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Cefiderocol is a new cephalosporin with a catechol in its chemical structure faciliting its access to the interior of bacteria through iron channels. In addition, it is broadly stable to beta-lactamases. The pharmacokinetic profile is a beta-lactam one: no oral absorption, and with a wide distribution within the vascular space and the interstitial fluid of well vascularized tissues, reaching therapeutic concentrations in the alveolar lavage fluid and within the macrophage. The binding of cefiderocol to human plasma proteins, primarily albumin, is moderate (range 40-60%). The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. Cefiderocol is mainly renally eliminated, so dose adjustments are recommended in subjects with moderate / severe renal impairment, in case of dialysis, and probably in patients with external clearance. Like other beta-lactams, the PK / PD parameter that has been shown to best correlate with efficacy is the efficacy time of unbound plasma concentrations (%fT>MIC), which must be close to 100% to achieve a bactericidal effect. This is possible with 2 g in a 3-hour infusion every 8 hours. In controlled trials appears to be well tolerated, similar to comparators: meropenem or imipenem-cilastatin. Cefiderocol has no apparent clinically significant effect on ECG parameters nor on plasma iron values.

Background Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies. Methods We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans. Results We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, β-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx. Conclusions These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.

ObjectivesThe addition of novel β-lactamase inhibitors to carbapenems restores the activity against multidrug-resistant Gram-negative bacteria. The aim of this study was to summarize the evidence on the efficacy and safety of novel carbapenem–β-lactamase inhibitor combinations.MethodsWe conducted a meta-analysis of clinical trials comparing novel carbapenem–β-lactamase inhibitor combinations with comparators to assess the clinical and microbiological responses, mortality, and adverse events (AEs).ResultsA total of 1,984 patients were included. The pooled risk ratios (RRs) of clinical cure, microbiological eradication, all-cause mortality, and 28-day mortality were 1.11 (95% CI: 0.98–1.26), 0.98 (95% CI: 0.82–1.16), 0.90 (95% CI: 0.49–0.94), and 0.68 (95% CI: 0.49–0.94) between the novel carbapenem–β-lactamase inhibitor combinations and control groups. Sensitivity analysis revealed that the phase II trial of imipenem–cilastatin/relebactam (ICR) against complicated urinary tract infections could be the most important factor of heterogeneity for the microbiological response. The therapeutic effect of novel carbapenem–β-lactamase inhibitor combinations was better in meropenem–vaborbactam (MEV), phase III trials, and number of patients less than 200. The RRs of AEs from any cause and serious adverse events (SAEs) for patients receiving novel carbapenem–β-lactamase inhibitor combinations were 0.98 (95% CI: 0.93–1.04) and 1.01 (95% CI: 0.75–1.36), respectively.ConclusionsICR and MEV were superior to comparators for clinical cure and survival rate in the treatment of complicated infections, and both were as tolerable as the comparators.

Background. Antibiotic dosing in critically ill patients is complicated by variations in the pharmacokinetics of antibiotics in this group. The dosing of imipenem/cilastatin is usually determined by severity of illness and renal function.Objectives. To determine the correlation between estimated glomerular filtration rates (eGFRs) calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and imipenem trough levels in critically ill patients.Methods. This prospective observational study was done in the surgical intensive care unit (ICU) at Steve Biko Academic Hospital, Pretoria, South Africa. Imipenem trough levels were measured by high-performance liquid chromatography and compared with eGFRs calculated with the CKD-EPI equation. Correlation was evaluated by the Pearson product-moment correlation coefficient.Results. The study population consisted of 68 critically ill patients aged between 18 and 81 years; 43 (63%) were male, and the mean weight was 78 kg (range 40 - 140). On admission, 30 patients (44%) had sepsis, 16 (24%) were admitted for trauma, and 22 (32%) were admitted for miscellaneous surgical conditions. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ranged from 4 to 39 (mean 18). The 28-day mortality rate was 29%. The mean albumin level was 16 g/L (range 7 - 25), the mean creatinine level 142 μmol/L (range 33 - 840), and the mean eGFR 91 mL/min/1.73 m2 (range 6 - 180). Imipenem trough levels ranged between 3.6 and 92.2 mg/L (mean 11.5). The unadjusted Pearson product-moment correlation coefficient between eGFR and imipenem trough level was –0.04 (p=0.761).Conclusion. Considering the high mortality rate of sepsis in ICUs and the rapid global increase in antimicrobial resistance, it is crucial to dose antibiotics appropriately. Owing to the variability of antibiotic pharmacokinetics in critically ill patients, this task becomes almost impossible when relying on conventional dosing guidelines. This study found that eGFRs do not correlate with imipenem blood levels in critically ill patients and should not be used to determine the dose of imipenem/cilastatin. Instead, the dose should be individualised for patients through routine therapeutic drug monitoring.

Introduction Relebactam, a novel class A/C β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin, restores imipenem activity against imipenem-nonsusceptible gram-negative pathogens. Methods This phase 3, multicenter, open-label, noncomparative study (NCT03293485) evaluated relebactam/imipenem/cilastatin (250 mg/500 mg/500 mg) dosed every 6 h for 5–14 days in Japanese patients with complicated intra-abdominal infections (cIAIs) or complicated urinary tract infections (cUTIs), including those with secondary sepsis. Sepsis was defined as an infection-induced systemic inflammatory response syndrome, with a documented positive blood culture; patients meeting these protocol-defined criteria were evaluated for efficacy against sepsis. Results Of 83 patients enrolled, 81 patients (cIAI, n = 37; cUTI, n = 44) received ≥1 dose of study treatment. Escherichia coli was the most common baseline pathogen isolated in both patients with cIAI and cUTI. Adverse events (AEs) were reported in 74.1% (n = 60/81) of patients, and drug-related AEs occurred in 18.5% (n = 15/81). The most common AEs were diarrhea and nausea (8.6%). Serious AEs occurred in nine patients, including one death, but none were considered treatment related. The primary efficacy endpoint for patients with cIAI was clinical response at end of treatment (EOT) in the microbiologically evaluable (ME) population, and for patients with cUTI was microbiological response at EOT in the ME population. The proportion of cIAI and cUTI patients achieving favorable responses were 85.7% (n = 24/28) and 100.0% (n = 39/39), respectively. All patients with sepsis (cIAI, n = 1; cUTI, n = 5) achieved a favorable composite clinical and microbiological response at EOT. Conclusions A favorable safety and efficacy profile for relebactam/imipenem/cilastatin was observed in Japanese patients with cIAI and cUTI.

Acute generalized exanthematic pustulosis (PEGA) is a rare dermatological pathology characterized by the sudden and generalized appearance of multiple, sterile, non-follicular, punctate pustules on an erythematous and edematous base. It is frequently triggered by drugs, among which antibiotics stand out. We present the case of a 40-year-old male patient who was admitted to the emergency room due to abdominal pain síndrome, to rule out intra-abdominal tumor pathology, initially indicating ceftriaxone and metronidazole. The next day, he was re-admitted to the emergency room, finding, after emergency surgery, acute appendicitis complicated with intestinal perforation, for which they rotated the antibiotic therapy to imipenem-cilastatin + metronidazole. At the next 48 hours, he presents generalized erythema and some small pustules and microvesicles in the thoracic region, upper extremities and neck. Likewise, it is shown in laboratory tests, neutrophilic leukocytosis and hypoalbuminemia. In the biopsy, subcorneal and intraepidermal neutrophilic pustules are found, with edematous papillary dermis and perivascular inflammatory infiltrate with the presence of neutrophils and few eosinophils. With everything described above, we reached the conclusion of a PEGA, triggered by received antibiotics, ceftriaxone or imipenemcilastatin. After 6 days of the suspension of imipenem-cilastatin, the patient shows improvement of dermal lesions, with mild erythema and scant fine scaling., La pustulosis exantematosa generalizada aguda (PEGA) es una patología dermatológica poco frecuente, caracterizada por la aparición brusca y generalizada de múltiples pústulas puntiformes, estériles, no foliculares, sobre una base eritematosa y edematosa. Es desencadenada frecuentemente por fármacos, entre los cuales resaltan los antibióticos. Presentamos el caso de un paciente varón de 40 años, que ingresó a emergencia por síndrome doloroso abdominal a descartar patología tumoral intraabdominal, indicándole inicialmente ceftriaxona y metronidazol. Al día siguiente, reingresó a emergencia encontrando, tras la cirugía de emergencia, una apendicitis aguda complicada con perforación intestinal, por lo cual rotan la antibioticoterapia a imipenem-cilastatina + metronidazol. A las siguientes 48 horas, presentó eritema generalizado y algunas pústulas pequeñas y microvesículas en región torácica, extremidades superiores y cuello. Asimismo, se observó en los exámenes de laboratorio, leucocitosis neutrofílica e hipoalbuminemia. En la biopsia, se encontró pústulas neutrofílicas subcorneales e intraepidérmicas, con dermis papilar edematosa e infiltrado inflamatorio perivascular con presencia de neutrófilos y escasos eosinófilos. Con todo lo descrito anteriormente, llegamos a la conclusión de una PEGA, desencadenado por los antibióticos recibidos, ceftriaxona o imipenem-cilastatina. Tras 6 días de la suspensión de imipenem-cilastatina, paciente mostró mejoría de lesiones dérmicas, con leve eritema y escasa descamación fina.

The drug levels and clearances of imipenem in critically ill patients are not comprehensively described in current literature, yet it is vital that adequate levels be achieved for therapeutic success.To determine the proportion of critically ill patients treated with imipenem/cilastatin with sub-therapeutic imipenem plasma levels, and to compare the clinical outcomes of those patients with therapeutic levels with those who had sub-therapeutic levels.Trough imipenem plasma levels of 68 critically ill patients from a surgical intensive care unit were measured using a validated high-performance liquid chromatography method. Imipenem trough levels were compared with the minimum inhibitory concentration (MIC) of the causative bacterial agents, based on a target value of 100% time above MIC (¦Tgt;MIC).The proportion of participants with sub-therapeutic imipenem levels was 22% (95% confidence interval (CI) 13% - 34%). The 14- and 28-day mortality rates in the sub-therapeutic group were 33% and 40%, respectively, compared with 19% (p=0.293) and 26% (p=0.346), respectively, in the therapeutic group. Sub-therapeutic imipenem plasma levels are associated with adjusted hazard ratio of 1.47 (95% CI 0.55 - 3.91).The lower proportion of critically ill patients with sub-therapeutic imipenem plasma levels in this study compared with previous studies may be attributed to the practice of higher dosages and the administration method of extended infusions of imipenem/cilastatin in our setting. The results demonstrate a trend of higher mortality in patients with sub-therapeutic imipenem levels, although the results were not statistically significant at this sample size.

With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and traditional salvage agents (eg, colistin, tigecycline, etc) confer high toxicity and/or have low efficacy. However, several β-lactam agents with activity against carbapenem-resistant organisms were approved recently by the US Food and Drug Administration, and more are anticipated to be approved in the near future. The primary goal of this review is to assist infectious disease practitioners with preferentially selecting 1 agent over another when treating patients infected with a carbapenem-resistant organism. However, resistance to some of these antibiotics has already developed. Antibiotic stewardship programs can ensure that they are reserved for situations in which other options are lacking and are paramount for the survival of these agents.

Background: This risk of vancomycin (VAN)-associated acute kidney injury (AKI) may be altered with combination regimens. The specific AKI risk when VAN is combined with imipenem-cilastatin/relebactam (IMP-C/REL) or piperacillin/tazobactam (TZP) has not been clearly defined.Objectives: To quantify the dose-AKI relationships of VAN alone and in combination with TZP or imipenem-cilastatin/relebactam (IMP-C/REL).Methods: Ten to twelve week old male C57BL/6J mice (Charles River Laboratory) were dosed with study drug regimens in three stages. Stage 1 consisted of a VAN dose-ranging design (0-600 mg/kg/day) over a 7-day period to identify the VAN monotherapy dose-AKI relationship in the murine model. Stage 2 evaluated the approximate VAN dose eliciting 50% AKI response in Stage 1 in combination with the highest human equivalent doses (HED) used in pre-clinical murine models (2.5 g/kg/day of TZP, 320 mg/kg/day of IMP-C/REL). Stage 3 tested these combinations with fractionated doses of TZP or IMP-C/REL administered at 6- and 12-hour intervals. In these studies, AKI was defined both by biomarkers (serum creatinine [SCr], blood urea nitrogen [BUN]) and histopathological assessment by a treatment-blinded pathologist.Results: VAN doses of 300 to 500 mg/kg/day reproducibly led to development of AKI within 4 days of dosing. Mice treated with VAN alone had a near doubling of their baseline SCr and BUN compared to control, IMP-C/REL alone, or TZP alone. Both VAN+IMP-C/REL and VAN+TZP had significantly (p

Purpose The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, efficacy, safety, and current regulatory status of imipenem/cilastatin/relebactam are reviewed. Summary Imipenem/cilastatin/relebactam is a newly approved anti-infective combination of a well-established β-lactam and a new β-lactamase inhibitor for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intra-abdominal infections (cIAIs) caused by susceptible gram-negative bacteria in patients 18 years of age or older with limited or no alternative treatment options. The antibiotic is also indicated for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The antibiotic is active in vitro against a wide range of pathogens, including multidrug-resistant (MDR) Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales (CRE) such as Klebsiella pneumoniae carbapenemase. The addition of relebactam does not restore the activity of imipenem against metallo-β-lactamase (MBL)–producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii. Two phase 3 clinical trials of imipenem/cilastatin/relebactam were conducted. In the RESTORE-IMI 1 trial, the efficacy and safety of imipenem/cilastatin/relebactam was found to be comparable to that of imipenem/cilastatin plus colistin for the treatment of infections caused by imipenem-nonsusceptible gram-negative bacteria in patients with HABP/VABP, cUTIs, and cIAIs, with a significantly lower incidence of nephrotoxicity reported with the new antibiotic. The RESTORE-IMI 2 trial demonstrated the noninferiority of imipenem/cilastatin/relebactam to piperacillin/tazobactam for the treatment of HABP/VABP. Commonly reported adverse events in clinical trials included anemia, elevated liver enzymes, electrolyte imbalances, nausea, vomiting, diarrhea, headache, fever, phlebitis and/or infusion-site reactions, and hypertension. Conclusion Imipenem/cilastatin/relebactam is a new β-lactam/β-lactamase inhibitor combination with activity against MDR gram-negative bacteria, including many CRE but excluding MBL-producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii. It is approved for the treatment of cUTIs, cIAIs, and HABP/VABP.

Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately.

An 86-year-old woman with Borrmann type III colorectal cancer (Union for International Cancer Control pT4aN2bM1c, pStage IVc) had received dexamethasone for the last 6 months as palliative care. She presented with a low-grade fever, chest pain and cough. Chest radiography on admission showed cavities and consolidations bilaterally in the upper lobes. A blood examination on admission revealed highly elevated serum β-d-glucan levels. The diagnosis by bronchoscopy was pulmonary nocardiosis. With trimethoprim/sulfamethoxazole and imipenem/cilastatin, the β-d-glucan levels were decreased, and chest X-ray showed improvement after 1 month. β-d-glucan is known to be a biomarker of fungal infection. It is possible that β-d-glucan levels also indicate a pulmonary infection by Nocardia.

Introduction Carbapenems are broad-spectrum antibacterial molecules. Imipenem-cilastatin and meropenem are the two main molecules used in French healthcare services. Objective We aimed to evaluate the relative strengths and weaknesses of these two molecules by considering their pharmacokinetic, pharmacodynamic, microbiological, and clinical properties. We demonstrated that imipenem-cilastatin and meropenem are not alike. Method Review of the literature by querying the MEDLINE network. Results Imipenem-cilastatin is the first marketed molecule of the carbapenem class. It is more effective against Gram-positive cocci. Its stability does not allow for long infusions and its main adverse effect on the central nervous system limits its use. Meropenem is more effective against Gram-negative bacilli. Its stability and its milder adverse effects distinguish it from imipenem-cilastatin. Conclusion Meropenem is preferred for daily use in healthcare services when carbapenems are to be used.

Durlobactam (DUR; also known as ETX2514) is a novel β-lactamase inhibitor with broad activity against Ambler class A, C, and D β-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii. The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem-cilastatin (IMI-CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In part A, subjects, including a cohort of elderly subjects (which received DUR at 1 g), received single ascending doses of DUR ranging from 0., Durlobactam (DUR; also known as ETX2514) is a novel β-lactamase inhibitor with broad activity against Ambler class A, C, and D β-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii. The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem-cilastatin (IMI-CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In part A, subjects, including a cohort of elderly subjects (which received DUR at 1 g), received single ascending doses of DUR ranging from 0.25 to 8 g. In part B, multiple ascending doses of DUR ranging from 0.25 to 2 g were administered every 6 h (q6h) for 29 doses. In parts C and D, the drug-drug interaction (DDI) potential, including the safety, of DUR (1 g) with SUL (1 g) and/or IMI-CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI-CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated when it was administered either alone or in combination with SUL and/or IMI-CIL. After single and multiple doses, DUR demonstrated linear dose-proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug-drug interaction potential between DUR and SUL and/or IMI-CIL was identified. SUL-DUR at 1 g (of each component) administered q6h with a 3-h intravenous (i.v.) infusion is under development for the treatment of serious infections due to A. baumannii. (This study has been registered at ClinicalTrials.gov under identifier NCT02971423.)

Supplemental Digital Content is available in the text, Purpose: Febrile neutropenia has a significant clinical and economic impact on cancer patients. This study evaluates the cost-effectiveness of different current empiric antibiotic treatments. Methods: A decision analytic model was constructed to compare the use of cefepime, meropenem, imipenem/cilastatin, and piperacillin/tazobactam for treatment of high-risk patients. The analysis was performed from the perspective of U.S.-based hospitals. The time horizon was defined to be a single febrile neutropenia episode. Cost-effectiveness was determined by calculating costs and deaths averted. Cost-effectiveness acceptability curves for various willingness-to-pay thresholds (WTP), were used to address the uncertainty in cost-effectiveness. Results: The base-case analysis results showed that treatments were equally effective but differed mainly in their cost. In increasing order: treatment with imipenem/cilastatin cost $52,647, cefepime $57,270, piperacillin/tazobactam $57,277, and meropenem $63,778. In the probabilistic analysis, mean costs were $52,554 (CI: $52,242-$52,866) for imipenem/cilastatin, $57,272 (CI: $56,951-$57,593) for cefepime, $57,294 (CI: $56,978-$57,611) for piperacillin/tazobactam, and $63,690 (CI: $63,370-$64,009) for meropenem. Furthermore, with a WTP set at $0 to $50,000, imipenem/cilastatin was cost-effective in 66.2% to 66.3% of simulations compared to all other high-risk options. Discussion: Imipenem/cilastatin is a cost-effective strategy and results in considerable health care cost-savings at various WTP thresholds. Cost-effectiveness analyses can be used to differentiate the treatments of febrile neutropenia in high-risk patients.

Durlobactam (DUR; ETX2514) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C, and D β-lactamases. Durlobactam restores the in vitro activity of sulbactam (SUL) against members of the Acinetobacter baumannii-A. calcoaceticus complex (ABC). Sulbactam (SUL)-durlobactam (SUL-DUR) is under development for the treatment of ABC infections., Durlobactam (DUR; ETX2514) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C, and D β-lactamases. Durlobactam restores the in vitro activity of sulbactam (SUL) against members of the Acinetobacter baumannii-A. calcoaceticus complex (ABC). Sulbactam (SUL)-durlobactam (SUL-DUR) is under development for the treatment of ABC infections. Eighty patients with complicated urinary tract infection (cUTI), including acute pyelonephritis (AP), were randomized 2:1 to receive SUL-DUR at 1 g/1 g intravenously (i.v.) or placebo every 6 h (q6h) for 7 days and background therapy with imipenem-cilastatin (IMI) at 500 mg i.v. q6h to evaluate the tolerability of SUL-DUR in hospitalized patients. Patients with bacteremia could receive up to 14 days of therapy. SUL-DUR tolerability and the values of various pharmacokinetic (PK) parameters were determined. Efficacy was recorded at the test-of-cure (TOC) visit. SUL-DUR was well tolerated, with no serious adverse events (AEs) being reported. Headache (5.7%), nausea (3.8%), diarrhea (3.8%), and vascular pain (3.8%) were the most common drug-related AEs with SUL-DUR and were mostly of mild or moderate severity. The PK profile of DUR and SUL in hospitalized patients was consistent with observations in healthy volunteers. Overall success in the microbiological modified intent-to-treat (m-MITT) population was similar between the groups, as would be expected with IMI background therapy in all patients (overall success at the TOC visit, 76.6% [n = 36] with SUL-DUR and 81.0% [n = 17] with placebo). SUL-DUR in combination with IMI was well tolerated in patients with cUTIs. The pharmacokinetics of SUL-DUR observed in hospitalized patients was similar to that observed in healthy volunteers. (This study has been registered at ClinicalTrials.gov under identifier NCT03445195.)

The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.).

Background: The appropriate use of broad-spectrum antibiotics, including appropriate de-escalation, is essential to reduce the emergence of antibiotic resistance. In surgical floors antibiotics are prescribed for prophylaxis (mostly, single dose), empirical treatment (started if infection is suspected till bacteria are identified with its sensitivity to antibiotics), or treatment of well-defined infection of previously isolated bacteria with its sensitivity to antibiotics. In this study, we aimed to evaluate the use of broad-spectrum antibiotics based on requests for cultures and de-escalation based on sensitivity results of culture tests at tertiary care hospital. Method: A retrospective cohort study was conducted to evaluate the utilization of broad-spectrum antibiotics on surgical floors at a tertiary care center in Jeddah, Saudi Arabia. Patients who are admitted to surgical floors were included if they received any of three broad-spectrum antibiotics (piperacillin–tazobactam, imipenem–cilastatin or meropenem) from 1 June 2014 to 31 August 2014. Data were collected on whether culture and sensitivity test requests were made within 24 h of starting antibiotics, the duration of antibiotic therapy and the number of days to de-escalation after receiving culture and sensitivity results. Results: Of the 163 patients who received broad-spectrum antibiotics, culture tests were requested in 112. Before receiving culture results, one patient was discharged and one died. The results of culture tests justified continuation of broad-spectrum antibiotics in only 22 patients, whereas 24 showed no microbial growth in any culture. De-escalation was delayed >24 h after culture results became available in 33 out of 64 eligible patients. On the other hand, 51 patients continued receiving broad spectrum antibiotics without any culture test during the whole treatment course. Conclusion: The use of broad-spectrum antibiotics in surgical floors at a tertiary care hospital in Saudi Arabia was largely unjustified by culture-test result. Interventions are needed to enforce culture and sensitivity test requests within 24 h of starting the broad spectrum antibiotics therapy with further follow up to ensure appropriate de-escalation and discontinuation whenever indicated. Keywords: Microbial drug resistance, Surgical, Antimicrobial stewardship, De-escalation, Imipenem–cilastatin, Piperacillin–tazobactam, Meropenem

Mycobacterium abscessus is a rapidly-growing, virulent, non-tuberculous mycobacterium that causes progressive inflammatory lung damage and significant decline in lung functionin patients with cystic fibrosis. M. abscessus complex pulmonary infections are notoriously difficult to treat, and while many antibiotics are approved for children, drug allergies or intolerances can prohibit their use. Intravenous imipenem/cilastatin is among the preferred antibiotics for treatment of M. abscessus, however, its use may result in systemic toxicities including hepatic injury and gastrointestinal effects. Case reports document the successful use of inhaled imipenem/cilastatin in adult cystic fibrosis and non- cystic fibrosis patients with non- M. abscessus pulmonary infections. To our knowledge, similar evidence does not exist for pediatric patients. In this case series, we describe two pediatric patients with cystic fibrosis and previous intolerance or lack of response to standard therapies who received inhaled imipenem/cilastatin for the treatment of chronic M. abscessus infection.

Background Burn patients are prone to infections which often necessitate broad antibiotic coverage. Vancomycin is a common antibiotic after burn injury and is administered alone (V), or in combination with imipenem-cilastin (V/IC) or piperacillin-tazobactam (V/PT). Sparse reports indicate that the combination V/PT is associated with increased renal dysfunction. The purpose of this study was to evaluate the short-term impact of the three antibiotic administration types on renal dysfunction. Methods All pediatric and adult patients admitted to our centers between 2004 and 2016 with a burn injury were included in this retrospective review if they met the criteria of exposition to either V, V/IC, or V/PT for at least 48 h, had normal baseline creatinine, and no pre-existing renal dysfunction. Creatinine was monitored for 7 days after initial exposure; the absolute and relative increase was calculated, and patient renal outcomes were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria depending on creatinine increases and estimated creatinine clearance. Secondary endpoints (demographic and clinical data, incidences of septicemia, and renal replacement therapy) were analyzed. Antibiotic doses were modeled in logistic and linear multivariable regression models to predict categorical KDIGO events and relative creatinine increase. Results Out of 1449 patients who were screened, 718 met the inclusion criteria, 246 were adults, and 472 were children. Between the study cohorts V, V/IC, and V/PT, patient characteristics at admission were comparable. V/PT administration was associated with a statistically higher serum creatinine, and lower creatinine clearance compared to patients receiving V alone or V/IC in adults and children after burn injury. The incidence of KDIGO stages 1, 2, and 3 was higher after V/PT treatment. In children, the incidence of KDIGO stage 3 following administration of V/PT was greater than after V/IC. In adults, the incidence of renal replacement therapy was higher after V/PT compared with V or V/IC. Multivariate modeling demonstrated that V/PT is an independent predictor of renal dysfunction. Conclusion Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in pediatric and adult burn patients when compared to vancomycin alone or vancomycin plus imipenem-cilastin. The mechanism of this increased nephrotoxicity remains elusive and warrants further scientific evaluation. Electronic supplementary material The online version of this article (doi:10.1186/s13054-017-1899-3) contains supplementary material, which is available to authorized users.

Imipenem is a carbapenem antibiotic largely used to treat infection diseases. The present study was designed to investigate the effects of imipenem/cilastatin (IMP) on oxidative stress, antioxidant levels, testicular structure and sperm parameters in rats. Adult Wistar rats (84days old; N=8/group) were treated intraperitoneally with physiological serum containing 0mg/kg, 30mg/kg, 50mg/kg and 80mg/kg of IMP for one week. The results revealed that exposure to IMP especially at high doses, significantly decreased sexual organs weights (testis, epididymis, seminal vesicle and prostate), sperm characteristics (motility, viability and count) and plasma testosterone level while increased sperm abnormality. In addition, the testicular tissue level of lipid peroxidation (LPO) was significantly increased while the level of activities of superoxide dismutase (SOD), catalase (CAT) and glutathion peroxidase (GPx) decreased compared to the control group. Severe testicular lesions were recorded in the seminiferous tubules as well as a significant impairment in sperm characteristics. In conclusion, IMP induced an oxidative stress-status and histopathological changes in the testis and altered spermatogenesis in particular at both 50 and 80mg/kg dose-levels (p

Objectives The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem non-susceptible pathogens. Methods To explore relebactam's safety, tolerability and efficacy, we conducted a randomized (1:1:1), controlled, Phase 2 trial comparing imipenem/cilastatin+relebactam 250 mg, imipenem/cilastatin+relebactam 125 mg and imipenem/cilastatin alone in adults with complicated urinary tract infections (cUTI) or acute pyelonephritis, regardless of baseline pathogen susceptibility. Treatment was administered intravenously every 6 h for 4-14 days, with optional step-down to oral ciprofloxacin. The primary endpoint was favourable microbiological response rate (pathogen eradication) at discontinuation of intravenous therapy (DCIV) in the microbiologically evaluable (ME) population. Non-inferiority of imipenem/cilastatin+relebactam over imipenem/cilastatin alone was defined as lower bounds of the 95% CI for treatment differences being above -15%. Results At DCIV, 71 patients in the imipenem/cilastatin + 250 mg relebactam, 79 in the imipenem/cilastatin + 125 mg relebactam and 80 in the imipenem/cilastatin-only group were ME; 51.7% had cUTI and 48.3% acute pyelonephritis. Microbiological response rates were 95.5%, 98.6% and 98.7%, respectively, confirming non-inferiority of both imipenem/cilastatin + relebactam doses to imipenem/cilastatin alone. Clinical response rates were 97.1%, 98.7% and 98.8%, respectively. All 23 ME patients with imipenem non-susceptible pathogens had favourable DCIV microbiological responses (100% in each group). Among all 298 patients treated, 28.3%, 29.3% and 30.0% of patients, respectively, had treatment-emergent adverse events. The most common treatment-related adverse events across groups (1.0%-4.0%) were diarrhoea, nausea and headache. Conclusions Imipenem/cilastatin + relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI. Both relebactam-containing regimens were well tolerated. (NCT01505634).

Background Non-tuberculous mycobacteria cause chronic pulmonary infection, but pleuritis and pleural effusion are rarely associated with infection with non-tuberculous mycobacteria, especially rapid-growing mycobacteria. Case presentation A 68-year-old woman with rheumatoid arthritis who was using prednisone, azathioprine, and certolizumab pegol presented complaining of fever, dry cough, and night sweats for the past 2 weeks. Chest examination revealed bilateral opacity that was more pronounced on her right side. Bronchoalveolar lavage fluid and pleural effusion fluid were obtained, and revealed coinfection with Mycobacterium fortuitum and Mycobacterium mageritense. Imipenem/cilastatin, levofloxacin, and minocycline were prescribed for 6 months, and the patient was well and asymptomatic for the subsequent 6 months. Conclusions This is the first case report describing pleural effusion associated with coinfection with two different mycobacterial species. If the species cannot be identified, the possibility of mycobacterial coinfection should be considered.

Imipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population. After children were treated with imipenem-cilastatin (IMP-CS), blood samples were collected from the children and the concentrations of imipenem were quantified using high-performance liquid chromatography with UV detection. Then, a population-level pharmacokinetic analysis was conducted using NONMEM software. Data were collected from 56 children (age range, 2.03 to 11.82 years) with hematological malignancies to conduct a population pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be the most suitable. The parameters of current weight, age, and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1%, and 67.1% of the children reached the pharmacodynamic target (the percentage of the time during the total dosing interval that the free drug concentration remains above the MIC of 70%) against sensitive pathogens with an MIC of 0.5 mg/liter with imipenem at 15, 20, and 25 mg/kg of body weight every 6 h (q6h), respectively. However, only 11.1% of the children achieved the pharmacodynamic target against Pseudomonas aeruginosa isolates with an MIC of 2 mg/liter at a dose of 25 mg/kg q6h. The population pharmacokinetics of imipenem were assessed in children. The current dosage regimens of imipenem result in underdosing against resistant pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h. (The study discussed in this paper has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT03113344","term_id":"NCT03113344"}}NCT03113344.)

Relebactam (REL [MK-7655]) is a novel class A/C β-lactamase inhibitor intended for use with imipenem for the treatment of Gram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas . In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were ≥18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains.

There have been few coherent reports on extraintestinal infection or bacteremia caused by Campylobacter jejuni (C. jejuni) or C. coli in Japan. To clarify the clinical and microbiological characteristics of invasive infections caused by these two species, we retrospectively analyzed the records of patients from whom these pathogens had been isolated from sterile sites between 2000 and 2015. During this study period, we identified 9 patients. The clinical syndrome of all of these patients was bacteremia. Three patients had underlying diseases with both liver cirrhosis and malignant neoplasm, and all of these patients were aged 60 years or older. The remaining 6 patients were immunocompetent and younger than 40 years of age. All 9 patients had a fever of 38.5 degrees C or higher. The proportion of patients with gastrointestinal symptoms was lower for the 3 patients with underlying diseases, compared with the 6 patients without underlying diseases (1/3 cases vs, 4/6 cases). Of the 8 strains evaluated for antimicrobial susceptibility, all were susceptible to imipenem/cilastatin, kanamycin and erythromycin, and 2 were resistant to levofloxacin. Antimicrobial treatment was administered to 8 patients, but one spontaneously recovered without any treatment. We were able to follow the outcomes of 8 patients, and all of these patients completely recovered without relapses. We also reviewed 14 Japanese patients reported in the Japanese and English literature and found similar clinical features consisting of a high-grade fever and an association with underlying diseases and gastrointestinal symptoms. Of note, 3 agammaglobulinemic patients presented with bacteremia and extraintestinal infections and had multiple relapses. Based on the findings of our 9 cases and previous reports, the affected patients were divided into two groups according to clinical syndrome and therapeutic intervention. One group consisted of previously healthy children or young adults showing bacteremia. Most of them had enterocolitis complications but had a good prognosis. The other group consisted of patients with underlying diseases or elderly patients who presented with bacteremia alone or bacteremia with extraintestinal infections. The latter group, especially among those with humoral immunodeficiency, should be parentally treated with antimicrobial agents and requires careful monitoring for relapse. This is the largest case series study to examine invasive C. jejuni/coli infections in Japan, and it provides important epidemiological information on this rare infection.

Introduction Optimisation of antibiotic therapy for extracorporeal membrane oxygenation (ECMO) patients remains a pharmacological challenge. The objective of this study was to observe the plasma concentrations of commonly used antibiotics in intensive care for patients treated with extracorporeal membrane oxygenation. Patients and methods The PHARMECMO study was a pilot, prospective study, conducted in a cardiac surgery intensive care unit. Every adult patient under ECMO support, with known or suspected sepsis and receiving antibiotic therapy, was eligible for inclusion. Plasma concentrations of antibiotics were determined by a combination of liquid chromatography and mass spectrometry. Results Forty-four eligible patients were enrolled for 68 inclusions on a twelve-month period. For the association piperacillin-tazobactam (n=19), 68.7% of CT50 and 93.7% of Cmin reached the pharmacokinetic goals defined (64 mg.L-1 for CT50 and 16 mg.L-1 for Cmin). For cefotaxime (n=12), the pharmacokinetic goals (4 mg.L-1 for CT50 and 1 mg.L-1 for Cmin) were achieved in 100% of the cases for CT50 and in 81.8% of the cases for Cmin. Regarding imipenem (n=10), the pharmacokinetic goals were 16 mg.L-1 for CT50 and 4 mg.L-1 for Cmin. Only one CT50 was above 16 mg.L-1. For Cmin, 60% of the doses did not reach the target concentration. In our 10 patients, only one patient was considered as reaching the pharmacokinetic goals. Finally, for amikacin (n=6), four Cmax (66.7%) were infra-therapeutics for a target between 60 and 80 mg.L-1. Conclusion These preliminary results suggest that therapeutic drug monitoring could optimise the achievement of pharmacokinetic objectives associated with an effective antibiotic therapy. For most patients, the recommended doses of imipenem and amikacin did not achieve the pK targets

Introduction: Drug fever is a febrile reaction caused by initiation of one drug or varieties of drugs and often disappears after cessation of the drug(s). Clinically, drug fever is frequently induced by antibiotics, anticonvulsants, and antineoplastics. There are few previous reports about drug fever caused by imipenem/cilastatin. Case Presentation: Here, we described a 66-year-old man undergoing the Ivor Lewis esophagectomy for esophageal carcinoma, who developed drug fever. The patient had a high temperature with shivering after administration of imipenem/cilastatin for 7 days. Furthermore, his temperature came down after discontinuing imipenem/cilastatin and receiving steroids. Body temperature increased rapidly 4 hours after intravenous readministration of imipenem/cilastatin and rapidly decreased to normal after discontinuing imipenem/cilastatin and administering steroids. Conclusion: Thorough history, blood tests, physical examination, and computed tomography (CT) did not reveal any evidence of fever. Drug fever caused by imipenem/cilastatin was considered. We also present a review of relevant literature and provide a point of reference for the clinical diagnosis and therapy of patients with drug fever.

Pneumonia caused by Acinetobacter baumannii has become a serious threat to the elderly. However, there are no experimental studies on the relevance between aging and A. baumannii infections. Here, we established an aged pneumonia mouse model by non-invasive intratracheal inoculation with A. baumannii. Higher mortality was observed in aged mice along with increased bacterial burdens and more severe lung injury. Increased inflammatory cell infiltration and enhanced pro-inflammatory cytokines at 24 hours post infection were detected in aged mice than those in young mice. Moreover, infected aged mice had lower myeloperoxidase levels in lungs and less reactive oxygen species-positive neutrophils in bronchoalveolar lavage fluid compared with infected young mice. Reduced efficacy of imipenem/cilastatin against A. baumannii was detected in aged mice. Vaccination of formalin-fixed A. baumannii provided 100% protection in young mice, whereas the efficacy of vaccine was completely diminished in aged mice. In conclusion, aging increased susceptibility to A. baumannii infection and impaired efficacies of antibiotics and vaccine. The aged mice model of A. baumannii pneumonia is a suitable model to study the effects of aging on A. baumannii infection and assess the efficacies of antibiotics and vaccines against A. baumannii for the elderly.