Beta-Lactam vs. Fluoroquinolone Monotherapy for Pseudomonas aeruginosa Infection: A Systematic Review and Meta-Analysis

Introduction: Pseudomonas aeruginosa (PA) is a leading cause of healthcare-associated infections. A variety of antibiotic classes are used in the treatment of PA infections, including beta-lactams (BLs) and fluoroquinolones (FQs), given either together in combination therapy or alone in monotherapy. A systematic review and meta-analysis were performed to evaluate the therapeutic efficacy of BL agents versus FQ agents as active, definitive monotherapy in PA infections in adults. Methods: Comprehensive literature searches of the Medline and Scopus electronic databases, alongside hand searches of the Cochrane Database of Systematic Reviews, PubMed, and Google Scholar, were performed without a time restriction to identify studies published in English comparing BL and FQ agents given as monotherapy for PA infection in hospitalized adults for which mortality, bacteriological eradication, or clinical response was evaluated. One reviewer screened search results based on pre-defined selection criteria. Two reviewers independently assessed included studies for methodological quality using NIH assessment tools. Two fixed-effects meta-analyses were performed. Results: A total of 368 articles were screened, and six studies involving 338 total patients were included in the meta-analysis. Upon evaluation of methodological quality, two studies were rated good, three fair, and one poor. A meta-analysis of three studies demonstrates FQ monotherapy is associated with significantly improved survival compared to BL monotherapy for patients with PA bacteremia (OR, 3.65; 95% CI, 1.27–10.44; p = 0.02). A meta-analysis of three studies demonstrates FQ monotherapy is associated with equivalent bacteriological eradication compared to BL monotherapy for PA pneumonia or skin and soft tissue infection (RD, 0.07; 95% CI, −0.09 to 0.24; p = 0.39). Conclusion: The meta-analyses demonstrate FQ monotherapy significantly improves survival in PA bacteremia and is associated with similar rates of bacteriological eradication in pneumonia and skin and soft tissue infection caused by PA compared to BL monotherapy. However, more research is needed to make meaningful clinical recommendations.

Beta-lactam vs Fluoroquinolone Monotherapy for Pseudomonas aeruginosa Infection: A Systematic Review and Meta-analysis

Introduction: Pseudomonas aeruginosa (PA) is a leading cause of healthcare-associated infections. A variety of antibiotic classes are used in the treatment of PA infections, including beta-lactams (BLs) and fluoroquinolones (FQs), given either together in combination therapy or alone in monotherapy. A systematic review and meta-analysis were performed to evaluate the therapeutic efficacy of BL agents versus FQ agents as active, definitive monotherapy in PA infections in adults.Methods: Comprehensive literature searches of Medline and Scopus electronic databases, alongside hand searches of the Cochrane Database of Systematic Reviews, PubMed, and Google Scholar, were performed without time restriction to identify studies published in English comparing BL and FQ agents given as monotherapy for PA infection in hospitalized adults for which mortality, bacteriological eradication, or clinical response was evaluated. One reviewer screened search results based on pre-defined selection criteria. Two reviewers independently assessed included studies for methodological quality using NIH assessment tools. Two fixed-effects meta-analyses were performed.Results: A total of 368 articles were screened, and 6 studies involving 338 total patients were included in the meta-analysis. Upon evaluation of methodological quality, 2 studies were rated good, 3 fair, and 1 poor. A meta-analysis of 3 studies demonstrates FQ monotherapy is associated with significantly improved survival compared to BL monotherapy for patients with PA bacteremia (OR, 3.65; 95% CI, 1.27-10.44; p=.02). A meta-analysis of 3 studies demonstrates FQ monotherapy is associated with equivalent bacteriological eradication compared to BL monotherapy for PA pneumonia or skin and soft tissue infection (RD, 0.07; 95% CI, -0.09 to 0.24; p=.39).Conclusion: The meta-analyses demonstrate FQ monotherapy significantly improves survival in PA bacteremia and is associated with similar rates of bacteriological eradication in pneumonia and skin and soft tissue infection caused by PA compared to BL monotherapy. However, more research is needed to make meaningful clinical recommendations.

129. Beta-lactam vs Fluoroquinolone Monotherapy for pseudomonas Aeruginosa infection: A Systematic Review and Meta-analysis

Background Pseudomonas aeruginosa (PA) is a leading cause of healthcare-associated infections, including pneumonia, bloodstream infections, and surgical site infections around the world. A variety of antibiotic classes are used in the treatment of PA infections, including beta-lactams (BLs) and fluoroquinolones (FQs), given either together in combination therapy or alone in monotherapy. Here, we report a systematic review and meta-analysis to evaluate the therapeutic efficacy of BL agents versus FQ agents as active, definitive monotherapy in PA infections in adults. Methods Comprehensive literature searches of Medline and Scopus electronic databases, alongside hand searches of the Cochrane Database of Systematic Reviews, PubMed, and Google Scholar, were performed in April 2019 without time restriction to identify studies published in English comparing BL and FQ agents given as monotherapy for PA infection in hospitalized adults for which mortality, bacteriological eradication, or clinical response was evaluated. One reviewer screened search results based on pre-defined selection criteria. Two reviewers independently assessed included studies for methodological quality using NIH assessment tools. Two fixed-effects meta-analyses were performed (Figure 1). Results A total of 368 articles were screened, and 6 studies were included in the meta-analysis. Upon evaluation of methodological quality, 2 studies were rated good, 3 fair, and 1 poor (Table 1). A meta-analysis of 3 cohort studies demonstrates FQ monotherapy for PA bacteremia is associated with increased survival compared to BL monotherapy (OR, 3.65; 95% CI, 1.27–10.44; p=.02; Figure 2). A meta-analysis of 3 randomized control studies demonstrates FQ monotherapy for PA pneumonia and skin and soft tissue infection is not significantly associated with increased bacteriological eradication compared to BL monotherapy (RD, 0.07; 95% CI, -0.09 to 0.24; p=.39; Figure 3). Conclusion The data appear to suggest FQ monotherapy is significantly associated with increased survival in PA bacteremia and associated with similar rates of bacteriological eradication in pneumonia and skin and soft tissue infection caused by PA compared to BL monotherapy. However, more research is needed to make meaningful clinical recommendations. Disclosures All Authors: No reported disclosures

Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study

Objective To determine whether total exposure to penicillin V can be reduced while maintaining adequate clinical efficacy when treating pharyngotonsillitis caused by group A streptococci. Design Open label, randomised controlled non-inferiority study. Setting 17 primary healthcare centres in Sweden between September 2015 and February 2018. Participants Patients aged 6 years and over with pharyngotonsillitis caused by group A streptococci and three or four Centor criteria (fever ≥38.5°C, tender lymph nodes, coatings of the tonsils, and absence of cough). Interventions Penicillin V 800 mg four times daily for five days (total 16 g) compared with the current recommended dose of 1000 mg three times daily for 10 days (total 30 g). Main outcome measures Primary outcome was clinical cure five to seven days after the end of antibiotic treatment. The non-inferiority margin was prespecified to 10 percentage points. Secondary outcomes were bacteriological eradication, time to relief of symptoms, frequency of relapses, complications and new tonsillitis, and patterns of adverse events. Results Patients (n=433) were randomly allocated to the five day (n=215) or 10 day (n=218) regimen. Clinical cure in the per protocol population was 89.6% (n=181/202) in the five day group and 93.3% (n=182/195) in the 10 day group (95% confidence interval −9.7 to 2.2). Bacteriological eradication was 80.4% (n=156/194) in the five day group and 90.7% (n=165/182) in the 10 day group. Eight and seven patients had relapses, no patients and four patients had complications, and six and 13 patients had new tonsillitis in the five day and 10 day groups, respectively. Time to relief of symptoms was shorter in the five day group. Adverse events were mainly diarrhoea, nausea, and vulvovaginal disorders; the 10 day group had higher incidence and longer duration of adverse events. Conclusions Penicillin V four times daily for five days was non-inferior in clinical outcome to penicillin V three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci. The number of relapses and complications did not differ between the two intervention groups. Five day treatment with penicillin V four times daily might be an alternative to the currently recommended 10 day regimen. Trial registration EudraCT 2015-001752-30; ClinicalTrials.gov NCT02712307 .

Evaluation of 3-day azithromycin or 5-day cefaclor in comparison with 10-day amoxicillin for treatment of tonsillitis in children

To evaluate the clinical efficacy of azithromycin, cefaclor, and amoxicillin in treatment of pediatric tonsillitis, a total of 256 children with Group A β-hemolytic streptococcus (GAS) tonsillitis were randomly divided into 3 groups. Only patients assessed with streptococcus-positive tonsillitis, considered to be compliant with treatment and complete clinical and microbiological evaluations at the end of therapy (day 14) and follow-up (day 30) were included in the efficacy analysis. Our study demonstrated that 96.4% of patients in the azithromycin group, 92.4% of patients in the cefaclor group, and 91.0% of patients in the amoxicillin group were recorded as clinical success at the end of therapy. Bacteriological eradication rates of the 3 groups at the end of therapy were 94.0%, 89.9%, and 88.5%, respectively. A pathogen recurrence rate was evaluated as 2.6%, 7.0%, and 5.9% at the follow-up. Treatment-stimulated adverse events occurred in 2.4% of patients in the azithromycin group, 11.3% in the cefaclor group, and 11.4% in the amoxicillin group. In summary, azithromycin showed an effective tendency for the treatment of pediatric tonsillitis with lower occurrence rate of adverse reactions, although there is no statistical significance for the clinical and bacteriological eradication efficacy between these 3 groups.

Optimal Treatment for Complicated Intra-abdominal Infections in the Era of Antibiotic Resistance: A Systematic Review and Meta-Analysis of the Efficacy and Safety of Combined Therapy With Metronidazole

Background. Carbapenem-resistant Enterobacteriaceae has increased dramatically in the last decade, resulting in infections that are difficult to treat and associated with high mortality rates. To prevent further antibacterial resistance, it is necessary to use carbapenem selectively. A combination of metronidazole with an antimicrobial agent active against aerobes is an alternative effective treatment for patients with complicated intra-abdominal infections (cIAIs). This study aimed to compare efficacy and safety of metronidazole combination therapies and carbapenem and to provide clinical evidence regarding the optimal treatment of cIAI. Methods. A systematic review and a meta-analysis of randomized clinical trials in the treatment of cIAI were conducted. The systematic review with PubMed, Embase, and the Cochrane Database of Systematic Reviews followed the Cochrane Handbook's recommended methodology, and the meta-analysis used a Mantel-Haenszel random-effects model with RevMan, version 5.3. Primary endpoints were clinical success and bacteriological eradication, and secondary endpoints were all-cause mortality and drug-related adverse events. Results. Eight studies comparing metronidazole combination therapies and carbapenem were included in the meta-analysis. No difference was found between combined therapy with metronidazole and carbapenem regarding clinical success (odds ratio [OR] = 1.31; 95% confidence interval [CI], .75–2.31), bacteriological eradication (OR = 1.27; 95% CI, .84–1.91), all-cause mortality (OR = 0.61; 95% CI, .37–1.00), or drug-related adverse events (OR = 0.58; 95% CI, .18–1.88). Sensitivity analyses found similar results. Conclusions. Combined therapy with metronidazole is as effective and safe as carbapenem in treatment of cIAI. Therefore, combined therapy with metronidazole offers an effective alternative to carbapenem with low risk of drug resistance.

Pharmacodynamic Analysis and Clinical Trial of Amoxicillin Sprinkle Administered Once Daily for 7 Days Compared to Penicillin V Potassium Administered Four Times Daily for 10 Days in the Treatment of Tonsillopharyngitis Due to Streptococcus pyogenes in Children

ABSTRACT An a priori pharmacokinetic/pharmacodynamic (PK/PD) target of 40% daily time above the MIC (T >MIC; based on the MIC90 of 0.06 μg/ml for Streptococcus pyogenes reported in the literature) was shown to be achievable in a phase 1 study of 23 children with a once-daily (QD) modified-release, multiparticulate formulation of amoxicillin (amoxicillin sprinkle). The daily T >MIC achieved with the QD amoxicillin sprinkle formulation was comparable to that achieved with a four-times-daily (QID) penicillin VK suspension. An investigator-blinded, randomized, parallel-group, multicenter study involving 579 children 6 months to 12 years old with acute streptococcal tonsillopharyngitis was then undertaken. Children were randomly assigned 1:1 to receive either the amoxicillin sprinkle (475 mg for ages 6 months to 4 years, 775 mg for ages 5 to 12 years) QD for 7 days or 10 mg/kg of body weight of penicillin VK QID for 10 days (up to the maximum dose of 250 mg QID). Unexpectedly, the rates of bacteriological eradication at the test of cure were 65.3% (132/202) for the amoxicillin sprinkle and 68.0% (132/194) for penicillin VK (95% confidence interval, −12.0% to 6.6%). Thus, neither antibiotic regimen met the minimum criterion of ≥85% eradication ordinarily required by the U.S. FDA for first-line treatment of tonsillopharyngitis due to S. pyogenes. The results of subgroup analyses across demographic characteristics and current infection characteristics and by age/weight categories were consistent with the primary-efficacy result. The clinical cure rates for amoxicillin sprinkle and penicillin VK were 86.1% (216/251) and 91.9% (204/222), respectively (95% confidence interval, −11.6% to −0.4%). The results of a post hoc PD analysis suggested that a requirement for 60% daily T >MIC90 more accurately predicted the observed high failure rates for bacteriologic eradication with the amoxicillin sprinkle and penicillin VK suspension studied. Based on the association between longer treatment courses and maximal bacterial eradication rates reported in the literature, an alternative composite PK/PD target taking into consideration the duration of therapy, or total T >MIC, was considered and provides an alternative explanation for the observed failure rate of amoxicillin sprinkle.

Designing Fluoroquinolone Breakpoints for Streptococcus pneumoniae by Using Genetics instead of Pharmacokinetics-Pharmacodynamics

ABSTRACT We determined fluoroquinolone microbiological resistance breakpoints for Streptococcus pneumoniae by using genetic instead of pharmacokinetic-pharmacodynamic parameters. The proposed microbiological breakpoints define resistance as the MIC at which >50% of the isolates carry quinolone resistance-determining region mutations and/or, if data are available, when Monte Carlo simulations demonstrate a <90% chance of bacteriological eradication. The proposed microbiological resistant breakpoints are as follows (in micrograms per milliliter): gatifloxacin, >0.25; gemifloxacin, >0.03; levofloxacin, >1; and moxifloxacin, >0.12. Monte Carlo simulations of the once daily 400-mg doses of gatifloxacin and 750-mg doses levofloxacin demonstrated a high level of target attainment (free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio of 30) by using these new genetically derived breakpoints.