none had a relapse, with only one 107 113 tween the two drugs. death due to treatment failure. Importantly, there were no The above-mentioned results should be interpreted with cau- reported severe haematological, nephrological or hepatological tion, as most of these studies are observational with high hetero- adverse effects due to linezolid. Another study followed se- geneity in various parameters. The design of larger randomized ven patients with penicillin-resistant pneumococcal meningitis trials is essential to shed light on the comparison of linezolid versus who were treated with linezolid, ceftriaxone and dexametha- daptomycin in VRE bacteraemia. Nevertheless, these data rendered sone. Of the seven patients, one died and one suffered severe se- linezolid, traditionally considered a bacteriostatic drug, a protagon- quelae. Another small study compared treatment of MRSA ist in the treatment of this specific bloodstream infection. meningitis with vancomycin or linezolid in 17 patients. The re- The favourable pharmacological properties of linezolid have sults showed that 7/9 patients treated with linezolid achieved led to its use in MRSA bacteraemia. A recent systematic review microbiological cure, compared with 2/8 of those treated with and meta-analysis included two RCTs, one pooled analysis of vancomycin (P = 0.044), with no severe adverse events occurring fiv e RCTs, one subgroup analysis (one RCT), and five case-control in either group. There has also been a case report of a post- and cohort studies involving 5328 patients and compared the ef- neurosurgical patient who developed VRE meningitis that was ficacy and safety of linezolid versus vancomycin, teicoplanin or successfully treated with IV linezolid, resulting in clinical and daptomycin, in patients with MRSA bloodstream infection. The microbiological cure. These studies highlight that linezolid primary effectiveness outcome was all-cause mortality, and sec- could prove effective in treating Gram-positive meningitis, espe- ondary effectiveness outcomes were clinical and microbiological cially MRSA meningitis, but larger controlled studies are still cure, length of hospital stay, recurrence and 90 day readmission needed to clearly evaluate its safety and efficacy, especially in rates. The primary safety outcome was defined as the rate of comparison with vancomycin. drug-related adverse events. Despite several limitations in the meta-analysis, all the above-mentioned outcomes were similar Conclusion between patient subgroups, concluding that linezolid could con- stitute a first-line therapeutic option in MRSA bacteraemia. The conventional classification of antibacterials as either bacteri- Owing to its oral form, linezolid remains a useful therapeutic op- cidal or bacteriostatic based on in vitro conditions, lacks clarity in tion in MRSA bacteraemia, with studies showing similar clinical the clinical setting, as indicated by current evidence. Some drugs success rate with treatment completion compared with paren- categorized as ‘bacteriostatic’ may exhibit ‘bactericidal’ effects teral antibiotics in selected low-risk patients. under specific in vitro conditions, and vice versa, considering the complexities observed in clinical contexts and the evolving understanding of antibacterial action. Therefore, predicting Meningitis whether a particular antibacterial will act as bacteriostatic or Meningitis is typically treated with bactericidal agents that easily bactericidal in an actual patient with a bacterial infection is likely reach the CSF. However, few studies have assessed the use of to be highly challenging. Moreover, the drug’s action may be con- bacteriostatic antibacterials, although some can readily pene- tingent on factors such as bacterial load and interaction with the trate the CNS. The first bacteriostatic antibacterial to show effi - immune system at the infection site. cient CSF levels and success in the treatment of meningitis was Extensive evidence indicates that the effectiveness of bacteri- chloramphenicol. In fact, in developing countries, it is often the cidal and bacteriostatic agents is comparable when employed in 13 Review 10 Zahedi Bialvaei A, Rahbar M, Yousefi M et al. Linezolid: a promising op- the treatment of various infections, including severe and compli- tion in the treatment of gram-positives. J Antimicrob Chemother 2017; cated SSTIs, community- and hospital-acquired pneumonia, 72: 354–64. https://doi.org/10.1093/jac/dkw450 intra-abdominal infections and osteomyelitis. 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Bactericidal versus bacteriostatic antibacterials: clinical significance, differences and synergistic potential in clinical practice

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Oxford University Press
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© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
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0305-7453
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10.1093/jac/dkae380
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Abstract

J Antimicrob Chemother 2025; 80: 1–17 https://doi.org/10.1093/jac/dkae380 Advance Access publication 29 October 2024 Bactericidal versus bacteriostatic antibacterials: clinical significance, differences and synergistic potential in clinical practice 1 2 3,4 5,6 Angela Ishak , Nikolaos Mazonakis , Nikolaos Spernovasilis , Karolina Akinosoglou and Constantinos Tsioutis * 1 2 Department of Internal Medicine, 48202 Henry Ford Hospital, Detroit, MI, USA; Department of Internal Medicine, Thoracic Diseases General Hospital Sotiria, 11527 Athens, Greece; Department of Infectious Diseases, German Oncology Centre, 4108 Limassol, Cyprus; 4 5 School of Medicine, University of Crete, 71500 Heraklion, Greece; School of Medicine, University of Patras, 26504 Rio, Greece; 6 7 Department of Internal Medicine and Infectious Diseases, University General Hospital of Patras, 26504 Rio, Greece; School of Medicine, European University Cyprus, 6 Diogenes str, Nicosia 2404, Cyprus *Corresponding author. E-mail: k.tsioutis@euc.ac.cy; kostsioutis@gmail.com @TsioutisC Antibacterial activity can be classified as either bactericidal or bacteriostatic, using methods such as the MBC/ MIC ratio and time–kill curves. However, such categorization has proven challenging in clinical practice, as these definitions only apply under specific laboratory conditions, which may differ from clinical settings. Several fac - tors, such as the specific bacteria or infectious medium, can affect the action of antibiotics, with many antibac - terials exerting both activities. These definitions have also led to the belief that bactericidal antibacterials are superior to bacteriostatic, especially in more severe cases, such as endocarditis, neutropenia and bacteraemia. Additionally, current dogma dictates against the combination of bactericidal and bacteriostatic antibacterials in clinical practice, due to potential antagonism. This review aimed to assess the differences in antibacterial activ- ity of bactericidal and bacteriostatic antibacterials based on in vitro and in vivo studies and examine their antag- onistic or synergistic effects. Our findings show that specific bacteriostatic agents, such as linezolid and tigecycline, are clinically non-inferior to bactericidals in multiple infections, including pneumonia, intra- abdominal infections, and skin and soft tissue infections. Studies also support using several bacteriostatic agents as salvage therapies in severe infections, such as neutropenic fever and endocarditis. Additionally, not all combinations of bacteriostatic and bactericidal agents appear to be antagonistic, with many combinations, such as linezolid and rifampicin, already being used. The findings should be interpreted with caution, as most evidence is from observational studies and there is a need for randomized controlled trials to assess their effect- iveness and combinations, especially within the context of rising antimicrobial resistance. at 24 h of growth in specific media, whereas the MBC is the min - Introduction imum concentration of antimicrobial required to give a 3-log The introduction of antimicrobial agents in clinical practice has (≥99.9% killing) reduction in surviving bacteria (cfu/mL) com- played a significant role in reducing the morbidity and mortality pared with the initial inoculum at 24 h of growth. To define associated with infections. As antimicrobial discovery rapidly whether an antibacterial agent is bactericidal or bacteriostatic evolved, various antibacterials with diverse mechanisms of ac- 4 in vitro, the MBC/MIC ratio can be used. If the MBC/MIC ratio is tion were introduced in clinical use and different classification ≤4, the effect is considered bactericidal, and if the MBC/MIC ratio systems were used to group them according to their function. is >4, the effect is defined as bacteriostatic. There are, however, One classification is based on their mode of action—either bac - certain limitations to this definition. Firstly, this definition is tericidal or bacteriostatic. In simple terms, bacteriostatic antibac- laboratory-based, and many of the techniques used to calculate terials are defined as those that prevent the growth of the this ratio differ between laboratories; moreover, some studies bacteria; bactericidal antibacterials are those that kill bacteria have used non-standardized methods. Additionally, these tests (Table 1). However, it is crucial to remember that even bacterio- are usually done in a specified time frame and against specific static antibacterials do kill bacteria, although they do not reach bacterial strains, thus providing data on antibacterial agent activ- specific laboratory thresholds to be termed as bactericidal. ity against specific strains only. Finally, these tests are per- The MIC is defined as the lowest concentration of the anti - microbial that will inhibit the visible growth of a microorganism formed in vitro and do not necessarily mimic in vivo conditions; © The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/ by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Review Table 1. Commonly used antibacterials categorized by their activity antibacterials that have demonstrated both bactericidal and bac- teriostatic activity in in vitro studies. Bactericidal agents Bacteriostatic agents The aim of this review is to further clarify the terms bacteri- cidal and bacteriostatic, especially in clinical settings, and de- Aminoglycosides Tetracyclines scribe the differences in applications of these agents based on β-Lactams Macrolides recent data from in vitro and in vivo studies. Furthermore, this re- Fluoroquinolones Oxazolidinones view will examine the antagonistic or synergistic effect of com- Glycopeptides Sulfonamides bining bactericidal and bacteriostatic antibacterials. Rifampicin Lincosamides Nitroimidazoles Trimethoprim Antibacterial combinations Lipopeptides Chloramphenicol Polymyxins Nitrofurantoin Combination therapy involving different antibacterials has been Fosfomycin Fusidic acid increasingly used to address the emergence of MDR bacterial in- fections. However, when choosing combinations it is paramount to understand which antibacterials act synergistically and which they do not consider the host’s immune system capability and its antagonistically to optimize treatment strategies. It is generally interaction with bacteria and antibacterial agents. believed that combinations of bacteriostatic and bactericidal The MIC and MBC of antimicrobials constitute measures of in antibacterials should not be used, as in vitro studies have shown 18–20 vitro efficacy against bacteria, whereas in vivo efficacy and, them to be antagonistic. It is hypothesized that antagonism correspondingly, the optimal antimicrobial dose depend on phar- results because bacteriostatic drugs slow the growth of macokinetic and pharmacodynamic (PK/PD) indices. For bacteria, hence reducing the efficiency of bactericidal drugs, as concentration-dependent antimicrobials, the ratio of the free the latter are most potent against actively growing cells. maximal concentration to MIC (fC /MIC) is critical, whereas Antagonism between bactericidal and bacteriostatic agents max time-dependent antimicrobials rely on the time above the MIC may also be explained by the balance in synthesis of the different expressed as a percentage of the dosing interval ( fT > MIC). For compartments of the bacterial cell (i.e. DNA and proteins), which co-dependent antimicrobials, the ratio of the (unbound) 24 h occurs due to the combination of the agents. More specifically, in AUC to MIC ( fAUC /MIC) is used. Moreover, calculation of the the presence of a DNA replication inhibitor (e.g. ciprofloxacin), dose administered is based on body clearance, targeted plasma protein synthesis is not affected and as a result, proteins are pro- concentration and drug bioavailability. duced more rapidly than DNA, leading the bacterial cell to a state Another in vitro model that can be used for the characterization of imbalance. When a translation-inhibiting drug (e.g. tetracyc- of an antibacterial as bactericidal or bacteriostatic is by use of line) is added, protein synthesis is suppressed, reinstating the time–kill curves. Even though these curves are not routinely used ratio of DNA to protein and rendering bacterial growth faster. for this purpose, they can aid in determining the kinetics of bacter- Moreover, some antibiotics (e.g. nitrofurantoin) induce polysac- ial killing and whether it is time-dependent or concentration- charide synthesis by bacterial cells. These molecules act as dependent. Time–kill curves are important to understand, as anti-adhesive agents and impede the cellular entry of other many of the studies discussed in this review use these curves drugs (e.g. ciprofloxacin), thereby developing an antagonistic 22,23 when expanding on antibacterial activity. Typically, they depict interaction. However, in clinical practice, several such combi- that the bacterial concentration stabilizes or is maintained (i.e. nations have proved to be synergistic, such as trimethoprim and growth is halted) when exposed to bacteriostatic agents, whereas streptomycin. An important study that tested this hypothesis there is a steady or rapid reduction in the bacterial concentration was by Ocampo et al., who combined five different drugs (nali - 6–8 when exposed to bactericidal agents. dixic acid, streptomycin, tetracycline, erythromycin and tri- In reality, the activity of antibacterials and whether they will ex- methoprim) at clinically relevant inhibitory concentrations and hibit bactericidal or bacteriostatic in vitro activity can be affected assessed their interaction using time–kill curves; they then ex- by multiple factors, such as the environmental conditions in the tended to assess combinations of 21 different antibiotics at sub- medium or tissue, the number of bacteria, the type of bacteria, inhibitory concentrations. Their results confirmed the hypothesis the duration of the treatment, the dose of the agent and its mech- that in the presence of a bacteriostatic agent, the killing rate of 1,9 anism of action. Prominent examples of these phenomena are bactericidal drugs declined, highlighting that antagonism was linezolid, eravacycline, ciprofloxacin and some aminoglycosides. present; however, it did differ according to the bactericidal drug Multiple in vitro studies have showed that linezolid exhibits bacteri- used. For example, there were higher degrees of antagonism be- cidal activity against Streptococcus spp. and is bacteriostatic tween nalidixic acid and tetracycline than between trimethoprim 10–12 24 against Gram-positive cocci such as enterococci and MRSA. and streptomycin. More importantly, their assessment of the Eravacylcine is another antibacterial that is generally bacteriostat- 21 different drug interactions using screening methods revealed ic against Gram-positive cocci such as staphylococci; however, it more information about antagonism among antibiotics using dif- has also demonstrated bactericidal activity in in vitro studies ferent mechanisms of action. Their results further proved that against certain strains of Acinetobacter baumannii, Escherichia antagonism among bactericidal and bacteriostatic drugs was coli and Klebsiella pneumoniae. Another example is ciprofloxacin, highly prevalent and that specific combinations such as tetracy - which exhibits bacteriostatic activity when DNA replication is ham- clines and aminoglycosides with β-lactams, macrolides with pered, by inhibiting DNA gyrase, whereas it is bactericidal through fluoroquinolones, and β-lactams with folic acid synthesis inhibi- 14 24 bacterial DNA fragmentation. Table 2 summarizes some of the tors, frequently showed antagonism. However, it is important 2 Review Table 2. Bacteriostatic antibacterial agents with dual bacteriostatic and bactericidal activity Antibacterial agent Bactericidal activity Bacteriostatic activity 10–12 Linezolid Streptococcus pneumoniae MRSA Bacteroides fragilis VRE Clostridium perfringens Chloramphenicol Haemophilus influenzae Enterobacterales Streptococcus pneumoniae Staphylococcus aureus Neisseria meningitidis Eravacycline Acinetobacter baumannii Staphylococcus aureus Escherichia coli Enterococcus faecalis Klebsiella pneumoniae 16,17 a Tigecycline MRSA Enterococcus faecalis MSSA VRE Penicillin-resistant Streptococcus pneumoniae Escherichia coli Klebsiella pneumoniae Streptococcus pneumoniae In prolonged therapy. to understand that these results came only from studies on E. coli Enterococcus faecium and E. faecalis and showed both were syn- and these combinations could act differently against different ergistic, which could aid in suppressing the selection of resistant bacteria and in in vivo environments, where many different fac- strains of enterococci against both antibiotics. tors can affect drug behaviour. Another bacteriostatic agent that has been used in combina- In clinical studies, many combinations of bacteriostatic and tions with bactericidal drugs in clinical practice is clindamycin. An bactericidal antibacterials have been used, even though many interesting combination used is clindamycin/rifampicin; many in in vitro studies showed antagonistic effects. A landmark study vitro studies have shown their synergistic activity and therefore for the treatment of endocarditis was the Partial Oral it has been extensively studied in clinical settings in several infec- Treatment of Endocarditis (POET) study that compared partial tions. A 2017 retrospective cohort study in the Netherlands as- oral antibiotic regimens with IV antibiotic regimens for the treat- sessed this combination (orally) in treating periprosthetic hip or ment of left-sided endocarditis. A closer look at the antibiotic knee infection by S. aureus or coagulase-negative staphylococci combinations used for many cases of bacterial endocarditis re- in 36 patients following surgical debridement for an early infec- vealed that combinations of bacteriostatic and bactericidal anti- tion or those who underwent aseptic revision of loose compo- biotics were frequently used. These combinations included nents that were later found to be culture-positive. Their amoxicillin plus fusidic acid, linezolid plus rifampicin, and dicloxa- results showed a cure rate of 86%; 78% (14/18) in the surgical de- cillin plus fusidic acid for Staphylococcus aureus, coagulase- bridement group and 94% (17/18) in the revision group. negative staphylococci (methicillin-resistant or sensitive) or Another retrospective cohort study in France showed a cure streptococcal endocarditis. Furthermore, a linezolid plus moxi- rate of 64.7% by intention to treat and 84.6% by per protocol floxacin combination was recommended for Enterococcus faeca- analysis, using an oral combination of clindamycin/rifampicin in lis endocarditis, whereas moxifloxacin and clindamycin were 37 cases of erythromycin-resistant and lincosamide-susceptible 25 30 recommended for streptococcal endocarditis. bone and joint infections due to Staphylococcus spp. In studies It appears that linezolid was commonly used in combinations that also assessed this combination in hidradenitis suppurativa, with other bactericidal drugs and is expected to continue to be where cases have been associated with Staphylococcus spp. in- used, especially against resistant Gram-positive infections. An fection, the reported success rate for oral clindamycin with rifam- in vitro study assessed the combination of linezolid with other picin ranged between 63.6% and 85.7%. bactericidal drugs using time–kill curves. It showed that the add- Tigecycline with colistin is another combination that has been ex- ition of linezolid to gentamicin and vancomycin resulted in reduc- tensively studied, especially against resistant Enterobacteriaceae. A tion of their antibacterial activity and was therefore deemed 2012 in vitro study assessed the interaction between tigecycline and antagonistic. However, linezolid with rifampicin resulted in an colistin against eight NDM-1-producing Enterobacteriaceae using additive interaction against susceptible S. aureus strains and in- time–kill curves, and showed that the addition of tigecycline to co- hibited rifampicin-resistant variants. Another study also re- listin sulphate and colistin methanesulfonate did not increase bac- vealed that linezolid was synergistic with imipenem, doripenem terial killing and in low concentration was antagonistic. However, a and plazomicin against MRSA and methicillin-resistant strains more recent in vitro study showed that this combination was effect- of Staphylococcus epidermidis. These studies suggest that not ive against five carbapenem-resistant NDM-producing E. coli strains, all bacteriostatic/bactericidal combinations are antagonistic, with colistin allowing increased uptake of tigecycline. These results and many can prove synergistic and could aid in reducing resist- were reproducible in an in vitro study that evaluated this combin- ance. For example, a recent in vitro study has examined the com- ation against MDR A. baumannii, with tigecycline increasing the bac- bination of linezolid and fosfomycin against 34 clinical isolates of tericidal effects of colistin. There is also a limited number of studies 3 Review that assessed this combination in clinical settings. A retrospective for treatment of hospitalized patients with CAP, indicating similar cohort study from Thailand assessed the use of IV colistin and tige- clinical response rates for the two drugs. This agent constitutes cycline compared with IV tigecycline monotherapy in the treatment an effective oral alternative option to fluoroquinolones in patients of 28 patients with post-surgical non-bacteraemic intra-abdominal with CAP and pneumonia severity index (PSI) risk class II/III and at infections (IAIs) due to carbapenem-resistant A. baumannii (CRAB), least one comorbidity. Additional subgroup analyses of the and showed that 14 day, 30 day and in-hospital mortality rates, the OPTIC study based on disease severity risk scores and presence rate of breakthrough bacteraemia and the rate of bacterial eradica- of COPD/asthma or bacteraemia, demonstrated that omadacy- tion, were not significantly different between the two groups, with cline was inferior to moxiflox acin only in the context of bacter- the combination therapy associated with more severe renal impair- aemia, exhibiting lower success rates at early clinical response. ment and higher costs. Additionally, a larger cohort study from Finally, with regard to aspiration pneumonia in elderly patients, Spain with 118 patients with bacteraemia due to CRAB showed simi- IV clindamycin as monotherapy was compared with ampicillin/ lar results, where the 30 day crude mortality was not significantly sulbactam and panipenem/betamiprom during a randomized different in the combination therapy as compared with colistin prospective study in Japan. Researchers observed that clindamy- monotherapy. These results highlight that, even though the ma- cin was cost-effective and had results similar to the two other jority of in vitro studies demonstrated synergy among both antibio- agents regarding cure and adverse event rates, concluding that tics, this does not necessarily translate to increased effectiveness in clindamycin monotherapy is an effective therapeutic option clinical settings, as patient factors such as severity of illness and co- against aspiration pneumonia. morbidities also play an important role in response to treatment. With respect to nosocomial pneumonia, a multicentre, rando- mized, double-blind study was carried out at 138 sites in 31 countries, comparing tigecycline with imipenem/cilastatin in Head-to-head comparison of bactericidal 945 patients with HAP. Patients received either tigecycline (100 versus bacteriostatic antibacterials in mg daily) plus an optional adjunctive therapy with ceftazidime for Pseudomonas aeruginosa coverage (and addition of an amino- common infections glycoside in some cases for double coverage) or imipenem/cilas- Pneumonia tatin plus an optional adjunctive treatment with vancomycin for Bacterial pneumonia remains a significant cause of mortality, es- MRSA coverage. Overall mortality was similar between the two pecially in older patients with comorbidities. Current guidelines groups of patients; however, death rates were higher in the sub- on management of community-acquired pneumonia (CAP), group of VAP patients treated with tigecycline. Nevertheless, in hospital-acquired pneumonia (HAP) and ventilator-associated a following study investigating the same topic, researchers used pneumonia (VAP), offer all necessary information to healthcare higher doses of tigecycline and observed a numerically higher 38,39 52 professionals. To this end, a head-to-head comparison be- clinical response with the use of 200 mg of tigecycline daily. tween bactericidal and bacteriostatic antibacterials in the treat- Direct comparison of linezolid with vancomycin in the treat- ment of bacterial pneumonia is of interest. ment of suspected MRSA nosocomial pneumonia has also In a study performed nearly 30 years ago in the Netherlands, grabbed the attention of researchers. A systematic review and the effect of oral azithromycin was compared with IV benzylpeni- meta-analysis including nine randomized controlled trials cillin in 104 hospitalized patients with suspected pneumococcal (RCTs), compared linezolid with vancomycin in the treatment of CAP, demonstrating higher clinical and radiological success 2618 patients with suspected MRSA pneumonia, and showed rates with azithromycin, although statistical significance was not that the overall clinical cure rate, the clinical cure rate for patients reached. Two years later, an open prospective randomized study with culture-confirmed MRSA pneumonia, and the MRSA eradica- contrasted IV clarithromycin with amoxicillin/clavulanic acid in 112 tion rate were similar for the two antimicrobials. A subsequent hospitalized patients with CAP in Switzerland. The rate of clinical systematic review and comparative meta-analysis including se- improvement was similar for the two administered drugs. In a ven RCTs with 1239 patients and eight retrospective cohort or subsequent study azithromycin was compared with cefuroxime case-control studies with 6125 patients, analysed the effect of in the treatment of 180 patients with CAP, demonstrating similar linezolid versus vancomycin against proven MRSA pneumonia. clinical efficacy and a shorter duration of therapy. The clinical cure rate and the microbiological eradication rate In the context of antibacterial management of CAP, direct com- were significantly lower in the vancomycin-treated subgroup of parison of tigecycline with levoflo xacin has been a matter of inter- patients in the RCTs. Mortality rates were indistinguishable for est in multiple studies, indicating non-inferiority of tigecycline and the two treatments in both RCTs and cohort or case-control stud- revealing comparable cure rates for the two antimicrobial ies. These results may reflect the better accessibility of linezolid 43–45 agents. Furthermore, doxycycline, another tetracycline de- compared with vancomycin in the epithelial lining fluid, rendering rivative, was studied side by side with levofl oxacin in the treatment this agent an effective treatment against MRSA pneumonia. of patients with CAP requiring hospitalization in a teaching hospital Overall, a systematic review and meta-analysis, published 46 55 in Cleveland, Ohio. According to the results of this prospective in 2015 by Nemeth et al., included 33 RCTs and compared double-blinded trial the therapeutic efficacy was not significantly bacteriostatic with bactericidal antibiotics in the management different between the two drugs. More recently, omadacycline, of severe infections. Subgroup analysis of 13 studies that covered a newer tetracycline, has been approved in the USA for the treat- pneumonia showed no significant difference in clinical cure, mor- ment of CAP, based on the results of the Omadacycline for tality and relapse rates between patients treated with bacterio- Pneumonia Treatment in the Community (OPTIC) trial, an inter- static or bactericidal antibiotics. These results were compatible national clinical trial that contrasted this agent with moxiflox acin with the findings of a subsequent systematic literature review 4 Review by Wald-Dickler et al., which also investigated bactericidal versus infections. Constituting a leading cause for antimicrobial pre- bacteriostatic antibiotics in the treatment of bacterial infections, scriptions, SSTIs contribute to approximately 10% of hospital ad- 65,66 including 56 RCTs. In 19 trials on pneumonia and additional trials missions in the USA. SSTIs can range from erysipelas and that included pneumonia in specific subgroup analyses, non- common cellulitis to more serious conditions, such as necrotizing inferiority of bacteriostatic agents regarding clinical efficacy was fasciitis or abscesses, which warrant meticulous wound care and observed, except for the aforementioned study of tigecycline ver- surgical interventions in severe cases. sus imipenem/cilastatin in HAP patients, which demonstrated in- In 2014, the IDSA released guidelines outlining the treatment 51 67 feriority of tigecycline in patients with VAP. Finally, a systematic of SSTIs. In brief, management of SSTIs is dependent on the se- review and meta-analysis of 43 RCTs contrasting bactericidal with verity, nature and type of infection. Purulent SSTIs, whether mild, bacteriostatic antibiotics in the treatment of pneumonia indicated moderate or severe, are recommended to be treated with incision no statistically significant difference with respect to clinical cure, and drainage followed by empirical treatment with one of vanco- mortality, microbiological eradication and treatment failure rates mycin, daptomycin, linezolid, telavancin or ceftaroline in severe, between the subgroups of patients treated either with bacteri- purulent infections. Moderate purulent infections, following inci- cidal or with bacteriostatic agents. This meta-analysis included sion and drainage, are empirically treated with trimethoprim/ RCTs with patients having CAP and HAP, and trials that compared sulfamethoxazole or doxycycline. Severe, non-purulent SSTIs multiple categories of antibacterials, such as oxazolidinones with are managed with aggressive surgical debridement to remove glycopeptides, macrolides with fluoroquinolones, and macrolides any necrotizing processes and empirically treated with vancomy- 56 68 with β-lactam antibacterials. cin plus piperacillin/tazobactam. Moderate non-purulent SSTIs are managed with IV penicillin, ceftriaxone, cefazolin or clindamy- cin. Finally, mild and non-purulent SSTIs are treated with oral Intra-abdominal infections penicillin, cephalosporin, dicloxacillin or clindamycin. Tigecycline, a broad-spectrum glycylcycline, has been used for the Numerous studies have compared the efficacy of linezolid, a treatment of complicated intra-abdominal infections (cIAIs) be- bacteriostatic, with vancomycin, a bactericidal, as monotherapy. cause of its activity against multiple microorganisms, such as Itani et al. conducted an open-label multicentre study in the Enterobacteriaceae, E. faecalis, E. faecium and anaerobes, consti- USA and found linezolid to be statistically superior to vancomycin tuting a suitable antibacterial option in polymicrobial infections. in the treatment of complicated SSTIs caused by MRSA, revealing A double-blind, multinational study comparing tigecycline with that hospitalized patients with linezolid had a significantly short- imipenem/cilastatin for treating patients with cIAIs exhibited er length of stay and duration of IV therapy. Several other studies similar clinical cure rates. comparing the two antibiotics found no statistical superiority in Two randomized studies of patients with cIAIs comparing tige- clinical outcomes and microbiological eradication in hospitalized cycline with a combination regimen of ceftriaxone plus metronida- patients with MRSA and other complicated SSTIs involving 59,60 zole have shown non-inferiority of tigecycline. The first study 70,71 72 73 Gram-positives. Other RCTs from Taiwan and India have was conducted in the USA, Canada and Latin America, evaluated compared tigecycline, a bacteriostatic, with vancomycin alone clinically 376 patients, and exhibited similar clinical response rates or with aztreonam in complicated SSTIs in hospitalized patients, between the two treatment arms. The second study was an inter- and revealed that tigecycline monotherapy is statistically non- national trial that evaluated 387 patients clinically and 227 patients inferior to the combination of vancomycin and aztreonam; how- microbiologically. Similar clinical and microbiological response rates ever, tigecycline use was associated with higher rates of nausea, were revealed between tigecycline and comparators. dyspepsia and anorexia, whereas vancomycin and aztreonam In the age of MDR, eravacycline, a newer tetracycline derivative, 72,73 combination led to pruritus and rash. In 2007 Cenizal represents an additional weapon in the therapeutic arsenal against et al. reported a prospective randomized trial in the USA, com- resistant bacteria, even CRAB. This agent has been recently ap- paring the efficacy of doxycycline monotherapy with trimetho- proved for use in the treatment of cIAIs, as it demonstrated non- prim/sulfamethoxazole for outpatient treatment of SSTIs and inferiority compared with ertapenem and meropenem in cIAIs in revealed no statistical difference in clinical outcomes. Similarly, two double-blind clinical trials, IGNITE (the Investigating Gram- linezolid monotherapy compared with teicoplanin monotherapy, Negative Infections Treated With Eravacycline) trial 1 and trimethoprim/sulfamethoxazole combined with rifampicin, or 62,63 IGNITE4. In terms of real-world evidence, according to the re- dalbavancin monotherapy, showed no statistical difference of sults from a Bayesian network meta-analysis including 25 RCTs and clinical outcomes in treatment of MRSA SSTIs in hospitalized pa- 9372 adult patients, it was indicated that eravacycline had similar 75–77 55 tients. A meta-analysis conducted by Nemeth et al. re- clinical efficacy and safety in patients with cIAIs, compared with vealed that linezolid demonstrated statistically significantly common bactericidal antibacterials, such as meropenem, ertapen- higher clinical cure rates when compared with its bactericidal em, ceftazidime/avivactam plus metronidazole, piperacillin/tazo- comparators and reported near-significant association of in- bactam, imipenem/cilastatin, and ceftriaxone plus meronidazole. creased mortality in patients treated with tigecycline. Moreover, eravacycline proved significantly better than tigecycline with respect to microbiological response rates. Osteomyelitis and prosthetic joint infections Skin and soft tissue infections Linezolid constitutes a reasonable antimicrobial therapeutic choice Skin and soft tissue infections (SSTIs) represent a spectrum of mi- for bone infections, when a Gram-positive microorganism is the crobial invasion involving the epidermis, dermis and underlying causative factor, including MRSA. The oral bioavailability of linezolid soft tissues, and are among the most frequent bacterial and its sufficient concentrations inside bone tissue render this 5 Review agent an attractive option against this type of infection, which re- microbiologically equally effective to ciproflo xacin, when adminis- quires prolonged treatment. Limited data exist regarding direct tered for a 7 day treatment course of adult patients with uncom- comparison of linezolid with bactericidal antibacterials in the treat- plicated disease. ment of bone infections. In a case-control study in Greece, linezolid Another bacteriostatic agent, chloramphenicol, was com- was administered to 34 patients with osteomyelitis or prosthetic pared with ceftriaxone in a randomized trial for treatment joint infections (PJIs), and results concerning efficacy and safety of 46 adults and children who had positive blood cultures for were compared with a group of well-matched controls, who re- S. enterica serotype Typhi or S. enterica serotype Paratyphi, dem- ceived monotherapy or combination regimen, including at least onstrating similar cure rates. Chloramphenicol has also been one bactericidal agent. Although initial treatment success rates compared with fluor oquinolones, such as ciproflo xacin and gati- were similar for the two subgroups, relapse rates were higher, flo xacin, for the treatment of enteric fever, revealing equivalent and discontinuation of antimicrobial therapy was more prevalent clinical efficacy, although requiring longer treatment duration. in the linezolid group. Poor tolerability occurred mostly due to mye- Despite these findings, the decision about the optimal anti- losuppression. Moreover, a retrospective study in China compared microbial option should not be based on the bacteriostatic or linezolid and vancomycin regimens combined with one-stage sur- bactericidal action of the agent. It should be guided by the re- gery, followed by implantation of a vancomycin-loaded calcium gional rates of antimicrobial resistance, as MDR and XDR S. enter- sulphate artificial bone in 64 patients with traumatic osteomyelitis ica serotype Typhi isolates are increasing worldwide, rendering of the limbs caused by MRSA. This showed that both antimicrobials the understanding of patterns and trends of antimicrobial resist- had satisfactory clinical outcomes, yet linezolid-treated patients ance essential to avoid treatment failure. had fewer adverse events, a shorter duration of antimicrobial ther- With respect to plague, a disease considered extinct in Europe, apy and a shorter hospital stay. Regarding PJIs, a retrospective anecdotal evidence exists regarding direct comparisons of bac- cohort study in Japan compared linezolid with daptomycin in 82 tericidal with bacteriostatic antimicrobials in the treatment of patients with PJIs caused by Gram-positive microorganisms, reveal- this infectious disease. Plague is caused by Yersinia pestis, re- ing comparable success rates for the two drugs. Nonetheless, lower mains a public health concern in countries of sub-Saharan c-reactive protein (CRP) values and fewer adverse events were ob- Africa, Asia and the Americas, and can be treated with various served in the daptomycin-treated subset of patients. Finally, in a classes of antibacterials, such as fluor oquinolones, aminoglyco- randomized non-inferiority trial in Switzerland of osteoarticular in- sides, tetracyclines and chloramphenicol. In a randomized clin- fections comparing linezolid monotherapy versus trimethoprim/ ical trial in Tanzania, 65 adult or paediatric patients with bubonic, sulfamethoxazole combined with rifampicin against various types septicaemic or pneumonic plague were enrolled, who received of MRSA infections, higher relapse rates were observed in the line- treatment with either gentamicin or doxycycline for 7 days. zolid group. Nevertheless, a major limitation of this trial was the Results were similar with high success rates for both regimens. small sample size. Conclusively, linezolid, a bacteriostatic agent, is a valuable Role of bacteriostatic antibacterials compared therapeutic option in bone infections caused by Gram-positive with bactericidal antibacterials in severe microorganisms, including MRSA, especially in terms of treat- ment completion in outpatient settings, because of its high oral infections bioavailability. However, caution is required in detecting adverse It is a long-held strategy in treatment of infections such as endo- effects, such as haematological toxicity, peripheral neuropathy carditis, meningitis, bacteraemia or infections in immunocom- and lactic acidosis, during prolonged treatment courses. promised patients including febrile neutropenia, to use a Tedizolid, a more recent oxazolidinone, may feature a more fa- bactericidal antibacterial in order to increase the odds of cure. vourable safety profile than linezolid in case of lengthy treatment However, with the rise of resistance to several bactericidal of osteoarticular infections, yet clinical data are still scarce. agents, use of bacteriostatic agents could prove useful, if not im- Clindamycin also constitutes a bacteriostatic agent that can perative. In this section, the recent literature evaluating the use be used for the treatment of Gram-positive bone infections. of bacteriostatic agents in severe infections is summarized. However, data are lacking regarding head-to-head comparisons Table 3 summarizes the studies that have assessed bacteriostatic of this agent with bactericidal drugs. It is usually used in combin- antibacterials in patients with neutropenic fever, endocarditis, ation with other bactericidal antibacterials, such as rifampicin, Gram-positive bacteraemia and meningitis. fusidic acid or trimethoprim/sulfamethoxazole. Neutropenia Other infections A 2009 systematic review of the role of linezolid in infections For treatment of enteric (typhoid and paratyphoid) fever, a disease caused by Gram-positives, including VRE in neutropenic patients, caused by Salmonella enterica serotype Typhi and S. enterica sero- included five studies (two of which were prospective comparative type Paratyphi, bacteriostatic antibacterials have been compared studies) and eight case studies where linezolid was used on a with bactericidal antibacterials in several studies. Azithromycin compassionate basis (i.e. after all available treatment options has been compared with third-generation cephalosporins, such failed) in 438 neutropenic patients. The overall cure rate ranged as ceftriaxone and cefixime, exhibiting non-inferiority regarding from 57% to 87%. Interestingly, in the prospective studies there clinical outcomes in children with uncomplicated typhoid was a 100% microbiological cure rate against VRE. Moreover, 82,83 fever. Moreover, a randomized trial conducted in Egypt more only 0.02% of bacterial isolates developed resistance to linezo- than 20 years ago revealed that azithromycin was clinically and lid. Of note, one of the included trials (a double-blinded, 6 Review Table 3. Summary of the characteristics and results of studies that have assessed the use of bacteriostatic antibacterials in severe infections such as febrile neutropenia, meningitis, bacteraemia and infective endocarditis Bacteriostatic Bactericidal antibiotic antibiotic Author (number of (number of (year) Type of study Patient characteristics Disease patients) patients) Main pathogen Main results Bucaneve RCT (open label) Hospitalized adults with Neutropenic Tigecycline + Piperacillin/ Multiple (Gram-negatives Clinical success rate was et al. 2004 neutropenic fever fever piperacillin/ tazobactam and Gram-positives 67.9% of patients in the secondary to tazobactam (n (n = 205) including MRSA) combination group, haematological = 187) compared with 44.3% of malignancy patients in the monotherapy group (P < 0.001). The combination regimen had a higher clinical success than monotherapy in bacteraemia (0.5%, compared with 27.7%; P < 0.001) Jaksic et al. RCT (double-blind) Hospitalized adults with Neutropenic Linezolid (n = 304) Vancomycin (n = Gram-positive including No statistically significant 2006 neutropenic fever fever 301) MRSA difference in clinical secondary to success [linezolid group malignancy 219 (87.3%) of 251; vancomycin group 202 (85.2%) of 237]; microbiological success rates [linezolid group, 41 (58%) of 71 patients; vancomycin group, 29 (50%) of 58 patients]; and mortality rate [linezolid group, 17 (5.6%) of 304; vancomycin group 23 (7.6%) of 301 vancomycin-treated patients]. Drug-related adverse events (24.0% vs 17.2%; P = 0.04) and renal failure (2.3% vs 0.3%; P = 0.04) were higher in the vancomycin group. No difference in haematological adverse effects Continued Review Table 3. Continued Bacteriostatic Bactericidal antibiotic antibiotic Author (number of (number of (year) Type of study Patient characteristics Disease patients) patients) Main pathogen Main results Faella et al. Case series Patients with Meningitis Linezolid N/A Penicillin-resistant 5/7 patients treated with the (2006) pneumococcal combined with Streptococcus combination of ceftriaxone meningitis ceftriaxone pneumoniae and linezolid survived (n = 7) Munoz et al. Case series Adult patients with Gram-positive Linezolid (n = 9), in N/A Staphylococcus aureus Clinical and microbiological (2007) Gram-positive endocarditis combination (including MRSA; n = 6), cure with no adverse endocarditis and with rifampicin Streptococcus mutans effects or relapses for all 9 refractory disease, in one case (n = 1), cases intolerance to other Corynebacterium drugs or need for oral striatum (n = 1), consolidation coagulase-negative treatment staphylococci (n = 1) Lauridsen Retrospective cohort Patients with infective Infective Linezolid (n = 38) N/A Gram-positive cocci No statistically significant et al. study endocarditis that endocarditis (including some cases differences in cure rate (2012) failed first-line of culture-negative (74% vs 71%, P > 0.05), treatment endocarditis) in-hospital mortality (13% vs 14%, P > 0.05) or post-discharge mortality at 1 year follow-up (26% vs 26%, P > 0.05) for patients receiving treatment with linezolid compared with patients without such treatment Sipahi et al. Case series Patients with MRSA Meningitis Linezolid (n = 9) Vancomycin MRSA Patients’ treatment with (2013) meningitis (n = 8) linezolid had a greater rate of MRSA clearance from CSF on Day 5 (7/9 vs 2/8; P = 0.044). One-month survival of the patients with microbiological cure was 2/ 2 in the vancomycin group and 4/7 in the linezolid group Balli et al. Systematic review Adult patients with VRE VRE Linezolid (n = 538) Daptomycin VRE Higher 30 day all-cause (2014) and bacteraemia bacteraemia (n = 429), mortality (OR, 1.61; 95% CI, meta-analysis heterogeneity 1.08–2.40) and (including 10 in daptomycin infection-related mortality retrospective dosage (OR, 3.61; 95% CI, 1.42– studies) 9.20) for patients treated with daptomycin. Overall Review mortality was also significantly increased among patients treated with daptomycin (OR, 1.41; 95% CI, 1.06–1.89). Relapse rates were higher in the daptomycin group of patients (not statistically significant), and adverse events did not demonstrate a statistically significant difference between the two subgroups of patients Chuang Systematic review Patients with VRE VRE Linezolid (n = 656) Daptomycin VRE Mortality was higher in et al. and bacteraemia bacteraemia (n = 532), patients receiving (2014) meta-analysis heterogeneity daptomycin (OR, 1.43; 95% (including 13 in daptomycin CI, 1.09–1.86; P = 0.009) retrospective dosage and subgroup analysis of studies) studies that reported adjusted ORs indicated that daptomycin was associated with higher mortality (OR, 1.59; 95% CI, 1.02–2.50; P = 0.04) Zhao et al. Systematic review Patients with VRE VRE Linezolid (n = 894) Daptomycin VRE Similar overall crude mortality (2016) and bacteraemia bacteraemia (n = 445), (RR = 1.07; 95% CI, 0.83– meta-analysis standard or 1.37), clinical cure (RR = (including 11 high dose 1.11; 95% CI, 0.88–1.42), retrospective microbiological cure (RR = studies) 0.99; 95% CI, 0.90–1.09) and relapse (RR = 1.08; 95% CI, 0.76–1.52) rates between daptomycin- and linezolid-treated patients. No statistically significant difference regarding adverse events between the two groups Continued Review Table 3. Continued Bacteriostatic Bactericidal antibiotic antibiotic Author (number of (number of (year) Type of study Patient characteristics Disease patients) patients) Main pathogen Main results Zhou et al. Prospective Hospitalized adults with Neutropenic Tigecycline N/A Gram-negative Clinical success rate was (2018) observational neutropenic fever that fever (n = 125) organisms 68.0% (85/125) and study failed first-line mortality rate was 18% treatment (23/125). Clinical success rate in patients with pneumonia as cause of neutropenic fever was 73.1% (49/67). Clinical success in patients with bacteraemia was 35.3% (6/ 17), with the 30 day mortality rate of 64.7% (11/ 17) Sipahi et al. Case series Patient with Meningitis Linezolid (n = 17) N/A Methicillin-resistant 15/17 patients achieved (2018) post-neurosurgical staphylococcal spp. microbiological cure with meningitis linezolid and 1 reported death due to treatment failure without documented relapse of meningitis due to methicillin-resistant Staphylococcus spp. Shi et al. Systematic review Patients with VRE VRE Linezolid (n = Daptomycin (n = VRE There was a trend towards (2019) and bacteraemia bacteraemia 2053) 1934), increased mortality for meta-analysis heterogeneity those in the daptomycin (including 21 in daptomycin arm vs those in the linezolid retrospective dosage arm, although this trend did observational not reach statistical studies and 1 significance (OR, 1.27; 95% prospective CI, 0.99–1.63; I = 42.9%). cohort study) In the subset of studies focusing on high-dose daptomycin, comparable mortality associated with daptomycin and linezolid treatment was observed (OR, 0.92; 95% CI, 0.46– 1.84; I = 49.4%). Overall, clinical response, microbiological cure, recurrence of bacteraemia Review and risk of CPK elevation were similar for the two agents. Finally, risk of thrombocytopenia was significantly lower in the daptomycin group of patients Munoz et al. Retrospective cohort Patients with infective Infective Linezolid (n = N/A S. aureus, Patients treated with linezolid (2021) study endocarditis treated endocarditis 295), only 11 coagulase-negative presented higher with linezolid patients were staphylococci, in-hospital mortality in included for Streptococcus spp. contrast to matched comparison controls not treated with with patients linezolid (54.5% vs 18.2%, not treated P = 0.04) with linezolid Modemann Retrospective Hospitalized adults with Neutropenic Tigecycline ± Carbapenem, MDR pathogens (including No statistically significant et al. observational neutropenic fever fever carbapenem, vancomycin or MRSA and VRE) difference in response rate; (2022) study with unknown origin vancomycin or linezolid (n = however, in patients secondary to AML/ALL linezolid (n = 30) receiving tigecycline there 43) was lower absolute sepsis (33% vs 47%, P = 0.235) and infection-associated mortality rates (5% vs 13%, P = 0.221) Kawasuji Systematic review Patients with MRSA MRSA Linezolid (n = 293) Daptomycin (n = MRSA All-cause mortality, clinical et al. and bacteraemia bacteraemia 114), and microbiological cure, (2023) meta-analysis vancomycin hospital length of stay, [including 2 RCTs, (n = 4894), recurrence, 90 day 1 pooled analysis teicoplanin (n readmission and adverse of 5 RCTs, 1 = 27) event rates were similar subgroup analysis between patients treated (1 RCT) and 5 with linezolid vs those case-control and treated with vancomycin, cohort studies] teicoplanin or daptomycin ALL, acute lymphocytic leukaemia; AML, acute myeloid leukaemia; CPK, creatine kinase; RR, relative risk. Review prospective RCT) compared vancomycin with linezolid in approxi- bactericidal agents in treating endocarditis. However, due to mately 600 neutropenic patients and showed no statistically sig- the increase in drug-resistant cases and the development of nificant difference in clinical success rates (linezolid, 87.3%; newer bacteriostatic agents that can reach desirable levels in vancomycin, 85.2%; P = 0.52) and mortality rates (linezolid, the bloodstream, there have been some published studies that 5.6%; vancomycin 7.6%). Moreover, linezolid was associated assess bacteriostatic agents in endocarditis. with fewer drug-related adverse events and drug-induced renal One example is linezolid, which was also regarded by the POET failure. One of the concerns of using linezolid in neutropenic pa- study as optimal for oral consolidation in endocarditis in combin- tients for Gram-positive coverage is the reported myelosuppres- ation with bactericidal drugs. A case series from 2007 described sion when used for longer than 14 days. Interestingly though, nine patients who were diagnosed with Gram-positive endocarditis the above-mentioned trial showed that blood count recovery and were treated with linezolid due to failure of previous therapies or was comparable among patients who received vancomycin and due to allergies to first-line therapies. All nine patients achieved clin- 91 95 those who received linezolid. ical and microbiological cure with no adverse effects or relapses. Another bacteriostatic agent studied in neutropenic patients Additionally, several published case reports document the success- is tigecycline. An open-label trial in 2014 from Italy compared ful treatment of endocarditis caused by MRSA, Corynebacterium spp. 96–100 monotherapy with piperacillin/tazobactam (a bactericidal agent) and VRE, using linezolid. Interestingly, in two cases, linezolid with a combination of piperacillin/tazobactam plus tigecycline (a was combined with bactericidal drugs, such as daptomycin and ci- 98,99 bacteriostatic agent) in 300 cancer patients with febrile neutro- proflox acin. In all these cases, linezolid was used either due to penia. The intention-to-treat analysis showed that there was vancomycin resistance, gentamicin resistance or failure of other a 23.6% risk difference in favour of combination therapy in first-line treatments to achieve microbiological cure. achieving a clinical cure. This was significant for neutropenic pa- The largest study to date describing the use of linezolid in tients with bacteraemia and clinically documented infections. endocarditis is a 2021 retrospective cohort study from Spain Another prospective cohort study from China assessed the use that compared in-hospital and 1 year mortality among patients of salvage tigecycline (i.e. following treatment failure with first- who received linezolid for endocarditis treatment (n = 295) versus line therapies) in 125 neutropenic patients with haematological patients who did not (n = 3172). When the authors were trying malignancies and showed a 68.0% treatment success. In this to assess the true impact of linezolid, only 11 cases fulfilled the study, tigecycline was not compared with other agents; however, criteria and were considered to have been administered linezolid it was used after bactericidal combination therapies such as car- as a definite treatment for endocarditis. Thus, only these 11 bapenems with vancomycin had failed. The use of another cases were used for comparison. Their results showed that pa- antibacterial in combination with tigecycline was not restricted tients treated with linezolid had higher in-hospital mortality and, of note, the most common combinations were with bacteri- (54.5% versus 18.2%, P = 0.04); however, it is important to note cidal agents, such as carbapenems and cephalosporins. In both that patients receiving linezolid were affected by a larger number studies mentioned above, the majority of isolated bacteria were of comorbidities and endocarditis complications, which could those that tigecycline is known to have bacteriostatic activity have affected the mortality rate. Another retrospective study against, such as VRE, K. pneumoniae and other Gram-negative from Denmark also compared linezolid (n = 38) with other treat- 92,93 bacteria. A more recent retrospective single-centre study ments (n = 512) in left-sided Gram-positive endocarditis. Their re- conducted in 2022 in Germany assessed tigecycline as salvage sults showed that there were no significant differences in the therapy in 73 neutropenic patients with leukaemia, either as cure rate, in-hospital mortality or mortality at 12 months be- monotherapy (n = 30) or in combination with a carbapenem tween linezolid and other treatments. These studies show (n = 43). Response rates and mortality rates were similar among that linezolid could prove to be an effective and well-tolerated both groups. It is important to note that in studies where com- treatment for endocarditis caused by Gram-positive organisms, bination therapies were used, the role of the bactericidal drug especially MRSA and VRE; however, larger studies are needed to 93,94 was to provide coverage against Pseudomonas spp. Overall, draw more concrete conclusions. these studies show that bacteriostatic agents can be effective and safe in neutropenic patients and their combination with bac- VRE and MRSA bacteraemia tericidal agents to broaden antimicrobial coverage is possible and can achieve significant clinical improvement. The dogma that rapid killing of bacteria in bloodstream infec- tions, by use of antibacterials traditionally considered bacteri- cidal, is also not clinically relevant in the case of linezolid use in Infective endocarditis bacteraemia caused by resistant Gram-positive microorganisms. It is widely believed that bacteriostatic agents are ineffective in In a systematic review and meta-analysis published in 2014 in- the treatment of infective endocarditis, and that bactericidal cluding 10 retrospective studies and 967 patients with VRE bac- antibacterials are the management hallmark. This is partly due teraemia, treatment with linezolid compared with daptomycin to older studies that have shown poor outcomes when using bac- exhibited lower 30 day all-cause, infection-related and overall teriostatic agents in endocarditis. Additionally, due to the large mortality, as well as comparable adverse event rates. These concentration of bacteria that can grow on cardiac valves and results were compatible with mortality outcomes presented in the poor accessibility of phagocytic cells, it is accepted that non- another meta-analysis, which included 13 retrospective cohort phagocytic killing by bactericidal agents is crucial to achieving a studies and 1188 patients with VRE bacteraemia, and compared 1,2 microbicidal cure. There are no current clinical trials that com- linezolid with daptomycin, showing higher mortality rates in the pare the effectiveness of specific bacteriostatic agents with daptomycin subgroup. However, it is of utmost importance 12 Review to emphasize the heterogeneity in daptomycin dosage used in first-line antibacterial for acute bacterial meningitis due to the above-mentioned studies. In several of them, daptomycin Haemophilus influenzae and Streptococcus pneumoniae. dosage was approximately 6 mg/kg/day, whereas some studies However, due to its toxicity, such as bone marrow suppression 103,104 did not mention dosage. Bactericidal activity of daptomy- and emergence of bacterial resistance, as well as studies show- cin is dose-dependent, and the safety and efficacy of high-dose ing better results with β-lactams, it is rarely used in developed daptomycin (>6 mg/kg/day) in difficult-to-treat Gram-positive in- countries. Nevertheless, data on its success in treating bacterial fections have been well established. meningitis highlight that bacteriostatic antibacterials have the 106 1 Another meta-analysis published by Zhao et al. in 2016, in- potential to result in cure of CNS infections. cluded 11 retrospective cohort studies and 1339 patients, and There are newer small studies that highlight the use of other compared the efficacy of linezolid versus standard- or high-dose bacteriostatic drugs in treating bacterial meningitis. Linezolid is daptomycin in VRE bacteraemia, observing similar overall mortal- one such drug that has also shown good CSF penetration, with 111,112 ity, clinical cure, microbiological cure, relapse and adverse event drug levels reaching 30%–70% of its serum levels. A small rates between the two agents. More recently, Shi et al. con- number of studies have assessed the effectiveness of linezolid in ducted a meta-analysis on the same topic and compared the treating meningitis caused by Gram-positive bacteria in combin- above-mentioned drugs in treatment of VRE bacteraemia. The ation with other bactericidal antibacterials or as salvage therapy. researchers included 22 observational studies involving 3987 pa- A case series of 17 patients from Turkey studied the use of tients and found a non-significant higher mortality rate and a sig- linezolid either as primary therapy or as salvage therapy in the nificantly lower risk of thrombocytopenia in patients treated with treatment of meningitis by MRSA and methicillin-resistant daptomycin. In the daptomycin-treated subgroup, a trend to- coagulase-negative staphylococci in post-neurosurgical pa- wards higher clinical response and microbiological cure as well as tients, after failure of first-line treatment with vancomycin and lower risk for bacteraemia relapse was observed, though without third-generation cephalosporin. Fifteen of the 17 patients statistical significance. Moreover, a subgroup analysis of studies had microbiological clearance of infection by Day 5 (88% micro- using high-dose daptomycin revealed similar mortality rates be- biological cure rate), and none had a relapse, with only one 107 113 tween the two drugs. death due to treatment failure. Importantly, there were no The above-mentioned results should be interpreted with cau- reported severe haematological, nephrological or hepatological tion, as most of these studies are observational with high hetero- adverse effects due to linezolid. Another study followed se- geneity in various parameters. The design of larger randomized ven patients with penicillin-resistant pneumococcal meningitis trials is essential to shed light on the comparison of linezolid versus who were treated with linezolid, ceftriaxone and dexametha- daptomycin in VRE bacteraemia. Nevertheless, these data rendered sone. Of the seven patients, one died and one suffered severe se- linezolid, traditionally considered a bacteriostatic drug, a protagon- quelae. Another small study compared treatment of MRSA ist in the treatment of this specific bloodstream infection. meningitis with vancomycin or linezolid in 17 patients. The re- The favourable pharmacological properties of linezolid have sults showed that 7/9 patients treated with linezolid achieved led to its use in MRSA bacteraemia. A recent systematic review microbiological cure, compared with 2/8 of those treated with and meta-analysis included two RCTs, one pooled analysis of vancomycin (P = 0.044), with no severe adverse events occurring fiv e RCTs, one subgroup analysis (one RCT), and five case-control in either group. There has also been a case report of a post- and cohort studies involving 5328 patients and compared the ef- neurosurgical patient who developed VRE meningitis that was ficacy and safety of linezolid versus vancomycin, teicoplanin or successfully treated with IV linezolid, resulting in clinical and daptomycin, in patients with MRSA bloodstream infection. The microbiological cure. These studies highlight that linezolid primary effectiveness outcome was all-cause mortality, and sec- could prove effective in treating Gram-positive meningitis, espe- ondary effectiveness outcomes were clinical and microbiological cially MRSA meningitis, but larger controlled studies are still cure, length of hospital stay, recurrence and 90 day readmission needed to clearly evaluate its safety and efficacy, especially in rates. The primary safety outcome was defined as the rate of comparison with vancomycin. drug-related adverse events. Despite several limitations in the meta-analysis, all the above-mentioned outcomes were similar Conclusion between patient subgroups, concluding that linezolid could con- stitute a first-line therapeutic option in MRSA bacteraemia. The conventional classification of antibacterials as either bacteri- Owing to its oral form, linezolid remains a useful therapeutic op- cidal or bacteriostatic based on in vitro conditions, lacks clarity in tion in MRSA bacteraemia, with studies showing similar clinical the clinical setting, as indicated by current evidence. Some drugs success rate with treatment completion compared with paren- categorized as ‘bacteriostatic’ may exhibit ‘bactericidal’ effects teral antibiotics in selected low-risk patients. under specific in vitro conditions, and vice versa, considering the complexities observed in clinical contexts and the evolving understanding of antibacterial action. Therefore, predicting Meningitis whether a particular antibacterial will act as bacteriostatic or Meningitis is typically treated with bactericidal agents that easily bactericidal in an actual patient with a bacterial infection is likely reach the CSF. However, few studies have assessed the use of to be highly challenging. Moreover, the drug’s action may be con- bacteriostatic antibacterials, although some can readily pene- tingent on factors such as bacterial load and interaction with the trate the CNS. The first bacteriostatic antibacterial to show effi - immune system at the infection site. cient CSF levels and success in the treatment of meningitis was Extensive evidence indicates that the effectiveness of bacteri- chloramphenicol. In fact, in developing countries, it is often the cidal and bacteriostatic agents is comparable when employed in 13 Review 10 Zahedi Bialvaei A, Rahbar M, Yousefi M et al. Linezolid: a promising op- the treatment of various infections, including severe and compli- tion in the treatment of gram-positives. J Antimicrob Chemother 2017; cated SSTIs, community- and hospital-acquired pneumonia, 72: 354–64. https://doi.org/10.1093/jac/dkw450 intra-abdominal infections and osteomyelitis. 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