Microbiological Eradication Rate Research Articles

1143. Safety and Efficacy of Ceftolozane/Tazobactam Versus Meropenem in Neonatal and Pediatric Participants With Complicated Urinary Tract Infection, Including Pyelonephritis: A Phase 2, Randomized, Clinical Trial

BackgroundCeftolozane/tazobactam (C/T) is a cephalosporin–β-lactamase inhibitor combination approved to treat complicated urinary tract infections (cUTI), complicated intra-abdominal infections, and nosocomial pneumonia in adults. Safety and efficacy of C/T in neonatal and pediatric participants with cUTI was assessed.MethodsThis phase 2, randomized, double-blind study (NCT03230838) compared C/T with meropenem (MEM) for treatment of cUTI, including pyelonephritis in participants from birth to 18 years of age. Treatment duration was 7-14 days. After 3 days of intravenous therapy, optional oral step-down therapy was allowed. Participants were stratified and dosed by age group (Table 1). The primary objective was to evaluate the safety and tolerability of C/T compared with MEM, and key secondary end points included clinical response and per-participant microbiologic response at end of treatment (EOT) and test of cure (TOC). ResultsParticipants were randomized 3:1 and treated with C/T (n=100) or MEM (n=33). The microbiologic modified intent-to-treat population (mMITT) included 95 participants in the C/T (n=71) and MEM (n=24) arms; the most common reason for mMITT exclusion was lack of a qualifying baseline uropathogen (28.4%). Pyelonephritis was the most common baseline diagnosis (83.2%), and Escherichia coli was the most common qualifying baseline uropathogen (77.9%). Overall mean treatment duration was comparable in both arms (C/T, 10.2 days; MEM, 10.7); a total of 50 (70.4%) and 20 (83.3%) participants switched to optional oral step-down therapy in the C/T and MEM arms, respectively, both for a mean of approximately 6 days. The overall incidence of adverse events (AE; all and drug related), serious AE (SAE), and AE leading to discontinuation was comparable between C/T and MEM arms. There were no AE leading to death, drug-related SAE, or discontinuations due to drug-related AE or SAE (Table 2). For C/T and MEM, rates of clinical cure and microbiologic eradication at EOT and TOC were high (Figure). ConclusionIn this study, C/T was well tolerated with a safety profile comparable to MEM and to the previously reported safety profile for C/T in adults with cUTI. C/T achieved high clinical cure and microbiologic eradication rates and is a potential new treatment option for children with cUTI.Disclosures Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Negar Ashouri, MD, Merck Sharp & Dohme Corp. (Grant/Research Support) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Julia Lonchar, MSc, Merck Sharp & Dohme Corp. (Employee, Shareholder) Feng-Hsiu Su, MPH, MBA, Merck Sharp & Dohme Corp. (Employee, Shareholder) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Myra W. Popejoy, PharmD, Merck Sharp & Dohme Corp. (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Carisa S. De Anda, PharmD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Elizabeth G. Rhee, MD, Merck Sharp & Dohme Corp (Employee, Shareholder) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

Clinical Efficacy and Safety of Cefoperazone-Sulbactam in Treatment of Intra-Abdominal Infections: A Systematic Review and Meta-Analysis.

Background: In this systematic review and meta-analysis, we aimed to assess the clinical efficacy and safety of cefoperazone-sulbactam against alternative antibiotics in the treatment of intra-abdominal infections. Methods: The PubMed, Cochrane, Web of Science, Ovid Medline, and CKNI databases were searched for relevant articles up to November 25, 2020. The primary outcome was clinical efficacy rate, and the secondary outcomes were microbiologic eradication rate, mortality rate, and adverse event (AE) risk. Results: Twelve studies involving 1,674 patients were included. Overall, the clinical efficacy rate of cefoperazone-sulbactam and comparators was 87.7% and 81.7%, respectively, and cefoperazone-sulbactam was associated with a higher clinical efficacy rate than that the comparator (odds ratio [OR] 1.98; 95% confidence interval [CI] 1.31-3.00; I2 = 36%). Additionally, cefoperazone-sulbactam was associated with a lower clinical failure rate (OR 0.40; 95% CI 0.28-0.57; I2 = 0) and a higher clinical cure rate (OR 1.54; 95% CI 1.17-2.03; I2 = 0) than the comparators. Cefoperazone-sulbactam was associated with a higher microbiologic eradication rate than the comparator (OR 2.54; 95% CI 1.72-3.76; I2 = 0). Finally, there was no significant difference between cefoperazone-sulbactam and the comparators in terms of mortality rate (OR 090; 95% CI 0.38-2.16; I2 = 0) and AE risk (OR 1.07; 95% CI 0.74-1.55; I2 = 0). Conclusions: The clinical efficacy and safety of cefoperazone-sulbactam were similar to those of alternative antibiotics in the treatment of intra-abdominal infections. Therefore, cefoperazone-sulbactam could be recommended as an effective and safe antibiotic for treating intra-abdominal infections.

Meta-analysis of vancomycin versus linezolid in pneumonia with proven methicillin-resistant Staphylococcus aureus

ObjectiveAmerican Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines suggest that linezolid (LZD) is preferred over vancomycin (VCM) for treating methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. We conducted a systematic review and comparative meta-analysis to compare VCM and LZD efficacy against proven MRSA pneumonia. MethodsWe searched EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed up to November 2019. The outcomes of the meta-analysis were mortality, clinical cure, microbiological evaluation, and adverse events. ResultsSeven randomized controlled trials (RCTs) with a total of 1239 patients and eight retrospective cohort or case–control studies (CSs) with a total 6125 patients were identified. Clinical cure and microbiological eradication rates were significantly increased in patients treated with LZD in RCTs (clinical cure: risk ratio (RR) = 0.81, 95% confidential interval (CI) = 0.71–0.92; microbiological eradication: RR = 0.71, 95% CI = 0.62–0.81) and CSs (clinical cure: odds ratio (OR) = 0.35, 95% CI = 0.18–0.69). However, mortality was comparable between patients treated with VCM and LZD in RCTs (RR = 1.08, 95% CI = 0.88–1.32) and CSs (OR = 1.20, 95% CI = 0.94–1.53). Likewise, there was no significant difference in adverse events between VCM and LZD in CSs (thrombocytopenia: OR = 0.95, 95% CI = 0.50–1.82; nephrotoxicity: OR = 1.72, 95% CI = 0.85–3.45). ConclusionsAccording to our meta-analysis of RCTs and CSs conducted worldwide, we found robust evidence to corroborate the IDSA guidelines for the treatment of proven MRSA pneumonia.

1257. A phase II Prospective Randomized Study to Assess Ceftolozane-Tazobactam in the Management of Febrile Neutropenia in Patients with Hematological Malignancies

BackgroundDespite the implementation of successful antibiotic stewardship programs, antibiotic resistance continue to emerge particularly against gram-negative bacteria. With the increase use of antibiotics in high risk patients with hematological malignancies, the empiric therapy with standard antibiotic could be inappropriate. New antibiotics may be useful to cover potential resistant pathogens. We evaluated the role of a new cephalosporin /β-lactamase inhibitor ceftolozane-tazobactam (C/T) in comparison to standard of care (SOC) antibiotics in the empiric treatment of febrile neutropenic cancer patients with hematological malignancies.MethodsWe conducted a prospective randomized open label comparative study to evaluate the safety and efficacy of C/T vs SOC antibiotics consisting of cefepime, piperacillin-tazobactam or meropenem when used in combination with gram positive antibacterial agents. Between May 2018 and March 2020, we enrolled 88 febrile neutropenic patients with hematological malignancies who presented to our emergency center. Patients received at least 72 hours of intravenous study drugs and were followed through end of IV therapy and for up to 42 days.ResultsA total of 88 patients were analyzed of whom 42 received C/T and 46 SOC antimicrobial agents. The rate of documented bloodstream infections was similar in both groups (CE-TZ 21% vs SOC 26%, p=0.61). Favorable clinical response at end of IV therapy was significantly better in the C/T arm compared to SOC therapy (88% vs 72%, p=0.039), at test of cure (21 days), and last follow-up (42 days). In patients with documented infections, the rate of microbiological eradication was similar in both groups. Drug-related adverse events that led to drug discontinuation was similar in both groups (7%). Similarly overall mortality was similar in both groups.ConclusionThe empiric use of C/T to cover gram negative organisms in high risk febrile neutropenic patients with hematological malignancies is safe and associated with better clinical outcome than SOC antimicrobial agents. The emergence of resistant pathogens should be further evaluated.Disclosures Issam I. Raad, MD, Citius (Other Financial or Material Support, Ownership interest)Cook Medical (Grant/Research Support)Inventive Protocol (Other Financial or Material Support, Ownership interest)Novel Anti-Infective Technologies (Shareholder, Other Financial or Material Support, Ownership interest)

1578. Treatments for complicated urinary tract infections (cUTI) caused by multidrug resistant (MDR) Gram-negative (GN) pathogens- a systematic review and network meta-analysis (NMA)

BackgroundAntimicrobial resistance is a major and growing threat to global public health. Cefiderocol (CFDC) is a new siderophore-cephalosporin with a wide activity spectrum covering all aerobic GN pathogens including all WHO critical priority pathogens, that was recently approved by FDA for the treatment of GN cUTI in susceptible organisms. We aim to understand the relative efficacy and safety of current treatment options for cUTI caused by MDR GN pathogens.MethodsWe conducted a systematic review to identify all relevant trials that investigated the efficacy and safety of antimicrobial regimens, for the treatment of GN pathogens in cUTI. Outcomes of interest included clinical cure and microbiological eradication (ME) at time of cure (TOC) and sustained follow up (SFU), and safety. Evidence networks were constructed using data for outcomes of interest and analyses were conducted in a frequentist framework using NMA methods outlined by the NICE decision support unit using the netmeta package in R.ResultsA total of 5 studies, 6 interventions and 2,349 randomised patients were included in the final analysis. Interventions included CFDC, imipenem-cilastatin (IPM-CIL), ceftazidime-avibactam (CAZ/AVI), doripenem (DOR), levofloxacin and ceftolozane-tazobactam (CEF/TAZ). Trials included predominantly Enterobacterales, and Pseudomonas aeruginosa and very few Acinetobacter baumannii. The patient population presented some clinical differences across trials, which were not adjusted for the NMA. Overall, there were numerical differences (especially in endpoints at SFU favouring CFDC), but all treatments showed similar efficacy and safety, with exception of higher ME rate at TOC for CFDC vs IPM, Table 1, also observed at SFU, consistent with the data from the individual clinical trial.Table 1- Results for microbiological eradicationTable 1- Results for microbiological eradication ConclusionThis NMA, showed superiority of CFDC vs IPM-CIL in ME at TOC and SFU and similar efficacy and safety vs all other comparators, with numeric differences favouring CFDC for outcomes at SFU. These traditional methodologies for NMA, are only valid within a similar pathogens pool and population across the trials, and may not reflect the full value of breadth of coverage that new therapeutic options bring for the treatment of MDR GN pathogens.DisclosuresTim Reason, PhD, Shionogi (Consultant) Karan Gill, MSc, Shionogi BV (Employee) Christopher Longshaw, PhD, Shionogi B.V. (Employee) Rachael McCool, PhD, York Health Economics Consortium (Employee, YHEC was commissioned by Shionogi to conduct the systematic review) Katy Wilson, PhD, York Health Economics Consortium (Employee, Shionogi commissioned YHEC to conduct the systematic review) Sara Lopes, PharmD, Shionogi BV (Employee)

Dual-route-administration versus single-route-administration of polymyxin B in VAP caused by MDR Klebsiella pneumoniae: An observational study

Background: Ventilator-associated pneumonia (VAP) in critically ill patients of intensive care units (ICUs) is associated with high rate of mortality and morbidity, and VAP caused by multidrug-resistant (MDR) gram-negative bacteria (GNB) such as, Klebsiella pneumoniae (KP) is a life threatening infectious event. In MDR KP-associated VAP (MDR-KP-VAP) infections, KP is generally found only sensitive to few last-line potential antibiotics including polymyxin B. Intravenous polymyxin B in MDR-KP-VAP treatment is practiced worldwide but, nebulized polymyxin B is a direct-to-infection site therapy. The objective of this study was to evaluate the clinical outcomes of dual-route (intravenous and nebulization) administration of polymyxin B versus single-route (intravenous) administration in MDR-KP-VAP treatment. Methods and materials: This observational study was conducted on 121 mechanically ventilated patients with MDR-KP-VAP infection where KP was resistant to penicillins, cephalosporins, aminoglycosides and fluoroquinolones but, only sensitive to polymyxin B. Polymyxin B intravenously and nebulization was administered to 64 patients in one group (PIVNL group) whereas 57 patients of another group (PIV group) found only intravenous polymyxin B for MDR-KP-VAP treatment. Intravenous levofloxacin was coexisted with polymyxin B therapies in both groups’ patients. Group-wise therapeutic outcomes were compared prospectively. Results: The microbiological eradication rate was higher (92.1%, n = 64) in PIVNL group than the PIV group (70.1%, n = 57) (p value = 0.002). PIV group showed higher secondary bacterial infection rate (19.2%, n = 57) than PIVNL group (6.2%, n = 64) (p value = 0.030), and 30-day mortality rate was also found higher in PIV group patients (15.7%, n = 57) than PIVNL group (7.8%, n = 64) (p value = 0.171). In terms of adverse drug reaction (ADR), polymyxin B-induced bronchospasm events were found (4, 6.2%, n = 64) in PIVNL group whereas nil in PIV group, and nephrotoxicity events were similarly happened in PIVNL (3, 4.6%, n = 64) and PIV group (3, 5.2%, n = 57). Conclusion: The emergence of MDR gram-negative bacterial infections in mechanically ventilated patients is an appalling issue worldwide and to treat with few last-line antibiotics is a do-or-die challenge at this moment. In this study, simultaneous intravenous administration of polymyxin B with its nebulization in MDR-KP-associated VAP patients exhibited better clinical success than with intravenous polymyxin B alone.

Efficacy and Tolerability of Eravacycline in Bacteremic Patients with Complicated Intra-Abdominal Infection: A Pooled Analysis from the IGNITE1 and IGNITE4 Studies.

Background: Eravacycline is a novel, fully synthetic fluorocycline antibiotic that was evaluated for the treatment of complicated intra-abdominal infections (cIAI) in two phase 3 clinical trials. The objective of this analysis was to evaluate the clinical cure and microbiologic response at the test-of-cure (TOC) visit and the safety of eravacycline in patients with cIAI and baseline bacteremia who received eravacycline versus comparators. Patients and Methods: Pooled data of patients with bacteremia from the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE) 1 and IGNITE4 studies were analyzed. All patients were randomly assigned in a one-to-one ratio to receive eravacycline 1 mg/kg intravenously every 12 hours, ertapenem 1 g intravensouly every 24 hours (IGNITE1), or meropenem 1 g intravenously every eight hours (IGNITE4) for four to 14 days. Blood and intra-abdominal samples were collected from all patients at baseline. Clinical outcome and microbiologic eradiation at the TOC visit (28 days after randomization) and safety in the microbiologic-intent-to-treat population (micro-ITT) were assessed. Results: Of 415 patients treated with eravacycline and 431 treated with carbapenem comparators, concurrent bacteremia was identified in 32 (7.7%) and 31 (7.2%) patients, respectively. Demographic and baseline characteristics were similar among treatment groups. In the micro-ITT population, the pooled clinical response at the TOC visit for eravacycline was 28 of 32 (87.5%) and was 24 of 31 (77.0%) for comparators among the subgroup with baseline bacteremia (treatment difference 5.9; 95% confidence interval [CI], -6.5 to 17.4). At TOC, microbiologic eradication of pathogens isolated from blood specimens occurred for 34 of 35 (97.1%) pathogens with eravacycline and 35 of 36 (97.2%) pathogens with comparators. The incidence of adverse events was comparable between treated groups and similar to that observed in the non-bacteremic population. Conclusion: Eravacycline demonstrated a similar clinical outcome and microbiologic eradication rate as comparator carbapenems in patients with cIAI and associated secondary bacteremia. Future clinical trials of cIAI should report outcomes of this important clinical cohort (cIAI with concurrent bacteremia) given their high risk for adverse outcomes.

Five-day antibiotic treatment for community-acquired bacterial pneumonia: A systematic review and meta-analysis of randomized controlled trials

ObjectivesThis systematic review and meta-analysis of randomized controlled trials (RCTs) investigated whether the clinical efficacy of a 5-day antibiotic course is comparable to that of a longer (≥7 d) course for treating adults with community-acquired bacterial pneumonia (CABP). MethodsThe PubMed, Web of Science, Cochrane Library, Ovid MEDLINE, and Embase. were searched before January 18, 2020. RCTs comparing the efficacy of a 5-day antibiotic course with a longer course (≥7 d) for CABP treatment were included. Primary outcomes included the clinical response, microbiological response, and risk of adverse events (AEs). ResultsIn this meta-analysis, 7 RCTs were included, and the 5-day antibiotic courses group, and a longer course group comprised 1499 and 1522 patients, respectively. The difference in the overall clinical response rates between the 5-day and longer courses (88.3% vs 88.8%, odds ratio [OR], 0.95, 95% confidence interval [CI], 0.70–1.28, I2 = 19%) was nonsignificant. Additionally, the microbiological eradication rates did not differ significantly between the groups, at 94.8% and 95.8% in the 5-day and longer courses groups, respectively (OR, 0.84, 95% CI, 0.38–1.87, I2 = 0%). Finally, all-cause mortality did not differ between the 2 groups (OR, 0.91, 95% CI, 0.31–2.66, I2 = 0%). ConclusionsFive-day treatment and longer antibiotic courses for CABP yield similar clinical and microbiological responses and exhibit similar safety profiles.

Oral and Intravenous Fosfomycin for the Treatment of Complicated Urinary Tract Infections.

Oral fosfomycin is approved in Canada for the treatment of acute uncomplicated cystitis. Several studies have reported “off label” use of oral fosfomycin in the treatment of patients with complicated lower urinary tract infection (cLUTI). This review summarizes the available literature describing the use of oral fosfomycin in the treatment of patients with cLUTI. Collectively, these studies support the use of a regimen of 3 grams of oral fosfomycin administered once every 48 or 72 hours for a total of 3 doses for patients who have previously failed treatment with another agent, are infected with a multidrug-resistant (MDR) pathogen, or cannot tolerate first-line treatment due to intolerance or adverse effects. Additionally, a Phase 2/3 clinical trial, known as the ZEUS study, assessed the efficacy and safety of intravenous (IV) fosfomycin versus piperacillin-tazobactam in the treatment of patients with complicated upper urinary tract infection (cUUTI) or acute pyelonephritis (AP) including in patients with concomitant bacteremia. IV fosfomycin was reported to be noninferior to piperacillin-tazobactam in treating patients with cUUTI and AP; however, when outcomes were independently evaluated according to baseline diagnosis (i.e., cUUTI versus AP), IV fosfomycin was superior to piperacillin-tazobactam in the treatment of patients with cUUTI and demonstrated superior microbiological eradication rates, across all resistant phenotypes including extended-spectrum β-lactamase- (ESBL-) producing Escherichia coli and Klebsiella spp. and carbapenem-resistant (CRE), aminoglycoside-resistant, and MDR Gram-negative bacilli (primarily Enterobacterales). Based on the ZEUS study, IV fosfomycin dosed at 6 grams every 8 hours for 7 days (14 days in patients with concurrent bacteremia) appears to be a safe and effective therapeutic option in treating patients with upper urinary tract infections, particularly those with cUUTI caused by antimicrobial-resistant Enterobacterales.

Effectiveness and Safety of High Dose Tigecycline for the Treatment of Severe Infections: A Systematic Review and Meta-Analysis.

BackgroundStudies assessing the effect of high dose tigecycline on severe infections are limited and remain controversial.ObjectivesTo assess systematically the effectiveness and safety of high dose tigecycline in the treatment of severe infections.MethodsPubmed, Web of Science, Embase, MEDLINE, Cochrane Library and ClinicalTrials were searched up to February 20, 2019 for studies that compared the effectiveness and safety of high dose tigecycline with standard dose tigecycline or other non-tigecycline-containing regimens in the treatment of severe infections. Rates for all-cause mortality, clinical cure, microbiological eradication and adverse events were analysed.ResultsTen studies with 593 patients were included. The results indicated that using high dose tigecycline resulted in better outcomes compared with controls with lower all-cause mortality (OR 0.44, 95% CI 0.30–0.66, p < 0.0001), higher clinical cure (OR 3.43, 95% CI 2.09–5.63, p < 0.00001), higher microbiological eradication (OR 2.25, 95% CI 1.44–3.50, p = 0.0003), and without increasing adverse events rates. Subgroup analysis showed that high dose tigecycline reduced all-cause mortality in nosocomial acquired pneumonia (OR 0.39, 95% CI 0.22–0.70, p = 0.002), bloodstream infections (OR 0.19, 95% CI 0.06–0.58, p = 0.004) and mixed infections (OR 0.20, 95% CI 0.07–0.59, p = 0.003), with no statistical differences in complicated intra-abdominal infections (OR 2.04, 95% CI 0.80–5.23, p = 0.14). In carbapenem-resistant pathogens, the microbiological eradication rate in those given high dose tigecycline did not differ from controls (OR 1.07, 95% CI 0.44–2.60, p = 0.87), although mortality was reduced (OR 0.20, 95% CI 0.09–0.45, p = 0.0001). The main limitation of the review is that most of the included studies are observational studies with small sample sizes and high risks of bias.ConclusionsHigh dose tigecycline treatment is effective and safe for severe infections owing to its lower all-cause mortality, higher clinical cure, microbiological eradication and comparable adverse events. However, as a result of the high risks of bias of the included studies, well-designed randomised clinical trials are warranted to establish the effectiveness and safety of high dose tigecycline compared with standard dose tigecycline and other commonly used antibiotics.

The use of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections and complicated urinary tract infections—A meta-analysis of randomized controlled trials

ObjectiveThe aim of this study was to assess the clinical efficacy and safety of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) in adult patients through meta-analysis. MethodsPubMed, Embase and Cochrane databases were searched up to June 2019. Only randomized controlled trials (RCTs) that evaluated ceftolozane-tazobactam and comparators for treating cIAIs and cUTIs in adult patients were included. Primary outcome was clinical cure rate; secondary outcomes were clinical failure rate, microbiological eradication rate, and risk of an adverse event (AE). ResultsThree RCTs were included. Overall, ceftolozane-tazobactam had a clinical cure rate similar to comparators in the microbiological intent-to-treat (mITT) population (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.43–1.79; I2 = 73%) and in the clinically evaluable (CE) population (OR, 1.22; 95% CI, 0.79–1.88; I2 = 0%). Furthermore, ceftolozane-tazobactam had a similar microbiological eradication rate for pathogens (OR, 1.31; 95% CI, 0.42–4.10; I2 = 37%). There were no significant differences in the risks of treatment-emergent AEs (OR, 1.04; 95% CI, 0.87–1.23; I2 = 0%), serious AEs (OR, 1.16; 95% CI, 0.67–1.99; I2 = 37%), discontinuation of study drug due to an AE (OR, 0.77; 95% CI, 0.17–3.47) and mortality (OR, 1.62; 95% CI, 0.69–3.77, I2 = 0%) between ceftolozane-tazobactam and comparators. ConclusionsThe clinical efficacy of ceftolozane-tazobactam is as high as that of comparators in the treatment of cIAIs and cUTIs in adult patients, and this antibiotic is well tolerated.

Novel β-Lactam/β-Lactamase Combination Versus Meropenem for Treating Nosocomial Pneumonia.

This study reports the integrated analysis of two phase III studies of novel β-lactam/β-lactamase combination versus meropenem for treating nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP). The ASPECT-NP trial compared the efficacy and safety of ceftolozane–tazobactam versus meropenem for treating NP/VAP. The REPROVE trial compared ceftazidime–avibactam and meropenem in the treatment of NP/VAP. A total of 1528 patients (361 in the ceftolozane–tazobactam group; 405 in the ceftazidime–avibactam group; 762 in the meropenem group) were analyzed. The clinical cure rates at test-of-cure among the novel β-lactam/β-lactamase combinations group were non-inferior to those of the meropenem (70.7% vs. 72.1%, risk difference (RD) −0.01, 95% confidence interval (CI) 0.06–0.05) in the clinical evaluable populations. Overall 28-day mortality did not differ between novel β-lactam/β-lactamase combinations and the meropenem group (RD, −0.02, 95% CI, −0.09 to 0.05). Regarding the microbiological eradication rate, novel β-lactam/β-lactamase combinations were non-inferior to meropenem for Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Staphylococcus marcescens, and Enterobacter cloacae. Finally, novel β-lactam/β-lactamase combinations had a similar risk of (i) treatment-emergent adverse events (RD, 0.02, 95% CI, −0.02 to 0.06), (ii) events leading to the discontinuation of the study drug (RD, 0.00, 95% CI, −0.02 to 0.03), (iii) severe adverse events (RD, 0.03, 95% CI, −0.01 to 0.07), and (iv) death (RD, 0.02, 95% CI, −0.02 to 0.05) when compared with meropenem group. In conclusion, our findings suggest that novel β-lactam/β-lactamase combinations of ceftolozane−tazobactam and ceftazidime–avibactam can be recommended as one of the therapeutic options in the treatment of NP/VAP.

Retrospective evaluation of the patients with urinary tract infections due to carbapenemase producing Enterobacteriaceae

In this study, we aimed to investigate retrospectively the patients with carbapenem-resistant Enterobacteriaceae urinary tract infections (UTIs) in the terms of demographic findings, antibiotic sensitivity patterns and clinical features along with the treatment options. This study was performed at a tertiary-care educational university hospital. Adult (>18 years old) patients diagnosed with culture proven UTI due to carbapenem-resistant Klebsiella pneumoniae (between December 2016 to December 2017) were included in the study. Antimicrobial susceptibility testing of the isolates was performed with the VITEK 2 system (bioMérieux). Resistance to imipenem, ertapenem, and meropenem was tested by E-test (bioMérieux). The results were interpreted according to the EUCAST criteria. A total number of 100 patients (34% female, mean age 61.69 ± 1.65 years) were included in this study. One month all-cause mortality rate was 19%. Microbiologic eradication rate was 88.7% while it was significantly higher in combination therapy (65/70 vs. 14/19, p = 0.019) and carbapenem long-lasting (4 h) infusion subgroups (54/56 vs. 2/56, p = 0.005). Relapse and reinfection rates were 61.7 and 29.7%, respectively. Logistic regression analysis for mortality risk factors resulted as history of ertapenem usage (OR: 4.74, 95% CI: 0.678–33.201, p = 0.117), lack of microbiologic eradication (OR: 21.7, 95% CI: 1.906–247.375, p = 0.013) and ICU stay (OR: 54.8, 95% CI: 4.145–726.324, p = 0.002). Combination, carbapenem long-lasting infusion and double carbapenem therapies seem to result in higher microbiologic eradication rates and thus may effect the mortality rates of these group of patients. Randomized-controlled studies should be performed in this critical patient group to confirm these results.

The Benefit of Individualized Vancomycin Dosing Via Pharmacokinetic Tools: A Systematic Review and Meta-analysis.

Background: Various pharmacokinetic (PK) equations and software have been developed to individualize vancomycin dosing. However, the benefit of using any PK information to guide vancomycin dosing has not been fully elucidated. Objective: To appraise available evidence on the effectiveness and safety of individualized vancomycin dosing via PK tools. Methods: PubMed, EMBASE, the Cochrane Library, and 2 Chinese literature databases were searched through August 1, 2019. Randomized controlled trials (RCTs) and cohort studies that reported the PK and clinical outcomes of individualized vancomycin dosing versus empirical dosing were included. Pooled risk ratios (RRs) and mean differences were calculated for dichotomous and continuous outcomes, respectively. Results: A total of 21 studies involving 4346 patients were finally included, of which 3 were RCTs and 18 were cohort studies. Meta-analysis revealed that PK-guided vancomycin dosing significantly increased the attainment of target trough concentration (RR = 1.59; 95% CI = 1.49-1.70) and decreased the incidence of nephrotoxicity (RR = 0.57; 95% CI = 0.46-0.71). Additionally, the available evidence showed that target area under the curve/minimum inhibitory concentration attainment rate and time to target concentration could improve. However, the evidence on clinical outcomes was scarce, and no significant differences were detected in clinical response rate, microbiological eradication rate, mortality, and length of hospital stay between PK-guided vancomycin dosing and empirical dosing strategies. Conclusion and Relevance: Individualized vancomycin dosing via PK tools significantly increases the attainment of target trough concentration and decreases the incidence of nephrotoxicity. Evidence on clinical effectiveness was limited and showed no significant benefit. Further well-designed studies are warranted to assess its clinical effectiveness and inform routine care.

Tigecycline in CR-Kp Associated VAP with High Dose vs. Conventional Dose: Adverse Events are the Key Superiority-determiner

Background: Multi-drug Resistant (MDR) pathogen Carbapenem-Resistance Klebsiella pneumonia (CR-Kp) associated Ventilator-Associated Pneumonia (VAP) is a serious infectious disease and tigecycline with high or conventional dose, is one of the last resort potential antibiotics for its treatment. Objective: The major objective of this study was to evaluate the key role of adverse events in preferring the better dosing option of tigecycline. Methods: Total 45 middle-aged MDR-CR-Kp associated VAP patients and treated with high (200 mg/day) and conventional dose (100 mg/day) of tigecycline (intravenous) distributed into two groups. Group-wise microbiological eradication rate, secondary infection rate, 30 days mortality rate and dose-related adverse events were analyzed and compared, accordingly. Result: After 5 days, highest microbiological eradication was observed in HD-group (79.17%) than CD-group (47.62%) with low rate of secondary infections (8.33% versus 33.33%). The 30 days mortality rate was relatively higher in HD-group (45.83% versus 38.10%). Severity and frequency of high-dose associated adverse events were higher in HD-group at all parameters than CD-group (elevation of ALT: 33.33%/23.81%; AST: 41.67%/28.57%; bilirubin: 37.50%/19.05%; reduction of blood pH: 45.83%/9.52%, respectively). Conclusion: High dose of tigecycline showed relatively higher therapeutic response in MDR-CR-Kp associated VAP treatment than conventional dose but, with increased rate of adverse events, which questioned its practice.

LB4. Efficacy and Safety of Cefiderocol vs. High-Dose Meropenem in Patients with Nosocomial Pneumonia—Results of a Phase 3, Randomized, Multicenter, Double-Blind, Non-Inferiority Study

BackgroundCefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. In this study, Day 14 all-cause mortality (ACM) rates were compared between CFDC and meropenem (MEM) in patients with nosocomial Gram-negative pneumonia.MethodsThe study (NCT03032380) was a Phase 3, international, double-blind, randomized, non-inferiority study in hospitalized patients with ventilator-associated, hospital-acquired, or healthcare-associated pneumonia caused by suspected Gram-negative bacteria. Patients were treated with CFDC (2 g, q8h) or MEM (2 g, q8h), both infused for 3 hours, for 7–14 days. Adjunctive linezolid (600 mg, q12h, ≥5 days) was given in both arms to cover Gram-positive bacteria. The primary endpoint was non-inferiority of CFDC to MEM for Day 14 ACM rate in the modified intent-to-treat population (mITT; non-inferiority margin: –12.5%). Key secondary endpoints were clinical and microbiological outcomes at test of cure (TOC), and Day 28 mortality. Safety was investigated up to 28 days after the end of treatment.ResultsIn the ITT population, 148 patients were randomized to CFDC and 150 to MEM: 59.7% were ventilated, 32.6% had failure of prior therapy, the median APACHE II score was 15, and 6.0% had concomitant Gram-negative bacteremia at baseline. In the mITT population, non-inferiority of CFDC to MEM for Day 14 ACM was demonstrated; CFDC: 12.4% (18 out of 145 patients) vs. MEM: 11.6% (17 out of 146 patients); treatment difference: 0.8; 95% confidence interval: –6.6; 8.2. Comparable Day 28 ACM (CFDC: 21.0% vs. MEM: 20.5%), clinical cure (CFDC: 64.8% vs. MEM: 66.7%), and microbiological eradication (CFDC: 47.6% vs. MEM: 48.0%) rates were demonstrated in the mITT population at TOC. Clinical cure rates for major target pathogens at TOC were similar between CFDC and MEM arms (figure). The rates of treatment-emergent adverse events (TEAEs), drug-related TEAEs, serious AEs, discontinuation due to TEAEs, and deaths were similar between treatment arms (table).ConclusionThis study demonstrated the non-inferiority of CFDC to high-dose MEM for the pre-specified endpoint of Day 14 ACM. No unexpected safety signals were observed in the study. DisclosuresRichard G. Wunderink, MD, Merck (Consultant, Grant/Research Support), Shionogi Inc. (Consultant), Yuko Matsunaga, MD, Shionogi Inc. (Employee), Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee), Roger Echols, MD, Shionogi Inc. (Consultant), Anju Menon, PhD, Shionogi Inc. (Employee), Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee).

Evaluation of the Therapeutic Effectiveness of Polymyxin B Versus Colistin in Carbapenem-resistanct Klebsiella pneumoniae-Associated Bacteremia

Polymyxins are the last resort antibiotics for treating carbapenem-resistance Klebsiella pneumoniae (CR-Kp)-associated bacteremia. The main aim of this study was to demonstrate the therapeutic effectiveness of polymyxin B versus colistin in the treatment of CR-Kp-associated Bacteremia. This 12-month long cross-sectional study was conducted on 54 and 47 patients suffering from CR-Kp-associated Bacteremia, and residing into two separate groups, they were treated with polymyxin B and colistin, respectively. After 5 day-treatment, the microbiological eradication rate was found 96.30% (52; n=54) in polymyxin B group and 87.23% (41; n=47) in colistin group. In the 30-day mortality rate-comparison, 51.03% more death was found in colistin group (34.04 %, n= 47) than the polymyxin B group (16.67 %, n= 54). In this study, Polymyxin B showed superior therapeutic potentiality with less number of secondary infections and 30-day mortality rate in CR-Kp-associated bacteremia than colistin.&#x0D; Dhaka Univ. J. Pharm. Sci. 18(2): 209-215, 2019 (December)

Efficacy and safety of high-dose tigecycline for the treatment of infectious diseases: A meta-analysis.

Background:High-dose (HD) tigecycline regimen is increasingly used in infectious diseases, however its efficacy and safety versus low-dose (LD) is still unclear.Methods:A systematic review and meta-analysis was performed; PubMed, Embase, Cochrane Library, ScienceDirect, Web of Science, clinicalTrials.gov, Wanfang, VIP, and China National Knowledge Infrastructure (CNKI), were searched using terms “tigecycline” AND “dose” up to October 31, 2018. Eligible studies were randomized trials or cohort studies comparing mortality, clinical response, microbiological eradication and safety of different tigecycline dose regimens for any bacterial infection. The primary outcome was mortality, and the secondary outcomes were clinical response rate, microbiological eradiation rate and adverse events (AEs). Meta-analysis was done with random-effects model, with risk ratios (RR) and 95% confidence intervals (CI) calculated for all outcomes.Results:Of 951 publications retrieved, 17 studies (n = 1041) were pooled in our meta-analysis. The primary outcome was available in 11 studies, and the RR for mortality was 0.67 (95% CI 0.53–0.84, P < .001). Clinical response (RR 1.46, 95% CI 1.30–1.65, P < .001) and microbiological eradication rate (RR 1.61, 95% CI 1.35–1.93, P < .001) were both higher in HD than in LD tigecycline regimen. However, non-Chinese study subgroup presented no statistical significance between HD and LD regimen, RR for mortality, clinical response and microbiological eradication were 0.79 (95% CI 0.56–1.14, P = .21), 1.35 (95% CI 0.96–1.92, P = .26), 1.00 (95% CI 0.22–4.43, P = 1.00), respectively. AEs did not differ between HD and LD tigecycline (RR 1.00, 95% CI 0.80–1.26, P = .97).Conclusion:HD tigecycline regimen reduced mortality meanwhile improved clinical efficacy and should be considered in serious infections caused by multidrug-resistant and extensively drug-resistant (MDR/XDR) bacteria.

Efficacy and safety of tigecycline in treatment of pneumonia caused by MDR Acinetobacter baumannii: a systematic review and meta-analysis.

Use of tigecycline in treating MDR Acinetobacter baumannii (MDRAB) remains controversial. To comprehensively assess the safety and efficacy of tigecycline in pneumonia caused by Acinetobacter baumannii. PubMed, Embase, Web of Science and Cochrane library databases were searched up to 12 March 2019. Studies were included if they compared tigecycline-based regimens with other antibiotic regimens for treating AB pulmonary infections and we pooled the clinical outcomes, microbiological response, adverse events or mortality. One prospective study and nine retrospective studies were included in this meta-analysis. The results showed similar clinical cure rates (OR = 1.04, 95% CI = 0.60-1.81; P = 0.89) and mortality rates (OR = 1.11, 95% CI = 0.65-1.89; P = 0.71) comparing tigecycline groups with the control groups. However, a significantly lower microbiological eradication rate was found in the tigecycline groups (OR = 0.43, 95% CI = 0.27-0.66; P = 0.0001). Incidence of nephrotoxicity in tigecycline-based regimens was significantly lower than in colistin-based regimens (OR = 0.34, 95% CI = 0.16-0.74, I2 = 35%, P = 0.006). There were no randomized controlled trials (RCTs) included; incomplete safety data and regional bias caused by the majority of the studies originating in China are the main limitations of this meta-analysis. Tigecycline can be used for treating MDRAB pulmonary infections owing to efficacy similar to that of other antibiotics. Moreover, tigecycline did not show a higher risk of mortality. Considering the lower microbiological eradication rate for tigecycline, which is likely to induce antimicrobial resistance, well-designed RCTs for high-dose tigecycline in treating pneumonia caused by AB are still needed.

The Efficacy and Safety of Doripenem in the Treatment of Acute Bacterial Infections-A Systemic Review and Meta-Analysis of Randomized Controlled Trials.

This study aims to assess the efficacy and safety of doripenem on treating patients with acute bacterial infections. The Pubmed, Embase, and Cochrane databases were searched up to April 2019. Only randomized clinical trials comparing doripenem and other comparators for the treatment of acute bacterial infection were included. The primary outcome was the clinical success rate and the secondary outcomes were microbiological eradication rate and risk of adverse events. Eight randomized controlled trials (RCTs) were included. Overall, doripenem had a similar clinical success rate with comparators (odds ratio [OR], 1.15; 95% CI, 0.79–1.66, I2 = 58%). Similar clinical success rates were noted between doripenem and comparators for pneumonia (OR, 0.84; 95% CI, 0.46–1.53, I2 = 72%) and for intra-abdominal infections (OR, 1.00; 95% CI, 0.57–1.72). For complicated urinary tract infection, doripenem was associated with higher success rate than comparators (OR, 1.89, 95% CI, 1.13–3.17, I2 = 0%). The pool analysis comparing doripenem and other carbapenems showed no significant differences between each other (OR, 0.96, 95% CI, 0.59–1.58, I2 = 63%). Doripenem also had a similar microbiological eradication rate with comparators (OR, 1.08; 95% CI, 0.86–1.36, I2 = 0%). Finally, doripenem had a similar risk of treatment-emergent adverse events as comparators (OR, 0.98; 95% CI, 0.83–1.17, I2 = 33%). In conclusion, the clinical efficacy of doripenem is as high as that of the comparator drugs in the treatment of acute bacterial infection; furthermore, this antibiotic is as well tolerated as the comparators.