Treatment Of Serious Gram-negative Infections Research Articles

In vitro activity of imipenem/relebactam against piperacillin/tazobactam-resistant and meropenem-resistant non-Morganellaceae Enterobacterales and Pseudomonas aeruginosa collected from patients with bloodstream, intra-abdominal and urinary tract infections in Western Europe: SMART 2018-2020.

Introduction. Piperacillin/tazobactam and carbapenems are important agents for the treatment of serious Gram-negative infections in hospitalized patients. Resistance to both agents is a significant concern in clinical isolates of Enterobacterales and Pseudomonas aeruginosa; new agents with improved activity are needed.Gap Statement. Publication of current, region-specific data describing the in vitro activity of newer agents such as imipenem/relebactam (IMR) against piperacillin/tazobactam-resistant and carbapenem-resistant Enterobacterales and P. aeruginosa are needed to support their clinical use.Aim. To describe the in vitro activity of IMR against non-Morganellaceae Enterobacterales (NME) and P. aeruginosa isolated from bloodstream, intra-abdominal and urinary tract infection samples by hospital laboratories in Western Europe with a focus on the activity of IMR against piperacillin/tazobactam-resistant and meropenem-resistant isolates.Methodology. From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 9487 NME and 1004 P. aeruginosa isolates. MICs were determined by CLSI broth microdilution testing and interpreted by EUCAST (2021) breakpoints. β-Lactamase genes were identified in selected isolate subsets (2018-2020) and oprD sequenced in molecularly characterized P. aeruginosa (2020).Results. IMR (99.4 % susceptible), amikacin (98.0 %), meropenem (97.7 %) and imipenem (97.6 %) were the most active agents against NME; 83.1 % of NME were piperacillin/tazobactam-susceptible. Relebactam increased imipenem susceptibility of NME from Italy by 8.3 %, from Portugal by 2.9 %, and from France, Germany, Spain and the UK by <1 %. In total, 96.4 % of piperacillin/tazobactam-resistant (n=1601) and 73.7 % of meropenem-resistant (n=152) NME were IMR-susceptible. Also, 0.4 % of NME were MBL-positive, 0.9 % OXA-48-like-positive (MBL-negative) and 1.5 % KPC-positive (MBL-negative). Amikacin (95.4 % susceptible) and IMR (94.1 %) were the most active agents against P. aeruginosa; 81.7 % of isolates were imipenem-susceptible and 79.6 % were piperacillin/tazobactam-susceptible. Relebactam increased susceptibility to imipenem by 12.5 % overall (range by country, 4.3-17.5 %); and by 30.7 % in piperacillin/tazobactam-resistant and 24.3 % in meropenem-resistant P. aeruginosa. In total, 1.6 % of P. aeruginosa isolates were MBL-positive. Seven of eight molecularly characterized IMR-resistant P. aeruginosa isolates from 2020 were oprD-deficient.Conclusion. IMR may be a potential treatment option for bloodstream, intra-abdominal and urinary tract infections caused by NME and P. aeruginosa in Western Europe, including infections caused by piperacillin/tazobactam-resistant and meropenem-resistant isolates.

Role of new antibiotics in extended-spectrum β-lactamase-, AmpC- infections.

Extended-spectrum β-lactamases (ESBL)- and ampicillinase class C (AmpC)-producing Enterobacterales represent one of the major public threats of the current era. As a consequence, during the last decades there have been great efforts to develop new therapeutic agents against these microorganisms. The aim of this review is to summarize the clinical features associated with novel antibiotics with activity against ESBL- and AmpC-producing isolates. There a number of therapeutic agents with activity against ESBL and AmpC than have been introduced and approved over the past few years. Ceftazidime-avibactam and ceftolozane-tazobactam are both carbapenem sparing agents that appear interesting alternatives for treatment of serious Gram-negative infections. Other new β-lactams/ β-lactamase inhibitors (e.g. cefepime-enmetazobactam; ceftaroline fosamil-avibactam; aztreonam-avibactam and cefepime-zidebactam) as well as eravacycline, omadacycline, and plazomicin are also promising agents for treatment of ESBL- and AmpC- infections, but further clinical data are needed to establish their efficacy in comparison to carbapenems. The role of carbapenems/ β-lactamase inhibitors remains to be clarified. New therapeutic agents against ESBL- and AmpC-producing Enterobacterales have distinctive specificities and limitations that require further investigations. Future randomized clinical trials are required to define the best strategy for their use in patients with serious infections due to ESBL- and/or AmpC- infections.

Ceftazidime-Avibactam for the Treatment of Serious Gram-Negative Infections with Limited Treatment Options: A Systematic Literature Review.

IntroductionA systematic literature review was undertaken to evaluate real-world use of ceftazidime-avibactam for infections due to aerobic Gram-negative organisms in adults with limited treatment options.MethodsLiterature searches retrieved peer-reviewed publications and abstracts from major international infectious disease congresses from January 2015 to February 2021. Results were screened using pre-defined criteria to limit the dataset to relevant publications (notable exclusions were paediatric data and outcomes data for bacteria intrinsically resistant to ceftazidime-avibactam). Data for included publications were subjected to qualitative synthesis.ResultsSeventy-three relevant publications (62 peer-reviewed articles; 10 abstracts) comprising 1926 patients treated with ceftazidime-avibactam (either alone or combined with other antimicrobials) and 1114 comparator/control patients were identified. All patients were hospitalised for serious illness and most had multiple comorbidities. The most common infections were pneumonia, bacteraemia, and skin/soft tissue, urinary tract, or abdominal infections; smaller numbers of patients with meningitis, febrile neutropenia, osteomyelitis, and cystic fibrosis were also included. Carbapenem-resistant or carbapenemase-producing Enterobacterales (CRE; n = 1718) and carbapenem-resistant, multidrug-resistant (MDR), and extensively drug-resistant Pseudomonas aeruginosa (n = 150) were the most common pathogens. Most publications reported positive outcomes for ceftazidime-avibactam treatment (clinical success rates ranged from 45 to 100% and reported 30-day mortality from 0 to 63%), which were statistically superior versus comparators in some studies. ceftazidime-avibactam resistance emergence occurred infrequently and mostly in Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains.ConclusionThis review provides qualitative evidence of successful use of ceftazidime-avibactam for the treatment of hospitalised patients with CRE and MDR P. aeruginosa infections with limited treatment options.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00507-6.

Genetic diversity and prevalence of aminoglycoside modifying enzymes among Escherichia coli strains isolated from inpatients with urinary tract infections

The aminoglycosides are broad-spectrum antibiotics that traditionally prescribed for the treatment of serious Gram-negative infections. The main mechanism of resistance to these antibiotics in Escherichia coli is enzymatic alteration of aminoglycosides by aminoglycoside-modifying enzymes (AMEs). The present study aimed to investigate the genetic diversity and prevalence of aminoglycoside-resistant strains of E. coli isolated from inpatients with urinary tract infection. This cross-sectional study was conducted during September 2018 to March 2019 on a total of 83 non-susceptible aminoglycosides E. coli in the North of Iran. Antimicrobial susceptibility test was performed by disk diffusion method. The presence of genes encoding aminoglycoside modifying enzymes (AMEs) was detected by PCR. The clonal relatedness of E. coli isolates was investigated by ERIC-PCR. Totally, 66.3% and 43.4% of isolates were non-susceptible to gentamicin and amikacin, respectively. The most common AME gene was aac(6′)-Ib (49.4%) followed by aac(3)-II (39.8%), ant(3″)-I (8.4%) and aph(3′)-VI (1.2%). Moreover, aac(6′)-II gene was not found among studied strains. All of the extended-spectrum beta-lactamases (ESBLs) producing isolates (55 isolates) were tested by ERIC-PCR. These isolates were classified into 10 ERIC types, and ERIC type A were the predominate type containing 52.7% of isolates. Findings showed a substantial proportion of AMEs among aminoglycosides-resistant UPEC isolates. Moreover, the clonal analysis showed that a remarkable rate (52.7%) of aminoglycosides-resistant and ESBL-producing isolates was closely related. These findings suggest the necessity of restricted infection control policy to prevent further dissemination of resistant strains.

An Appraisal of the Pharmacokinetic and Pharmacodynamic Properties of Meropenem-Vaborbactam.

Carbapenem-resistant gram-negative pathogens remain an urgent public health threat, and safe, effective treatment options are limited. Although several agents are now available to combat these infections, meropenem-vaborbactam was the first to combine a novel, cyclic, boronic acid-based, β-lactamase inhibitor with a carbapenem backbone. Vaborbactam emanated from a discovery program specifically designed to identify candidate β-lactamase inhibitors with biochemical, microbiologic, and pharmacologic properties optimized for use in conjunction with a carbapenem. Meropenem was selected as the ideal carbapenem given its broad-spectrum in vitro activity, well established safety profile, and proven efficacy in the treatment of serious gram-negative infections. The combination has demonstrated potent in vitro activity against resistant gram-negative pathogens, particularly KPC-producing Klebsiella pneumoniae (MIC50 values typically ≤ 0.06 mg/l). Importantly, the pharmacokinetic (PK) profiles of the two agents are well matched, and the approved optimized dosing regimen of 4 g every 8 h (Q8h) as a 3-h infusion provides reliable probability of target attainment against the majority of commonly encountered carbapenem-resistant Enterobacteriaceae (CRE). Robust in vitro and in vivo PK/pharmacodynamic (PD) data support the ability of this dosing regimen to achieve specified PK/PD targets for both bactericidal activity and prevention of resistance among pathogens with MICs up to 8 mg/l. This concerted effort into optimizing the PK and PD parameters of both the β-lactam and β-lactamase inhibitor alone and in combination contributed to the clinical success of meropenem-vaborbactam demonstrated in phase 3 trials in patients with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), and serious CRE infections. As the use of meropenem-vaborbactam increases concomitantly with the prevalence of KPC-producing CRE, continued pharmacovigilance and antimicrobial stewardship efforts will be of upmost importance to ensure that these PK/PD efforts translate into improved patient outcomes.

Pharmacokinetics-Pharmacodynamics of Enmetazobactam Combined with Cefepime in a Neutropenic Murine Thigh Infection Model.

Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae are classified as critical priority pathogens, with extended-spectrum β-lactamases (ESBLs) as principal resistance determinants. Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empirical treatment of serious Gram-negative infections in settings where ESBLs are prevalent. Cefepime-enmetazobactam has been investigated in a phase 3 trial in patients with complicated urinary tract infections or acute pyelonephritis. This study examined pharmacokinetic-pharmacodynamic (PK-PD) relationships of enmetazobactam, in combination with cefepime, for ESBL-producing isolates of Klebsiella pneumoniae in 26-h murine neutropenic thigh infection models. Enmetazobactam dose fractionation identified the time above a free threshold concentration (fT > CT ) as the PK-PD index predictive of efficacy. Nine ESBL-producing isolates of K. pneumoniae, resistant to cefepime and piperacillin-tazobactam, were included in enmetazobactam dose-ranging studies. The isolates encoded CTX-M-type, SHV-12, DHA-1, and OXA-48 β-lactamases and covered a cefepime-enmetazobactam MIC range from 0.06 to 2 μg/ml. Enmetazobactam restored the efficacy of cefepime against all isolates tested. Sigmoid curve fitting across the combined set of isolates identified enmetazobactam PK-PD targets for stasis and for a 1-log10 bioburden reduction of 8% and 44% fT > 2 μg/ml, respectively, with a concomitant cefepime PK-PD target of 40 to 60% fT > cefepime-enmetazobactam MIC. These findings support clinical dose selection and breakpoint setting for cefepime-enmetazobactam.

Minocycline Intravenous for the Treatment of Serious Infections Due to Gram-Negative Nonpseudomonal Bacteria, Including Stenotrophomonas maltophilia, Acinetobacter baumannii, and Burkholderia cepacia

Background Data on the role of minocycline intravenous (IV) in the treatment of serious gram-negative infections under real-world conditions are sparse. This study sought to provide evidence of real-world practices, including outcomes and safety. Methods A multicenter observational study was conducted of 71 consecutive adult inpatients enrolled at 6 geographically diverse US hospitals between May 2015 and February 2018 who were treated with minocycline IV for gram-negative infections for at least 48 hours as monotherapy or combination therapy. Results Infections included pneumonia (51%) and bacteremia (25%). The most prevalent gram-negative pathogens included Stenotrophomonas maltophilia (52%), Acinetobacter baumannii (30%), and Burkholderia complex (10%). In vitro susceptibility to minocycline was 100% for S. maltophilia. Clinical plus microbiologic response was observed in 80% of evaluable patients. Treatment of 29 evaluable patient infections due to S. maltophilia resulted in a clinical response rate of 79% and a microbiologic response rate of 72%. All patients with bacteremia due to S. maltophilia responded to minocycline IV. There were 17 (24%) in-hospital deaths of which 8 responded to minocycline. Minocycline was well tolerated. Conclusions Minocycline demonstrated that high in vitro susceptibility against problematic gram-negative pathogens and administered as an IV formulation was associated with good clinical and microbiologic outcomes alone or in combination in a seriously ill patient population.

Pharmacologic optimization of antibiotics for Gram-negative infections.

Antimicrobial resistance among Gram-negative organisms is a rapidly escalating global challenge. Pharmacologic dose optimization based on pharmacokinetic/pharmacodynamic principles is essential for managing Gram-negative infections. High-risk patient populations may receive nonoptimized antimicrobial dosing because pf physiologic changes in acute illness and/or medical interventions. The purpose of this review is to discuss opportunities for pharmacologic optimization of new agents and highlight patient populations that are often associated with poor drug exposure profiles. Dose optimization of the novel β-lactam-β-lactamase inhibitor combinations has been evaluated through optimizing exposure at the site of infection, evaluating target attainment of both the β-lactam and the β-lactamase-inhibitor in critically ill patients, and evaluating drug exposure to prevent the development of resistance. Plazomicin, a novel aminoglycoside, has pharmacodynamic optimization potential via therapeutic drug monitoring and nomogram-based dosing. Recent studies have evaluated the adequacy of dosing in varying degrees of renal function specifically acute kidney injury, continuous renal replacement therapy (CRRT), and augmented renal clearance (ARC). The application of fundamental pharmacokinetic/pharmacodynamic principles is required to optimize new antimicrobials in the treatment of serious Gram-negative infections. Exposure at the site of infection, pharmacokinetics in critically ill patients, and exposures to prevent resistance are all considerations to improve microbiologic and clinical outcomes. Therapeutic drug monitoring may be needed for high-risk patients.

Meropenem–nacubactam activity against AmpC-overproducing and KPC-expressing Pseudomonas aeruginosa in a neutropenic murine lung infection model

Nacubactam is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor under development for the treatment of serious Gram-negative infections. This study assessed the efficacy of human-simulated epithelial lining fluid (ELF) exposure of nacubactam in combination with meropenem against AmpC-overproducing (n=4) and Klebsiella pneumoniae carbapenemase (KPC)-expressing (n=3) Pseudomonas aeruginosa isolates in the neutropenic murine lung infection model. Meropenem, nacubactam and meropenem-nacubactam (1:1 concentration ratio) minimum inhibitory concentrations (MICs) were determined in triplicate using broth microdilution. Regimens that provided ELF profiles mimicking those observed in humans given nacubactam 2 g q8h (1.5-h infusion) alone and in combination with a subtherapeutic ELF exposure of meropenem were administered 2 h after inoculation. Efficacy was assessed as the change in log10 colony-forming units (CFU)/lung at 24 h compared with 24-h meropenem monotherapy. Meropenem, nacubactam and meropenem-nacubactam MICs were 8->64, 128->256 and 2-16 mg/L, respectively. Meropenem and nacubactam monotherapy groups demonstrated bacterial growth over 24 h for each isolate. Against AmpC-overproducing and KPC-expressing P. aeruginosa isolates, meropenem-nacubactam resulted in -2.73±0.93 and -4.35±1.90 log10CFU/lung reduction, respectively, relative to meropenem monotherapy. Meropenem-nacubactam showed promising in-vivo activity against meropenem-resistant P. aeruginosa, indicative of a potential role for the treatment of infections caused by these challenging pathogens.

1477. A Randomized Phase 2 Study of Cefepime Combined with the Novel Extended Spectrum β-Lactamase Inhibitor Enmetazobactam in Hospitalized Adults with Complicated Urinary Tract Infections (cUTI) Including Acute Pyelonephritis (AP)

BackgroundThird-generation cephalosporin (3GC)-resistant Enterobacteriaceae has been classified as critical priority pathogens. The novel extended-spectrum β-lactamase (ESBL) inhibitor enmetazobactam (formerly AAI101; EMT) in combination with cefepime (FEP) is currently being developed as a carbapenem-sparing treatment of serious Gram-negative infections in settings with a high prevalence of 3GC-resistant Enterobacteriaceae. We report here the results from a phase 2 study that assessed safety, tolerability, and pharmacokinetics of FEP-EMT in patients with cUTI/AP.MethodsForty-five patients were enrolled in a randomized, multicenter, double-blind study of hospitalized adults with cUTI/AP. Patients received dosing regimens of FEP or FEP-EMT IV therapy q8h by 2 hours infusion (table) for 7 to 10 days with a 28-day follow-up. Efficacy was evaluated in the microbiological-modified ITT (µMITT) population. Safety was monitored in patients who received at least 1 dose of study drug. Clinical cure was designated as the resolution of cUTI symptoms present at study entry. Plasma and urine PK were determined from all patients.ResultsThe study drugs were well tolerated in each cohort, with similar % adverse events and no new or unexpected safety concerns (table). Two discontinuations were due to allergic dermatitis. The microbiological- and clinical responses at test-of-cure for the combined FEP-EMT group were 83.3% (20/24) and 95.8% (23/24) compared with responses in the combined FEP group of 73.3% (11/15) and 93.3% (14/15), respectively (table). The most common baseline pathogens were Escherichia coli (66.7%) and Klebsiella pneumoniae (23.1%): 28.2% of isolates produced ESBLs with eradication rates for the combined FEP-EMT group of 85.7% (6/7) and for the combined FEP group of 75.0% (3/4). FEP and EMT PK were best described by a 2-compartment, linear PK model. Both agents exhibited half-lives of 2.3 hours. Creatinine clearance had a significant covariate effect on FEP and EMT, consistent with predominant renal excretion of both agents.ConclusionResults from this phase 2 study justify advancement to phase 3 studies to evaluate the safety and efficacy of FEP-EMT in patients with cUTI/AP.Disclosures All authors: No reported disclosures.

Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects

BackgroundCefiderocol, a novel siderophore cephalosporin, has shown potent activity against Gram-negative bacteria, including MDR pathogens. Cefiderocol is under clinical investigation for the treatment of serious Gram-negative infections including nosocomial pneumonia.ObjectivesThis study assessed intrapulmonary penetration after a single intravenous dose of cefiderocol (2000 mg infused over 60 min) in healthy adult males.Materials and methodsEach subject underwent one bronchoscopy with bronchoalveolar lavage (BAL) to collect BAL fluid (BALF). Fifteen subjects were assigned to one of three collection timepoints (1, 2 or 4 h from start of infusion). Five additional subjects were assigned to a collection timepoint at 6 h, which was added based on concentration data between 1 and 4 h predicting measurable BALF cefiderocol concentrations at 6 h.ResultsCefiderocol concentrations in plasma, epithelial lining fluid (ELF) and alveolar macrophages (AMs) were calculated for each subject. The ELF concentration of cefiderocol was 13.8, 6.69, 2.78 and 1.38 mg/L at 1, 2, 4 and 6 h after single intravenous dosing, respectively. Over 6 h, geometric mean concentration ratios ranged from 0.0927 to 0.116 for ELF to total plasma and from 0.00496 to 0.104 for AMs to total plasma. AUC ratios of ELF and AMs to plasma were 0.101 and 0.0177 based on total drug in plasma, respectively, and 0.239 and 0.0419 based on free drug in plasma, respectively. There were no major drug-related adverse events.ConclusionsResults of this study indicate that cefiderocol penetrates into ELF, and ELF and plasma concentrations appear to be parallel.

Polymyxins Nebulization over Intravenous Injection: Pharmacokinetics and Pharmacodynamics-Based Therapeutic Evaluation

Polymyxins are the last line potential antibiotics against multi-drug resistant gram-negative bacteria and consist of two sister antibiotics: Polymyxin B and colistin (polymyxin E). Intravenous use of polymyxins was started from a long ago in the treatment of serious gram-negative infections and once their uses were restricted due to potential adverse drug reactions, such as nephrotoxicity and neurotoxicity. Lack of in vivo clinical studies on polymyxins mostly, in human body makes the pharmacokinetics and pharmacodynamics of polymyxin B and colistin unclear in many aspects, such as the distribution of polymyxins in different compartments of lung. The nebulization of polymyxins is practicing very limitedly and lack of clinical evidence has not justified this administration technique yet properly to date. The main objective of this review study was to evaluate the pharmacokinetic and pharmacodynamic properties of intravenous and nebulized polymyxins and the related therapeutic potentialities. Aerosolized polymyxins directly administered to the respiratory tract was found with higher drug concentration in different subcompartments of lungs than the intravenous administration and sustainably meets the minimum inhibitory concentration locally with superior bactericidal properties in respiratory tract infections. In contrast, intravenous administration of polymyxins shows similar anti-infective superiority in other organs, such as blood, urinary tract etc. So, during this alarming situation of rapidly emerging multidrug-resistant organisms in human communities, therapeutic administration techniques of last resort polymyxins should be clinically evidence-based for achieving optimum therapeutic outcomes with minimum chance of adverse drug reactions.

Tebipenem, the first oral carbapenem antibiotic

ABSTRACTIntroduction: Infections caused by antibiotic-resistant pathogens, particularly Gram-negative bacteria, have become increasingly challenging to successfully treat. The beta-lactam antibiotic subclass, the carbapenems, have proven valuable for the treatment of such Gram-negative bacterial infections due to their spectrum and β-lactamase stability properties. However, all marketed carbapenems to date are parenterally administered to adult patients.Areas covered: One carbapenem, tebipenem-pivoxil (TBPM-PI), is an oral prodrug that was approved in Japan for pediatric use only in 2009. This review summarizes preclinical and clinical data for TBPM-PI, which is now in clinical development again this time for use as the first oral carbapenem available for treatment of bacterial infections in adult patients.Expert commentary: There is an urgent unmet need with an increasing prevalence of fluoroquinolone-resistant and ESBL-producing Gram-negative pathogens in the hospital and community setting. Carbapenems have traditionally been considered the drugs of choice for infections caused by enterobacteria producing ESBL and AmpC enzymes because they are not affected by these resistance mechanisms. The carbapenem, TBPM-PI, offers an oral option, particularly as step-down therapy, for use of this class in the treatment of serious Gram-negative infections.

Determination of Disk Diffusion and MIC Quality Control Guidelines for High-Dose Cefepime-Tazobactam (WCK 4282), a Novel Antibacterial Combination Consisting of a β-Lactamase Inhibitor and a Fourth-Generation Cephalosporin.

High-dose cefepime-tazobactam (1:1; WCK 4282), a novel antibacterial combination consisting of the β-lactamase inhibitor tazobactam and a fourth-generation cephalosporin, is under clinical development for the treatment of serious Gram-negative infections. A quality control (QC) study was performed to establish disk diffusion and MIC ranges for cefepime-tazobactam for multiple QC reference strains. The cefepime-tazobactam QC ranges for a fixed tazobactam MIC of 8 μg/ml and disk diffusion (30/20-μg disk) test methods were approved by the CLSI Subcommittee on Antimicrobial Susceptibility Testing in January 2015 and January 2016. These QC ranges will be important for accurate in vitro activity evaluations of cefepime-tazobactam when tested against clinical Gram-negative bacteria during clinical studies and routine patient care.

Effects of atorvastatin on biomarkers of acute kidney injury in amikacin recipients: A pilot, randomized, placebo-controlled, clinical trial.

Background:The most common clinical indication of aminoglycosides (AG) is the treatment of serious Gram-negative infections. The aim of this study was to evaluate plausible effects of atorvastatin on the biomarkers of acute kidney injury (AKI) in patients receiving amikacin.Materials and Methods:In this double-blinded randomized clinical trial, fifty patients (25 in each group) receiving amikacin (15 mg/kg/day) were randomly assigned to either atorvastatin (40 mg/day) or placebo (40 mg/day) groups for 7 days. Blood urea nitrogen (BUN), serum creatinine (SCr), and urinary neutrophil gelatinase-associated lipocalin (NGAL) levels were measured at days 0, 1, and 7 of amikacin treatment.Results:During the study period, 4 (8%) patients including two patients in each atorvastatin and placebo group experienced AKI. Urine NGAL/urine Cr did not change significantly between and within placebo and atorvastatin groups during the study period. Similarly, the mean changes in SCr, BUN, and urine NGAL/urine Cr values did not differ significantly between and within patients with and without AKI.Conclusion:Our data suggested that the changing pattern of urine NGAL/urine Cr ratio did not differ significantly between the atorvastatin and placebo groups during the early phase of amikacin treatment.

Thrice-weekly temocillin administered after each dialysis session is appropriate for the treatment of serious Gram-negative infections in haemodialysis patients

In patients with end-stage renal disease (ESRD) treated with intermittent haemodialysis, a limited number of antibiotics have been studied for their suitability for parenteral administration after dialysis sessions only in a thrice-weekly regimen. Temocillin is a β-lactam antibiotic with a long half-live and enhanced activity against most Gram-negative bacteria, including extended-spectrum β-lactamase-producers, thus making it an ideal candidate for use in this setting. This study aimed to evaluate the reliability of thrice-weekly parenteral temocillin in haemodialysis patients by characterising the pharmacokinetics of total and free temocillin. Free and total temocillin concentrations were determined with a validated HPLC method in 448 samples derived from 48 administration cycles in 16 patients with ESRD treated with intermittent haemodialysis and temocillin. Pharmacokinetics were non-linear partly due to saturation in protein binding. Median clearance and half-life for the free drug during intradialysis and interdialysis periods were 113mL/min vs. 26mL/min and 3.6h vs. 24h, respectively, with dialysis extracting approximately one-half of the residual concentration. The free temocillin concentration remained >16mg/L (MIC90 threshold for most Enterobacteriaceae) during 48%, 67% and 71% of the dosing interval for patients receiving 1g q24h, 2g q48h and 3g q72h, respectively, suggesting appropriate exposure for the two latter therapeutic schemes. Temocillin administered on dialysis days only in a dosing schedule of 2g q48h and 3g q72h is appropriate for the treatment of serious and/or resistant Gram-negative infections in patients with ESRD undergoing intermittent haemodialysis. These doses are higher than those previously recommended.

Cefepime and Ceftazidime Safety in Hospitalized Infants.

Cefepime and ceftazidime are cephalosporins used for the treatment of serious Gram-negative infections. These cephalosporins are used off-label in the setting of minimal safety data for young infants. We identified all infants discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012 who were exposed to either cefepime or ceftazidime in the first 120 days of life. We reported clinical and laboratory adverse events occurring in infants exposed to cefepime or ceftazidime and used multivariable logistic regression to compare the odds of seizures and death between the 2 groups. A total of 1761 infants received 13,293 days of ceftazidime, and 594 infants received 4628 days of cefepime. Laboratory adverse events occurred more frequently on days of therapy with ceftazidime than with cefepime (373 vs. 341 per 1000 infant days, P < 0.001). Seizure was the most commonly observed clinical adverse event, occurring in 3% of ceftazidime-treated infants and 4% of cefepime-treated infants (P = 0.52). Mortality was similar between the ceftazidime and cefepime groups (5% vs. 3%, P = 0.07). There was no difference in the adjusted odds of seizure [odds ratio (OR) = 0.96 (95% confidence interval: 0.89-1.03)] or the combined outcome of mortality or seizures [OR = 1.00 (0.96-1.04)] in infants exposed to ceftazidime versus those exposed to cefepime. In this cohort of infants, cefepime was associated with fewer laboratory adverse events than ceftazidime, although this may have been due to a significant difference in clinical exposures and severity of illness between the 2 groups. There was no difference in seizure risk or mortality between the 2 drugs.

Antimicrobial Treatment of Serious Gram-Negative Infections in Newborns

The choice of antibiotics for serious Gram-negative bacterial infections in the newborn must balance delivery of effective antibiotics to the site(s) of infection with the need to minimize selection of antibiotic resistance. To reduce the risk of selective pressure from large-scale cephalosporin usage, a penicillin-aminoglycoside combination is recommended as empiric therapy for neonatal sepsis. Where Gram-negative sepsis is strongly suspected or proven, a third-generation cephalosporin should ordinarily replace penicillin. Piperacillin-tazobactam can provide better Gram-negative cover than penicillin-aminoglycoside combinations, without the risk of selecting antibiotic resistance seen with cephalosporins, but further clinical studies are required before this approach to empiric therapy can be recommended. For antibiotic-resistant infections, a carbapenem remains the mainstay of treatment. However, rapid emergence and spread of resistance to these antibiotics means that in the future, neonatologists may have to rely on antibiotics such as colistin, whose pharmacokinetics, safety, and clinical efficacy in neonates are not well-defined.

Sildenafil Ameliorates Gentamicin-Induced Nephrotoxicity in Rats: Role of iNOS and eNOS.

Gentamicin, an aminoglycoside antibiotic, is used for the treatment of serious Gram-negative infections. However, its usefulness is limited by its nephrotoxicity. Sildenafil, a selective phosphodiesterase-5 inhibitor, was reported to prevent or decrease tissue injury. The aim of this study is to evaluate the potential protective effects of sildenafil on gentamicin-induced nephrotoxicity in rats. Male Wistar rats were injected with gentamicin (100 mg/kg/day, i.p.) for 6 days with and without sildenafil. Sildenafil administration resulted in nephroprotective effect in gentamicin-intoxicated rats as it significantly decreased serum creatinine and urea, urinary albumin, and renal malondialdehyde and nitrite/nitrate levels, with a concomitant increase in renal catalase and superoxide dismutase activities compared to gentamicin-treated rats. Moreover, immunohistochemical examination revealed that sildenafil treatment markedly reduced inducible nitric oxide synthase (iNOS) expression, while expression of endothelial nitric oxide synthase (eNOS) was markedly enhanced. The protective effects of sildenafil were verified histopathologically. In conclusion, sildenafil protects rats against gentamicin-induced nephrotoxicity possibly, in part, through its antioxidant activity, inhibition of iNOS expression, and induction of eNOS production.

Disposition and Metabolism of GSK2251052 in Humans: A Novel Boron-Containing Antibiotic

(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gram-negative infections. In this study, six healthy adult male subjects received a single i.v. dose of [¹⁴C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite.