Which of the following would NOT, be bacteriostatic

Johannes Nemeth, Gabriela Oesch, Stefan P. Kuster, Bacteriostatic versus bactericidal antibiotics for patients with serious bacterial infections: systematic review and meta-analysis, Journal of Antimicrobial Chemotherapy, Volume 70, Issue 2, February 2015, Pages 382–395, https://doi.org/10.1093/jac/dku379

Introduction

The distinction between bactericidal and bacteriostatic antibiotics is a successful concept to discriminate antibiotics that kill bacteria—‘bactericidal’—from antibiotics that inhibit bacterial growth, i.e. ‘bacteriostatic’. This classification is applied in major textbooks of medicine and infectious diseases, clinical guidelines and advertisements of novel antibiotics.1–5 The intuitively understandable concept between the two groups of antibiotics suggests that bactericidal drugs have more powerful antibacterial action and are able to kill bacteria. In contrast, bacteriostatic antibiotics are assumed to require phagocytic cells to definitely clear bacteria and are therefore thought to be less effective without an efficient immune response. This theoretical model has led to the recommendation that severely ill and immunosuppressed patients with bacterial infections should be treated with bactericidal antibiotics.2–4 Furthermore, some specific conditions are also thought to require bactericidal antibiotics, such as endocarditis.1 The cardiac valves are considered as focal, immunosuppressed regions poorly accessible for phagocytic cells. Therefore, a phagocyte-independent killing by bactericidal drugs is generally recommended under such circumstances.

Unfortunately, there are no clinical data supporting the concept of bacteriostatic versus bactericidal antibiotics. This is quite remarkable given the major influence on recommendations for treatment of severely ill patients. The reason may lie in the difficulties of assessing a drug class effect in a clinically meaningful way.

The main challenge is that during bacterial infection and its treatment, relevant clinical outcomes such as cure rates and mortality are influenced by three main factors: the host, the pathogen and the drug. A drug class effect can only be secondary to these three main factors and is therefore difficult to assess. Our methodological assumption was that the drug class effect ‘bactericidal versus bacteriostatic’ may be measurable if the three main factors—host, drugs and pathogens—are as heterogeneous as possible. If the common denominator is limited to the difference between bacteriostatic and bactericidal drugs amongst different clinical trials, the results may be reduced to the difference between bactericidal and bacteriostatic antibiotics. This approach introduces a meta-level that is beyond the range of a single randomized trial. We therefore conducted a meta-analysis including a wide variety of prospective clinical trials using bacteriostatic versus bactericidal antibiotic drugs for the treatment of patients with severe bacterial infections. The main outcome measures were clinical outcome and overall mortality.

Methods

Definitions

Severity

Requirement of hospitalization was used as a determinant to screen for severity, unless the authors explicitly provided a definition for severity in the study. Studies including patients with different levels of severity, such as e.g. pneumonia and bronchitis, were excluded. Furthermore, studies performed with relatively benign infections were excluded (i.e. infections in the oral cavity, uncomplicated otolaryngeal infections, uncomplicated gastrointestinal infections, sexually transmitted diseases, Lyme disease, exacerbation of chronic bronchitis, pneumonia in the outpatient setting etc.). Chronic infections such as diabetic foot infections were excluded under the assumption that successful antibiotic therapy in this setting does not rely on rapid killing but rather elimination of the biofilm, vascular supply and joint and bone involvement.

Antibiotics

In the bacteriostatic antibiotic patient group, bacteriostatic single therapy only without the concomitant use of any bactericidal drug was allowed, with few exceptions: if all three authors agreed that the bactericidal component of the combination therapy had no effect on bacteria, these studies were included as well. Seven studies met these criteria.6–12 Six out of seven allowed the use of aztreonam in case of infection with Gram-positive bacteria; one study allowed aminoglycosides in case of proven aminoglycoside resistance of Staphylococcus aureus infection.6 The rate of resistance was similar between bacteriostatic and bactericidal antibiotics. For the seven studies with combination therapy, only the microbiologically confirmed cases were extracted for analysis in the clinical cure groups. In all other studies, the ITT population was assessed. If no ITT population was available, results from PP analyses were extracted.

In the bactericidal antibiotic treatment group, combination therapy was allowed. Antibiotics were defined as bactericidal and bacteriostatic according to a classification obtained from a major textbook of infectious diseases, with one important exception (Table 1).3 Aminoglycosides act at the ribosome and are therefore classified as bacteriostatic by some authors. At higher concentrations, however, aminoglycosides display a very rapid bactericidal effect. Due to considerations regarding side effects, aminoglycosides are recommended to be given once daily at high concentrations for most indications.13 Therefore, aminoglycosides are most likely to be bactericidal in routine clinical practice and were classified accordingly.

Table 1.

Definition of bacteriostatic and bactericidal antibiotics (adapted from Cohen et al.3)

Bactericidal  aminoglycosides  β-lactams  fluoroquinolones  glycopeptides  lipopeptides  nitroimidazoles and nitrofurans Bacteriostatic  glycylcyclines  lincosamides  macrolides  oxazolidinones  streptogramins  sulphonamides 

Bactericidal  aminoglycosides  β-lactams  fluoroquinolones  glycopeptides  lipopeptides  nitroimidazoles and nitrofurans Bacteriostatic  glycylcyclines  lincosamides  macrolides  oxazolidinones  streptogramins  sulphonamides 

Table 1.

Definition of bacteriostatic and bactericidal antibiotics (adapted from Cohen et al.3)

Bactericidal  aminoglycosides  β-lactams  fluoroquinolones  glycopeptides  lipopeptides  nitroimidazoles and nitrofurans Bacteriostatic  glycylcyclines  lincosamides  macrolides  oxazolidinones  streptogramins  sulphonamides 

Bactericidal  aminoglycosides  β-lactams  fluoroquinolones  glycopeptides  lipopeptides  nitroimidazoles and nitrofurans Bacteriostatic  glycylcyclines  lincosamides  macrolides  oxazolidinones  streptogramins  sulphonamides 

Studies using inappropriate antibiotics in terms of microbiological spectrum were excluded. Hence, possible differences are not attributable to resistance of bacteria.

Outcomes

For the primary endpoint, clinical outcome as defined by the respective study authors was used. Secondary endpoints were mortality and relapse rates. Relapse rates were defined as recurrence of signs and symptoms associated with the primary infection during follow-up after initial clinical resolution or ‘relapse’ as defined by the authors. Subgroup analyses for different diseases were performed.

Data sources and searches

With the help of an experienced librarian with expertise in literature search for systematic reviews and meta-analyses, we performed an electronic search of OVID MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials (CENTRAL). We also searched relevant references of included studies and conference proceedings using the Web of Science and Scopus databases. No time limits were applied. The search strategy is displayed in detail in Supplementary Data.

Study selection

We included all randomized controlled trials comparing bacteriostatic versus bactericidal antibiotics in patients with serious bacterial infections requiring hospitalization. There was no restriction by study site/country or follow-up period and there was no restriction by dose, frequency or method of drug administration. One author (J. N.) screened the title and abstract of each reference identified by the search and applied the inclusion criteria. For possibly relevant articles, the full-text article was obtained and reviewed independently by two out of the three authors (J. N., G. O. and S. P. K.). Final inclusion of studies was determined by agreement of both reviewers and involvement of a third author in case of discrepancy. After in-depth discussion of the different opinions, the authors agreed unanimously on the final classification. Only studies published in English were considered eligible.

Data extraction and quality assessment

Two out of the three authors (J. N., G. O. and S. P. K.) independently extracted data from included trials. Data extraction was performed using a standardized data collection form. When missing data were encountered, the corresponding authors were contacted to retrieve them.

For the assessment of clinical cure, data from ITT populations were extracted if possible. Some studies did not report the clinical cure rates of the ITT population or—in case of older studies—did not discern between different study populations at all. In such a case, results from modified ITT or PP populations were extracted. In case of the seven studies with combination therapy, only the microbiologically confirmed cases were extracted.6–12

For mortality analysis, the ITT (‘safety’) population was used throughout. The primary outcome measures were (i) clinical cure rate as defined by the investigators in the study and (ii) mortality rate. Data were extracted as proportions if results were only reported as probability of events or mortality and if the number of events was not explicitly provided. Unfortunately, follow-up data and periods of follow-up after end of treatment were heterogeneous.

Subgroup analysis was performed for different diseases and different classes of antibiotics. Meta-analysis was performed only if at least three studies included the same disease or antibiotic.

To assess methodological quality and risk of bias, included articles were examined for (i) randomization process, (ii) blinding, (iii) incomplete outcome data and (iv) reporting bias/sponsorship as described in the Cochrane Handbook for Systematic Reviews of Interventions.14

Data synthesis and analysis

Data synthesis was performed using Review Manager (version 5.2, The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). P values <0.05 were considered statistically significant. Subgroup analyses for differences between different classes of antibiotics and differences between different diseases were performed. Because heterogeneity was anticipated between studies, a random-effects model was used for all analyses. Statistical heterogeneity was inspected graphically (forest plot) and the degree of heterogeneity quantified using the I2 statistic. Publication bias was investigated using a funnel plot in which the standard error of the effect estimate of each study was plotted against the estimate. An asymmetric plot suggested possible publication bias.

We used STATA 13 (StataCorp 2013, College Station, TX, USA) for meta-regression assessing differences between bacteriostatic drug classes.

Results

Study selection

The literature search yielded 16 490 references. After screening titles and abstracts, 81 articles were selected for full-text screening (Figure 1). Thirty-three studies met the inclusion criteria (Table 2). The bacteriostatic agents included tigecycline, linezolid, macrolides, sulphonamides, tetracyclines and streptogramins. The bactericidal agents included β-lactam antibiotics, glycopeptide antibiotics, fluoroquinolones and aminoglycosides. Diseases under study included pneumonia (13 studies6,11,15–19,21–26), skin and soft tissue infections (8 studies7,8,27–32), intra-abdominal infections (4 studies33–36) and others (8 studies10,20,37–42). No trials in neutropenic patients or patients with endocarditis or meningitis met inclusion criteria. All studies except one study on children with typhoid included adults only.37

Author . Year . Type of study . Disease . Antibiotics, bactericidal . Antibiotics, bacteriostatic . Bergallo et al.15 2009 Phase 3, multicentre, double-blind study community-acquired pneumonia levofloxacin tigecycline Bernard et al.27 1992 prospective, randomized, multicentre trial complicated skin and soft tissue infections penicillin roxithromycin Bohte et al.16 1995 open-label, randomized, multicentre study community-acquired pneumonia penicillin azithromycin Breedt et al.28 2005 randomized, double-blind, controlled, multicentre trial complicated skin and soft tissue infections vancomycin tigecycline Chen et al.33 2010 Phase 3, multicentre, open-label study complicated intra-abdominal infection imipenem/cilastatin tigecycline Chuang et al.29 2011 two Phase 3, multicentre, randomized, double-blind studies complicated skin and soft tissue infections vancomycin/aztreonam tigecycline Dartois et al.17 2008 randomized, Phase 3, multicentre trial community-acquired pneumonia levofloxacin tigecycline Ellis-Grosse et al.30 2005 two Phase 3, randomized, double-blind, multicentre studies complicated skin and soft tissue infections vancomycin/aztreonam tigecycline Frenck et al.37 2000 randomized, open-label, controlled, single-centre trial typhoid fever ceftriaxone azithromycin Genne et al.18 1997 open-label, prospective, randomized, single-centre study community-acquired pneumonia amoxicillin clarithromycin Itani et al.7 2010 prospective, randomized, open-label, controlled, multicentre, Phase 4 study complicated skin and soft tissue infections vancomycin linezolid Jauregui et al.8 2005 randomized, double-blind, controlled, multicentre, Phase 3 trial complicated skin and soft tissue infections dalbavancin linezolid Kohno et al.38 2007 randomized, open-label, comparator-controlled, multicentre study nosocomial pneumonia, complicated skin and soft tissue infections or sepsis caused by MRSA vancomycin linezolid Kuzman et al.19 2005 randomized, open-label, multicentre study community-acquired pneumonia cefuroxime azithromycin Lin et al.10 2008 randomized, double-blind, comparator-controlled, multicentre study pneumonia or complicated skin and soft tissue infection due to suspected or known Gram-positive pathogens vancomycin linezolid Markowitz et al.39 1992 randomized, double-blind, comparative, single-centre study infection with S. aureus vancomycin trimethoprim/sulfamethoxazole Mehtar et al.20 1982 open-label, randomized, single-centre study severe respiratory tract infections cefuroxime trimethoprim/sulfamethoxazole Mwengee et al.40 2006 randomized, controlled, comparative, open-label trial plague gentamicin doxycycline Mokabberi et al.21 2010 prospective, randomized, double-blind, single-centre trial community-acquired pneumonia levofloxacin doxycycline Ode et al.41 1983 open-label, randomized, prospective, single-centre, Phase 3 trial acute pyelonephritis ampicillin/mecillinam trimethoprim/sulfamethoxazole Oliva et al.34 2005 prospective, randomized, double-blind, multicentre trial complicated intra-abdominal infection imipenem tigecycline Plouffe et al.22 2000 two multicentre, open-label Phase 3 trials, one parallel-group, randomized, one non-comparative with sequential inclusion community-acquired pneumonia cefuroxime azithromycin Qvist et al.35 2012 randomized, open-label, multicentre, Phase 3b/4 trial complicated intra-abdominal infections ceftriaxone/metronidazole tigecycline Raad et al.42 1999 evaluator-blind, prospective, randomized, Phase 2, multicentre trial catheter-related infections vancomycin quinupristin/dalfopristin Sacchidanand et al.31 2005 Phase 3, randomized, double-blind, multicentre study complicated skin and soft tissue infections vancomycin/aztreonam tigecycline San Pedro et al.11 2002 multicentre, randomized, open-label trial pneumonia with Streptococcus pneumoniae ceftriaxone/cefpodoxime linezolid Shanson et al.23 1984 prospective, randomized, single-centre trial community-acquired pneumonia ampicillin/flucloxacillin erythromycin Sterner et al.24 1967 randomized, open-label, single-centre trial community-acquired pneumonia cefaloridine erythromycin Stevens et al.32 2000 randomized, double-blind, multicentre trial complicated skin and soft tissue infection oxacillin/dicloxacillin linezolid Tanaseanu et al.26 2009 prospective, double-blind, non-inferiority, multicentre, Phase 3 trial community-acquired pneumonia levofloxacin tigecycline Tanaseanu et al.25 2008 two Phase 3, multicentre, randomized, double-blind studies community-acquired pneumonia levofloxacin tigecycline Towfigh et al.36 2010 multicentre, open-label, randomized, Phase 3b/4 study complicated intra-abdominal infection ceftriaxone/metronidazole tigecycline Wunderink et al.6 2012 prospective, double-blind, controlled, multicentre trial confirmed MRSA pneumonia vancomycin linezolid 

Author . Year . Type of study . Disease . Antibiotics, bactericidal . Antibiotics, bacteriostatic . Bergallo et al.15 2009 Phase 3, multicentre, double-blind study community-acquired pneumonia levofloxacin tigecycline Bernard et al.27 1992 prospective, randomized, multicentre trial complicated skin and soft tissue infections penicillin roxithromycin Bohte et al.16 1995 open-label, randomized, multicentre study community-acquired pneumonia penicillin azithromycin Breedt et al.28 2005 randomized, double-blind, controlled, multicentre trial complicated skin and soft tissue infections vancomycin tigecycline Chen et al.33 2010 Phase 3, multicentre, open-label study complicated intra-abdominal infection imipenem/cilastatin tigecycline Chuang et al.29 2011 two Phase 3, multicentre, randomized, double-blind studies complicated skin and soft tissue infections vancomycin/aztreonam tigecycline Dartois et al.17 2008 randomized, Phase 3, multicentre trial community-acquired pneumonia levofloxacin tigecycline Ellis-Grosse et al.30 2005 two Phase 3, randomized, double-blind, multicentre studies complicated skin and soft tissue infections vancomycin/aztreonam tigecycline Frenck et al.37 2000 randomized, open-label, controlled, single-centre trial typhoid fever ceftriaxone azithromycin Genne et al.18 1997 open-label, prospective, randomized, single-centre study community-acquired pneumonia amoxicillin clarithromycin Itani et al.7 2010 prospective, randomized, open-label, controlled, multicentre, Phase 4 study complicated skin and soft tissue infections vancomycin linezolid Jauregui et al.8 2005 randomized, double-blind, controlled, multicentre, Phase 3 trial complicated skin and soft tissue infections dalbavancin linezolid Kohno et al.38 2007 randomized, open-label, comparator-controlled, multicentre study nosocomial pneumonia, complicated skin and soft tissue infections or sepsis caused by MRSA vancomycin linezolid Kuzman et al.19 2005 randomized, open-label, multicentre study community-acquired pneumonia cefuroxime azithromycin Lin et al.10 2008 randomized, double-blind, comparator-controlled, multicentre study pneumonia or complicated skin and soft tissue infection due to suspected or known Gram-positive pathogens vancomycin linezolid Markowitz et al.39 1992 randomized, double-blind, comparative, single-centre study infection with S. aureus vancomycin trimethoprim/sulfamethoxazole Mehtar et al.20 1982 open-label, randomized, single-centre study severe respiratory tract infections cefuroxime trimethoprim/sulfamethoxazole Mwengee et al.40 2006 randomized, controlled, comparative, open-label trial plague gentamicin doxycycline Mokabberi et al.21 2010 prospective, randomized, double-blind, single-centre trial community-acquired pneumonia levofloxacin doxycycline Ode et al.41 1983 open-label, randomized, prospective, single-centre, Phase 3 trial acute pyelonephritis ampicillin/mecillinam trimethoprim/sulfamethoxazole Oliva et al.34 2005 prospective, randomized, double-blind, multicentre trial complicated intra-abdominal infection imipenem tigecycline Plouffe et al.22 2000 two multicentre, open-label Phase 3 trials, one parallel-group, randomized, one non-comparative with sequential inclusion community-acquired pneumonia cefuroxime azithromycin Qvist et al.35 2012 randomized, open-label, multicentre, Phase 3b/4 trial complicated intra-abdominal infections ceftriaxone/metronidazole tigecycline Raad et al.42 1999 evaluator-blind, prospective, randomized, Phase 2, multicentre trial catheter-related infections vancomycin quinupristin/dalfopristin Sacchidanand et al.31 2005 Phase 3, randomized, double-blind, multicentre study complicated skin and soft tissue infections vancomycin/aztreonam tigecycline San Pedro et al.11 2002 multicentre, randomized, open-label trial pneumonia with Streptococcus pneumoniae ceftriaxone/cefpodoxime linezolid Shanson et al.23 1984 prospective, randomized, single-centre trial community-acquired pneumonia ampicillin/flucloxacillin erythromycin Sterner et al.24 1967 randomized, open-label, single-centre trial community-acquired pneumonia cefaloridine erythromycin Stevens et al.32 2000 randomized, double-blind, multicentre trial complicated skin and soft tissue infection oxacillin/dicloxacillin linezolid Tanaseanu et al.26 2009 prospective, double-blind, non-inferiority, multicentre, Phase 3 trial community-acquired pneumonia levofloxacin tigecycline Tanaseanu et al.25 2008 two Phase 3, multicentre, randomized, double-blind studies community-acquired pneumonia levofloxacin tigecycline Towfigh et al.36 2010 multicentre, open-label, randomized, Phase 3b/4 study complicated intra-abdominal infection ceftriaxone/metronidazole tigecycline Wunderink et al.6 2012 prospective, double-blind, controlled, multicentre trial confirmed MRSA pneumonia vancomycin linezolid 

Author . Year . Type of study . Disease . Antibiotics, bactericidal . Antibiotics, bacteriostatic . Bergallo et al.15 2009 Phase 3, multicentre, double-blind study community-acquired pneumonia levofloxacin tigecycline Bernard et al.27 1992 prospective, randomized, multicentre trial complicated skin and soft tissue infections penicillin roxithromycin Bohte et al.16 1995 open-label, randomized, multicentre study community-acquired pneumonia penicillin azithromycin Breedt et al.28 2005 randomized, double-blind, controlled, multicentre trial complicated skin and soft tissue infections vancomycin tigecycline Chen et al.33 2010 Phase 3, multicentre, open-label study complicated intra-abdominal infection imipenem/cilastatin tigecycline Chuang et al.29 2011 two Phase 3, multicentre, randomized, double-blind studies complicated skin and soft tissue infections vancomycin/aztreonam tigecycline Dartois et al.17 2008 randomized, Phase 3, multicentre trial community-acquired pneumonia levofloxacin tigecycline Ellis-Grosse et al.30 2005 two Phase 3, randomized, double-blind, multicentre studies complicated skin and soft tissue infections vancomycin/aztreonam tigecycline Frenck et al.37 2000 randomized, open-label, controlled, single-centre trial typhoid fever ceftriaxone azithromycin Genne et al.18 1997 open-label, prospective, randomized, single-centre study community-acquired pneumonia amoxicillin clarithromycin Itani et al.7 2010 prospective, randomized, open-label, controlled, multicentre, Phase 4 study complicated skin and soft tissue infections vancomycin linezolid Jauregui et al.8 2005 randomized, double-blind, controlled, multicentre, Phase 3 trial complicated skin and soft tissue infections dalbavancin linezolid Kohno et al.38 2007 randomized, open-label, comparator-controlled, multicentre study nosocomial pneumonia, complicated skin and soft tissue infections or sepsis caused by MRSA vancomycin linezolid Kuzman et al.19 2005 randomized, open-label, multicentre study community-acquired pneumonia cefuroxime azithromycin Lin et al.10 2008 randomized, double-blind, comparator-controlled, multicentre study pneumonia or complicated skin and soft tissue infection due to suspected or known Gram-positive pathogens vancomycin linezolid Markowitz et al.39 1992 randomized, double-blind, comparative, single-centre study infection with S. aureus vancomycin trimethoprim/sulfamethoxazole Mehtar et al.20 1982 open-label, randomized, single-centre study severe respiratory tract infections cefuroxime trimethoprim/sulfamethoxazole Mwengee et al.40 2006 randomized, controlled, comparative, open-label trial plague gentamicin doxycycline Mokabberi et al.21 2010 prospective, randomized, double-blind, single-centre trial community-acquired pneumonia levofloxacin doxycycline Ode et al.41 1983 open-label, randomized, prospective, single-centre, Phase 3 trial acute pyelonephritis ampicillin/mecillinam trimethoprim/sulfamethoxazole Oliva et al.34 2005 prospective, randomized, double-blind, multicentre trial complicated intra-abdominal infection imipenem tigecycline Plouffe et al.22 2000 two multicentre, open-label Phase 3 trials, one parallel-group, randomized, one non-comparative with sequential inclusion community-acquired pneumonia cefuroxime azithromycin Qvist et al.35 2012 randomized, open-label, multicentre, Phase 3b/4 trial complicated intra-abdominal infections ceftriaxone/metronidazole tigecycline Raad et al.42 1999 evaluator-blind, prospective, randomized, Phase 2, multicentre trial catheter-related infections vancomycin quinupristin/dalfopristin Sacchidanand et al.31 2005 Phase 3, randomized, double-blind, multicentre study complicated skin and soft tissue infections vancomycin/aztreonam tigecycline San Pedro et al.11 2002 multicentre, randomized, open-label trial pneumonia with Streptococcus pneumoniae ceftriaxone/cefpodoxime linezolid Shanson et al.23 1984 prospective, randomized, single-centre trial community-acquired pneumonia ampicillin/flucloxacillin erythromycin Sterner et al.24 1967 randomized, open-label, single-centre trial community-acquired pneumonia cefaloridine erythromycin Stevens et al.32 2000 randomized, double-blind, multicentre trial complicated skin and soft tissue infection oxacillin/dicloxacillin linezolid Tanaseanu et al.26 2009 prospective, double-blind, non-inferiority, multicentre, Phase 3 trial community-acquired pneumonia levofloxacin tigecycline Tanaseanu et al.25 2008 two Phase 3, multicentre, randomized, double-blind studies community-acquired pneumonia levofloxacin tigecycline Towfigh et al.36 2010 multicentre, open-label, randomized, Phase 3b/4 study complicated intra-abdominal infection ceftriaxone/metronidazole tigecycline Wunderink et al.6 2012 prospective, double-blind, controlled, multicentre trial confirmed MRSA pneumonia vancomycin linezolid 

Author . Year . Type of study . Disease . Antibiotics, bactericidal . Antibiotics, bacteriostatic . Bergallo et al.15 2009 Phase 3, multicentre, double-blind study community-acquired pneumonia levofloxacin tigecycline Bernard et al.27 1992 prospective, randomized, multicentre trial complicated skin and soft tissue infections penicillin roxithromycin Bohte et al.16 1995 open-label, randomized, multicentre study community-acquired pneumonia penicillin azithromycin Breedt et al.28 2005 randomized, double-blind, controlled, multicentre trial complicated skin and soft tissue infections vancomycin tigecycline Chen et al.33 2010 Phase 3, multicentre, open-label study complicated intra-abdominal infection imipenem/cilastatin tigecycline Chuang et al.29 2011 two Phase 3, multicentre, randomized, double-blind studies complicated skin and soft tissue infections vancomycin/aztreonam tigecycline Dartois et al.17 2008 randomized, Phase 3, multicentre trial community-acquired pneumonia levofloxacin tigecycline Ellis-Grosse et al.30 2005 two Phase 3, randomized, double-blind, multicentre studies complicated skin and soft tissue infections vancomycin/aztreonam tigecycline Frenck et al.37 2000 randomized, open-label, controlled, single-centre trial typhoid fever ceftriaxone azithromycin Genne et al.18 1997 open-label, prospective, randomized, single-centre study community-acquired pneumonia amoxicillin clarithromycin Itani et al.7 2010 prospective, randomized, open-label, controlled, multicentre, Phase 4 study complicated skin and soft tissue infections vancomycin linezolid Jauregui et al.8 2005 randomized, double-blind, controlled, multicentre, Phase 3 trial complicated skin and soft tissue infections dalbavancin linezolid Kohno et al.38 2007 randomized, open-label, comparator-controlled, multicentre study nosocomial pneumonia, complicated skin and soft tissue infections or sepsis caused by MRSA vancomycin linezolid Kuzman et al.19 2005 randomized, open-label, multicentre study community-acquired pneumonia cefuroxime azithromycin Lin et al.10 2008 randomized, double-blind, comparator-controlled, multicentre study pneumonia or complicated skin and soft tissue infection due to suspected or known Gram-positive pathogens vancomycin linezolid Markowitz et al.39 1992 randomized, double-blind, comparative, single-centre study infection with S. aureus vancomycin trimethoprim/sulfamethoxazole Mehtar et al.20 1982 open-label, randomized, single-centre study severe respiratory tract infections cefuroxime trimethoprim/sulfamethoxazole Mwengee et al.40 2006 randomized, controlled, comparative, open-label trial plague gentamicin doxycycline Mokabberi et al.21 2010 prospective, randomized, double-blind, single-centre trial community-acquired pneumonia levofloxacin doxycycline Ode et al.41 1983 open-label, randomized, prospective, single-centre, Phase 3 trial acute pyelonephritis ampicillin/mecillinam trimethoprim/sulfamethoxazole Oliva et al.34 2005 prospective, randomized, double-blind, multicentre trial complicated intra-abdominal infection imipenem tigecycline Plouffe et al.22 2000 two multicentre, open-label Phase 3 trials, one parallel-group, randomized, one non-comparative with sequential inclusion community-acquired pneumonia cefuroxime azithromycin Qvist et al.35 2012 randomized, open-label, multicentre, Phase 3b/4 trial complicated intra-abdominal infections ceftriaxone/metronidazole tigecycline Raad et al.42 1999 evaluator-blind, prospective, randomized, Phase 2, multicentre trial catheter-related infections vancomycin quinupristin/dalfopristin Sacchidanand et al.31 2005 Phase 3, randomized, double-blind, multicentre study complicated skin and soft tissue infections vancomycin/aztreonam tigecycline San Pedro et al.11 2002 multicentre, randomized, open-label trial pneumonia with Streptococcus pneumoniae ceftriaxone/cefpodoxime linezolid Shanson et al.23 1984 prospective, randomized, single-centre trial community-acquired pneumonia ampicillin/flucloxacillin erythromycin Sterner et al.24 1967 randomized, open-label, single-centre trial community-acquired pneumonia cefaloridine erythromycin Stevens et al.32 2000 randomized, double-blind, multicentre trial complicated skin and soft tissue infection oxacillin/dicloxacillin linezolid Tanaseanu et al.26 2009 prospective, double-blind, non-inferiority, multicentre, Phase 3 trial community-acquired pneumonia levofloxacin tigecycline Tanaseanu et al.25 2008 two Phase 3, multicentre, randomized, double-blind studies community-acquired pneumonia levofloxacin tigecycline Towfigh et al.36 2010 multicentre, open-label, randomized, Phase 3b/4 study complicated intra-abdominal infection ceftriaxone/metronidazole tigecycline Wunderink et al.6 2012 prospective, double-blind, controlled, multicentre trial confirmed MRSA pneumonia vancomycin linezolid 

Clinical cure rates

Data from 9597 patients were available for meta-analysis of clinical cure rates. Of these patients, 4717 (49.2%) were treated with a bacteriostatic agent. Meta-analysis indicated that clinical cure rates were not different between bactericidal and bacteriostatic drugs [risk ratio (RR), 0.99; 95% CI, 0.97–1.01; P = 0.11; Figure 2], with an overall heterogeneity of I2 = 24%. Analysis of subgroups was performed on studies using tigecycline, linezolid, macrolides, β-lactam antibiotics, glycopeptides and fluoroquinolones. For the other drug classes, an insufficient number of studies were found, precluding statistical analysis. Subgroup analyses revealed that treatment with linezolid appeared to be associated with better clinical cure rates compared with its bactericidal comparator (RR, 0.93; 95% CI, 0.87–0.99; P = 0.04; Figure 2). In meta-regression, combined cure rates of trials using linezolid were better than those from tigecycline trials (RR, 1.07; 95% CI, 1.02–1.12; P = 0.01). There was no benefit detectable for clinical cure rates among subgroups of bactericidal antibiotics (Figure 3).

RRs for clinical cure rates stratified by use of different bacteriostatic antibiotics. Data markers indicate RRs and error bars indicate 95% CIs.

RRs for clinical cure rates stratified by use of different bactericidal antibiotics. Data markers indicate RRs and error bars indicate 95% CIs.

Mortality

The population for the assessment of mortality consisted of 13 098 patients in total. There was no significant increase in overall mortality in the patient group treated with bacteriostatic antibiotics compared with patients treated with bactericidal antibiotics (RR, 0.91; 95% CI, 0.76–1.08; P = 0.28; Figure 4). Heterogeneity was low (I2 = 0%). An increased mortality was found in studies using tigecycline in the bacteriostatic regimen group (RR, 0.66; 95% CI, 0.46–0.94; P = 0.02; Figure 4). In meta-regression, there was a strong trend towards reduced mortality in studies using linezolid compared with tigecycline trials (RR, 0.64; 95% CI, 0.41–1.00; P = 0.05). There was no mortality benefit detectable for subgroups of bactericidal antibiotics (Figure 5).

RRs for mortality rates stratified by use of different bacteriostatic antibiotics. Data markers indicate RRs and error bars indicate 95% CIs.

RRs for mortality rates stratified by use of different bactericidal antibiotics. Data markers indicate RRs and error bars indicate 95% CIs.

Relapse

In 12 studies, relapse rates were reported.7,8,17,18,20,34,35,37,39–42 Five studies included relapse rates in the clinical cure rate endpoint.17,18,35,39,42 In the remaining seven studies, differences in relapse rates between bacteriostatic and bactericidal antibiotics were not significant (RR, 0.76; 95% CI, 0.43–1.35; P = 0.51; data not shown).

Different diseases

We performed subgroup analyses of the most frequent diseases: abdominal infections, skin and soft tissue infections and pneumonia. No differences in clinical outcome between diseases could be found (Figure 6). However, increased mortality was detected in skin and soft tissue infections treated with bacteriostatic agents (RR, 0.43; 95% CI, 0.23–0.84; P = 0.01; Figure 7). If studies using tigecycline were excluded, the difference was no longer significant (RR, 0.57; 95% CI, 0.26–1.27; P = 0.17), suggesting that this effect was again due to the increased overall mortality attributed to tigecycline. Notably, all four studies with abdominal infections had tigecycline in the bacteriostatic regimen arm without difference in mortality.

RRs for clinical cure rates stratified by different diseases. Data markers indicate RRs and error bars indicate 95% CIs.

RRs for mortality rates stratified by different diseases. Data markers indicate RRs and error bars indicate 95% CIs.

Study quality

The quality of included studies was variable (Supplementary Data). More than half of studies (17/33) were unblinded, resulting in significant risk of performance bias. More than 50% of studies were sponsored by the pharmaceutical company that manufactured the respective drug and were thus regarded to be at high risk of reporting bias. Funnel plots did not suggest publication bias (Supplementary Data).

Discussion

In our meta-analysis comparing bactericidal with bacteriostatic antibiotics, no significant differences in clinical cure rates were found in the diseases under study. Subgroup analysis even suggested that linezolid may have better clinical cure rates if compared with its bactericidal comparators. This subgroup included severely ill patients with confirmed MRSA infections, amongst others.6,38 Sufficient antibacterial action of antibiotics in such a patient group is therefore crucial. As a note of caution, involvement of the sponsor in the trials using linezolid was substantial and meta-analysis showed some heterogeneity. Furthermore, vancomycin, which is difficult to dose appropriately, was the comparator drug in the majority of studies. Therefore, it is premature to conclude that linezolid is more efficient than bactericidal antibiotics. However, our findings suggest that linezolid monotherapy is on par with the standard bactericidal therapy in this patient group.

Our meta-analysis did not detect differences in overall mortality between the patient groups. However, there was an increased mortality associated with the use of tigecycline, an observation in line with data published recently.43 Meta-regression showed a trend towards increased mortality of patients treated with tigecycline compared with linezolid. The association between increased mortality and tigecycline was predominantly found amongst patients with severe skin infections. Remarkably, mortality was not increased in 931 patients treated with tigecycline for complicated intra-abdominal infections. An increased mortality in specific patient populations without differences in clinical cure rates may have various reasons, such as toxicity of the drug, pharmacokinetic/pharmacodynamic issues or other reasons.43 Some authors suggest that the drug may be inadequately dosed, at least for ventilator-associated pneumonia.44 This may well explain observed breakthrough bacteraemias as well.45 In conclusion, increased mortality is probably a specific feature of tigecycline and not a class effect inherent to all bacteriostatic drugs. A possible difference from a previously published meta-analysis on tigecycline is the strict exclusion of concomitant bactericidal medication.43

It is important to note that the analysis of clinical cure rates and mortality includes two different populations. Clinical cure rates included all patients who were followed up adequately; overall and including all the older studies, they represent a sample that is closer to PP. The mortality analysis consists of safety data, resembling to a great extent an ITT population. These two populations cannot be distinguished by contemporary definitions, because we included a substantial number of older studies.

Furthermore, it is important to note that the subgroup analyses are supportive of the main research question, i.e. whether a class effect between bacteriostatic and bactericidal drugs is detectable. They should not be regarded as ‘independent’ investigations and their results should not be overemphasized.

Renowned textbooks suggest that immunocompromised patients should be treated with bactericidal antibiotics.3,4 Our analyses include a wide variety of serious bacterial infections, including respiratory tract infections, complicated abdominal infections and skin infections. It is widely accepted that a central pathogenetic feature of most bacterial infections is either local (e.g. disruption of the membrane integrity, such as injury of the skin serving for severe skin infection, or obstruction, such as appendicitis caused by luminal obstruction) or systemic immunosuppression (e.g. neutropenia).46 As it is generally assumed that bacteriostatic antibiotics require a fully functioning immune system to kill bacteria, one would expect differences in clinical cure rates in the patient group receiving bacteriostatic drugs. Our meta-analysis suggests that this is not the case. Therefore, it may be hypothesized that either the local immunosuppression in respiratory tract infections, complicated abdominal infections and skin infections is not clinically relevant enough to require the presence of a bactericidal drug or that the biology of bacterial killing is much more complex than the simplistic concept of bacteriostatic versus bactericidal drug activity suggests, even in local immunosuppression. In any case, our data suggest class indifference for infection where the immune system is intact or at least not impaired in a major way. Based on the data analysed, no conclusions regarding severely immunosuppressed patients, such as patients with neutropenia, can be drawn.

Because of our strict inclusion criteria, we were unable to include studies assessing neutropenic patients or patients with endocarditis. These are the ‘classical’ indications for a bactericidal drug regimen. Only one randomized controlled trial using a bacteriostatic drug—linezolid—in patients with neutropenia was found.47 Unfortunately, a bactericidal add-on medication was allowed, precluding inclusion in our meta-analysis.47 Thus, the findings from our work can only be applied to the diseases under study in our meta-analysis and may not be extended to endocarditis and neutropenia.

A major theoretical complication of bacteriostatic agents is relapse of infection after treatment because of the failure to clear the infection. In the current investigation, there was no detectable difference in relapse rates between bactericidal and bacteriostatic antibiotics.

Our study has limitations. To our knowledge, this is the first study to undertake a meta-analysis on a class effect of drugs. Therefore, we have no means to measure if the studies included are heterogeneous enough regarding the three main factors (host, pathogen and drug) to conclude that the only difference between the two patient groups really is the difference between bacteriostatic and bactericidal antibiotics. There are, however, sound arguments in favour of such a conclusion. Regarding the pathogen, we included studies on a wide array of diseases, ranging from Yersinia pestis to methicillin-resistant staphylococci.6,40 Regarding the host, patients with severe local infections such as severe skin infections or severe abdominal infections were analysed as well as patients with systemic infections such as salmonellosis or central line-associated infections. Regarding the drugs, a total of 10 different antibiotic classes were assessed. These different drugs may vary significantly in tissue distribution and may have different effects according to their dosing schedules. Amongst the bacteriostatic drugs, the newer drugs tigecycline and linezolid are over-represented. The numbers of patients included in clinical trials increases over time, probably due to a rising standard in research practice. This may explain the observed over-representation of newer bacteriostatic drugs.

The included studies have a significant risk for performance and publication bias. In general, there may be a publication bias in favour of bacteriostatic drugs—i.e. linezolid and tigecycline. However, some studies may have a publication bias in favour of the bactericidal component as well, as in the case of dalbavancin compared with linezolid.8

The microbiological definition of bacteriostatic versus bactericidal suggests a degree of clarity that is not supported by the evidence. Some drugs labelled as ‘bacteriostatic’ do have ‘bactericidal’ effects under some in vitro conditions and vice versa.48 For example, the exchange of culture media—media used for growing of eukaryotic cells instead of ‘classical’ Mueller–Hinton broth—may significantly affect drug susceptibility in vitro.49 Thus, it is probably very difficult to predict the action of a given antibiotic drug in terms of bacteriostatic or bactericidal in an actual patient with an ongoing bacterial infection. Furthermore, the action of a given drug may be dependent on the bacterial load and the interaction with the immune system at the site of infection. For example, the capacity of neutrophils to phagocytose bacteria is limited by the sheer quantity of bacteria.50

To our knowledge, this is the first study using clinical data to investigate the difference between bactericidal and bacteriostatic antibiotics. Summarized, the data at hand suggest that this classification is clinically irrelevant if used for abdominal infections, skin and soft tissue infections and pneumonia. These findings cannot be applied directly to patients with meningitis, neutropenia or endocarditis, because we were unable to include these types of infection in our meta-analysis.

Funding

This study was carried out as part of our routine work.

Transparency declarations

None to declare.

Author contributions

Study concept and design: J. N., G. O. and S. P. K. Acquisition of data: J. N., G. O. and S. P. K. Statistical analysis: J. N. and S. P. K. Analysis and interpretation of data: J. N., G. O. and S. P. K. Drafting of the manuscript: J. N. and S. P. K. Critical revision of the manuscript for important intellectual content: J. N., G. O. and S. P. K.

Acknowledgements

We are thankful for fruitful discussions with Rainer Weber, Nicolas Müller, Jan S. Fehr, Dominique L. Braun, Huldrych F. Guenthard, Ulrich Matt, Elisabeth and Titus Nemeth.

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