Successful Treatment of Carbapenem-Resistant Acinetobacter baumannii Meningitis with Sulbactam-Durlobactam.

BACKGROUND: The treatment of carbapenem-resistant Acinetobacter baumannii/calcoaceticus complex (CRAB) presents significant treatment challenges. METHODS: We report the case of a 42-year-old woman with CRAB meningitis who experienced persistently positive cerebrospinal fluid (CSF) cultures for 13 days despite treatment with high-dose ampicillin-sulbactam and cefiderocol. On day 13, she was transitioned to sulbactam-durlobactam and meropenem; four subsequent CSF cultures remained negative. After 14 days of sulbactam-durlobactam, she was cured of infection. Whole genome sequencing investigations identified putative mechanisms that contributed to reduced cefiderocol susceptibility observed during cefiderocol therapy. Blood and CSF samples were collected pre-dose and 3-hours post initiation of a sulbactam-durlobactam infusion. RESULTS: The CRAB isolate belonged to sequence type 2. An acquired blaOXA-23 and an intrinsic blaOXA-51-like (i.e., blaOXA-66) carbapenemase gene were identified. The paradoxical effect (i.e., no growth at lower cefiderocol dilutions but growth at higher dilutions) was observed by broth microdilution after 8 days of cefiderocol exposure but not by disk diffusion. Potential markers of resistance to cefiderocol included mutations in the start codon of piuA and piuC iron transport genes and a A515V substitution in PBP3, the primary target of cefiderocol. Sulbactam and durlobactam were detected in CSF at both timepoints, indicating CSF penetration. CONCLUSIONS: This case describes successful treatment of refractory CRAB meningitis with the administration of sulbactam-durlobactam and meropenem and highlights the need to be cognizant of the paradoxical effect that can be observed with broth microdilution testing of CRAB isolates with cefiderocol.

Identifying Effective Durations of Antibiotic Therapy for the Treatment of Carbapenem-resistant Enterobacterales Bloodstream Infections: A Multicenter Observational Study.

In a propensity-score-weighted cohort of 183 adults with carbapenem-resistant Enterobacterales bacteremia at 24 US hospitals, patients receiving short courses of active therapy (7-10 days, median 9 days) experienced similar odds of recurrent bacteremia or death within 30 days as those receiving prolonged courses of active therapy (14-21 days, median 14 days).

Cefepime versus carbapenems for treatment of AmpC beta-lactamase-producing Enterobacterales bloodstream infections.

PURPOSE: Cefepime is recommended for treating infections caused by AmpC beta-lactamase-producing Enterobacterales (AmpC-PE), though supporting evidence is limited. Therefore, this study compared outcomes associated with cefepime versus carbapenem therapy for bloodstream infections (BSIs) caused by AmpC-PE after phenotypic exclusion of ESBL-co-producing isolates. METHODS: This retrospective cohort study compared definite cefepime versus carbapenem treatment for AmpC-PE BSI in hospitalized patients of the University Hospital Basel, Switzerland, between 01/2015 and 07/2020. Primary outcomes included in-hospital death, renal impairment and neurologic adverse events; secondary outcomes included length of hospital stay and recurrent infection. RESULTS: Two hundred and seventy episodes of AmpC-PE BSI were included, 162, 77 and 31 were treated with a carbapenem, cefepime and other antibiotics, respectively. Patients treated with carbapenems were more likely to be transferred to the ICU on admission and more frequently had central venous catheter as a source of infection. In uni- and multivariable analyses, primary and secondary outcomes did not differ between the two treatment groups, except for more frequent occurrence of neurological adverse events among patients treated with carbapenems and shorter length of hospital stay among survivors treated with cefepime. CONCLUSION: After excluding isolates with phenotypic ESBL-co-production, cefepime was not associated with adverse outcomes compared to carbapenems when used to treat BSIs caused by AmpC-PE. Our study provides evidence to support the use of cefepime as a safe treatment strategy for AmpC-PE BSI, particularly in clinically stable patients without initial renal impairment or increased susceptibility to neurological adverse events.

Navigating Available Treatment Options for Carbapenem-Resistant Acinetobacter baumannii-calcoaceticus Complex Infections.

Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other antibiotic-resistant threats, none of the available therapies have been shown to consistently reduce mortality or improve patient outcomes in clinical trials. Antibiotic combination therapy is routinely used in clinical practice; however, the preferred combination has not been defined. This narrative review focuses on evidence-based solutions for the treatment of invasive CRAB infections. We dissect the promise and perils of traditional agents used in combination, such as colistin, sulbactam, and the tetracyclines, and offer clinical pearls based on our interpretation of the available data. Next, we investigate the merits of newly developed ß-lactam agents like cefiderocol and sulbactam-durlobactam, which have demonstrated contrasting results in recent randomized clinical trials. The review concludes with the authors' perspective on the evolving treatment landscape for CRAB infections, which is complicated by limited clinical data, imperfect treatment options, and a need for future clinical trials. We propose that effective treatment for CRAB infections requires a personalized approach that incorporates host factors, the site of infection, pharmacokinetic-pharmacodynamic principles, local molecular epidemiology of CRAB isolates, and careful interpretation of antibiotic susceptibility testing results. In most clinical scenarios, a dose-optimized, sulbactam-based regimen is recommended with the addition of at least one other in vitro active agent. Should sulbactam-durlobactam receive regulatory approval, recommendations will need to be re-evaluated with the most recent evidence.

Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum ß-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa).

BACKGROUND: The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. The initial guidance document on infections caused by extended-spectrum ß-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa) was published on 17 September 2020. Over the past year, there have been a number of important publications furthering our understanding of the management of ESBL-E, CRE, and DTR-P. aeruginosa infections, prompting a rereview of the literature and this updated guidance document. METHODS: A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections reviewed, updated, and expanded previously developed questions and recommendations about the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. RESULTS: Preferred and alternative treatment recommendations are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, duration of therapy, and other management considerations are also discussed briefly. Recommendations apply for both adult and pediatric populations. CONCLUSIONS: The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial-resistant infections. This document is current as of 24 October 2021. The most current versions of IDSA documents, including dates of publication, are available at www.idsociety.org/practice-guideline/amr-guidance/.

Infectious Diseases Society of America Guidance on the Treatment of AmpC ß-Lactamase-Producing Enterobacterales, Carbapenem-Resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia Infections.

The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. A previous guidance document focused on infections caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Here, guidance is provided for treating AmpC ß-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia infections. A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated questions about the treatment of AmpC-E, CRAB, and S. maltophilia infections. Answers are presented as suggested approaches and corresponding rationales. In contrast to guidance in the previous document, published data on the optimal treatment of AmpC-E, CRAB, and S. maltophilia infections are limited. As such, guidance in this document is provided as "suggested approaches" based on clinical experience, expert opinion, and a review of the available literature. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. Preferred and alternative treatment suggestions are provided, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, duration of therapy, and other management considerations are also discussed briefly. Suggestions apply for both adult and pediatric populations. The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial-resistant infections. This document is current as of 17 September 2021 and will be updated annually. The most current version of this document, including date of publication, is available at www.idsociety.org/practice-guideline/amr-guidance-2.0/.

Progressive Development of Cefiderocol Resistance in Escherichia coli During Therapy is Associated With an Increase in blaNDM-5 Copy Number and Gene Expression.

BACKGROUND: As cefiderocol is increasingly being prescribed in clinical practice, it is critical that we understand key mechanisms contributing to acquired resistance to this agent. METHODS: We describe a patient with acute lymphoblastic leukemia and a New Delhi metallo-ß-lactamase (NDM)-5-producing Escherichia coli intra-abdominal infection in whom resistance to cefiderocol evolved approximately 2 weeks after the start of treatment. Through whole-genome sequencing (WGS), messenger RNA expression studies, and ethylenediaminetetraacetic acid inhibition analysis, we investigated the role of increased NDM-5 production and genetic mutations contributing to the development of cefiderocol resistance, using 5 sequential clinical E. coli isolates obtained from the patient. RESULTS: In all 5 isolates, blaNDM-5 genes were identified. The minimum inhibitory concentrations for cefiderocol were 2, 4, and >32 µg/mL for isolates 1-2, 3, and 4-5, respectively. WGS showed that isolates 1-3 contained a single copy of the blaNDM-5 gene, whereas isolates 4 and 5 had 5 and 10 copies of the blaNDM-5 gene, respectively, on an IncFIA/FIB/IncFII plasmid. These findings were correlated with those of blaNDM-5 messenger RNA expression analysis, in which isolates 4 and 5 expressed blaNDM-5 1.7- and 2.8-fold, respectively, compared to, isolate 1. Synergy testing with the combination of ceftazidime-avibactam and aztreonam demonstrated expansion of the zone of inhibition between the disks for all isolates. The patient was successfully treated with this combination and remained infection free 1 year later. CONCLUSIONS: The findings in our patient suggest that increased copy numbers of blaNDM genes through translocation events are used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased blaNDM-5 expression in contributing to cefiderocol resistance needs investigation.

Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum ß-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa).

BACKGROUND: Antimicrobial-resistant infections are commonly encountered in US hospitals and result in significant morbidity and mortality. This guidance document provides recommendations for the treatment of infections caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). METHODS: A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated common questions regarding the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Based on review of the published literature and clinical experience, the panel provide recommendations and associated rationale for each recommendation. Because of significant differences in the molecular epidemiology of resistance and the availability of specific anti-infective agents globally, this document focuses on treatment of antimicrobial-resistant infections in the United States. RESULTS: Approaches to empiric treatment selection, duration of therapy, and other management considerations are briefly discussed. The majority of guidance focuses on preferred and alternative treatment recommendations for antimicrobial-resistant infections, assuming that the causative organism has been identified and antibiotic susceptibility testing results are known. Treatment recommendations apply to both adults and children. CONCLUSIONS: The field of antimicrobial resistance is dynamic and rapidly evolving, and the treatment of antimicrobial-resistant infections will continue to challenge clinicians. This guidance document is current as of 17 September 2020. Updates to this guidance document will occur periodically as new data emerge. Furthermore, the panel will expand recommendations to include other problematic gram-negative pathogens in future versions. The most current version of the guidance including the date of publication can be found at www.idsociety.org/practice-guideline/amr-guidance/.

Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum ß-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa).

BACKGROUND: Antimicrobial-resistant infections are commonly encountered in US hospitals and result in significant morbidity and mortality. This guidance document provides recommendations for the treatment of infections caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). METHODS: A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated common questions regarding the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Based on review of the published literature and clinical experience, the panel provide recommendations and associated rationale for each recommendation. Because of significant differences in the molecular epidemiology of resistance and the availability of specific anti-infective agents globally, this document focuses on treatment of antimicrobial-resistant infections in the United States. RESULTS: Approaches to empiric treatment selection, duration of therapy, and other management considerations are briefly discussed. The majority of guidance focuses on preferred and alternative treatment recommendations for antimicrobial-resistant infections, assuming that the causative organism has been identified and antibiotic susceptibility testing results are known. Treatment recommendations apply to both adults and children. CONCLUSIONS: The field of antimicrobial resistance is dynamic and rapidly evolving, and the treatment of antimicrobial-resistant infections will continue to challenge clinicians. This guidance document is current as of 17 September 2020. Updates to this guidance document will occur periodically as new data emerge. Furthermore, the panel will expand recommendations to include other problematic gram-negative pathogens in future versions. The most current version of the guidance including the date of publication can be found at www.idsociety.org/practice-guideline/amr-guidance/.

A Decision Tree Using Patient Characteristics to Predict Resistance to Commonly Used Broad-Spectrum Antibiotics in Children With Gram-Negative Bloodstream Infections.

BACKGROUND: As rates of multidrug-resistant gram-negative infections rise, it is critical to recognize children at high risk of bloodstream infections with organisms resistant to commonly used empiric broad-spectrum antibiotics. The objective of the current study was to develop a user-friendly clinical decision aid to predict the risk of resistance to commonly prescribed broad-spectrum empiric antibiotics for children with gram-negative bloodstream infections. METHODS: This was a longitudinal retrospective cohort study of children with gram-negative bacteria cared for at a tertiary care pediatric hospital from June 2009 to June 2015. The primary outcome was a bloodstream infection due to bacteria resistant to broad-spectrum antibiotics (ie, cefepime, piperacillin-tazobactam, meropenem, or imipenem-cilastatin). Recursive partitioning was used to develop the decision tree. RESULTS: Of 689 episodes of gram-negative bloodstream infections included, 31% were resistant to broad-spectrum antibiotics. The decision tree stratified patients into high- or low-risk groups based on prior carbapenem treatment, a previous culture with a broad-spectrum antibiotic resistant gram-negative organism in the preceding 6 months, intestinal transplantation, age ≥3 years, and ≥7 prior episodes of gram-negative bloodstream infections. The sensitivity for classifying high-risk patients was 46%, and the specificity was 91%. CONCLUSION: A decision tree offers a novel approach to individualize patients' risk of gram-negative bloodstream infections resistant to broad-spectrum antibiotics, distinguishing children who may warrant even broader antibiotic therapy (eg, combination therapy, newer ß-lactam agents) from those for whom standard empiric antibiotic therapy is appropriate. The constructed tree needs to be validated more widely before incorporation into clinical practice.

Is Piperacillin-Tazobactam Effective for the Treatment of Pyelonephritis Caused by Extended-Spectrum ß-Lactamase-Producing Organisms?

BACKGROUND: Limited data exist regarding the efficacy of piperacillin-tazobactam (TZP) for the management of nonbacteremic pyelonephritis caused by extended-spectrum ß-lactamase (ESBL)-producing organisms. METHODS: We conducted a multicenter observational study comparing clinical outcomes of adults hospitalized with ESBL-producing pyelonephritis who were receiving TZP versus carbapenems, using an inverse probability of treatment weighted propensity score analysis. Patients were eligible for inclusion if all of the following criteria were met: (1) urine cultures growing Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, or Proteus mirabilis at ≥50 000 colony-forming units/mL; (2) identification of an ESBL gene; (3) pyuria (≥10 white blood cells per high powered field in the urine); and (4) dysuria and fever plus at least 1 of the following symptoms: emesis, rigors, hypotension, or flank pain. RESULTS: There were 186 patients included in the propensity score-weighted cohort; 45 (24%) received TZP and 141 (76%) received a carbapenem. Of these 186 patients, 27% were admitted to the intensive care unit, 48% were immunocompromised, and 45% had underlying urologic abnormalities. There were no differences between the 2 groups in the proportion of patients (20% vs 25%) with recurrent cystitis or pyelonephritis with the same ESBL-producing organism within 30 days (odds ratio, 0.75; 95% confidence interval, .31-1.81; P = .52). There were no differences in the resolution of clinical symptoms by Day 7 or in 30-day mortality. There was 1 (2%) patient in the TZP arm and 11 (8%) patients in the carbapenem arm who had incident carbapenem-resistant organisms isolated within 30 days (P = .09). CONCLUSIONS: TZP may be a reasonable alternative to carbapenems for the management of ESBL-producing pyelonephritis and may mitigate the risk of emergence of carbapenem-resistant organisms, compared with carbapenem therapy.

Successful Treatment of Persistent Burkholderia cepacia Complex Bacteremia with Ceftazidime-Avibactam.

We report our clinical experience treating a 2-month-old infant with congenital diaphragmatic hernia who experienced prolonged bacteremia with Burkholderia cepacia complex (Bcc) despite conventional antibiotic therapy and appropriate source control measures. The infection resolved after initiation of ceftazidime-avibactam. Whole-genome sequencing revealed that the isolate most closely resembled B. contaminans and identified the mechanism of resistance that likely contributed to clinical cure with this agent. Ceftazidime-avibactam should be considered salvage therapy for Bcc infections if other treatment options have been exhausted.

Point-Counterpoint: Piperacillin-Tazobactam Should Be Used To Treat Infections with Extended-Spectrum-Beta-Lactamase-Positive Organisms.

INTRODUCTIONBeta-lactam/beta-lactamase inhibitor combination antimicrobials (BLBLIs) are among the most controversial classes of antibiotic agents available for the treatment of infections caused by extended-spectrum-beta-lactamase (ESBL)-producing Gram-negative bacteria (ESBL-GNR). Piperacillin-tazobactam (PTZ) is one of the most frequently utilized antibiotic agents for empirical Gram-negative bacterial coverage and remains active against a large proportion of ESBL-GNR strains. Furthermore, good antimicrobial stewardship practices encourage the use of carbapenem-sparing treatment regimens for infections due to ESBL-GNR. As rapid diagnostics are increasingly used in the clinical microbiology laboratory and have the capability of detecting CTX-M type or other ESBL resistance mechanisms, this issue continues to be pertinent. Some data imply reduced efficacy of PTZ against ESBLs. Several factors may affect a clinician's choice to use BLBLIs, including the isolate's MIC, the site and severity of infection, and the type of resistance mechanism. These factors are explored in this review of the pros and cons of BLBLI treatment of invasive infections due to ESBL-producing bacteria, as well as how laboratories should report results for BLBLIs for these organisms as they relate to antimicrobial stewardship. In this Point-Counterpoint, Audrey Schuetz provides the pro point of view and Sergio Reyes and Pranita Tamma provide the con, counterpoint view.

The Use of Noncarbapenem ß-Lactams for the Treatment of Extended-Spectrum ß-Lactamase Infections.

The continued rise in infections caused by extended-spectrum ß-lactamase (ESBL)-producing pathogens is recognized globally as one of the most pressing concerns facing the healthcare community. Carbapenems are widely regarded as the antibiotics of choice for the treatment of ESBL-producing infections, even when in vitro activity to other ß-lactams has been demonstrated. However, indiscriminant carbapenem use is not without consequence, and carbapenem overuse has contributed to the emergence of carbapenem-resistant Enterobacteriaceae. The use of non-carbapenem ß-lactams for the treatment of ESBL infections has yielded conflicting results. In this review, we discuss the available data for the use of cephamycins, cefepime, piperacillin-tazobactam, ceftolozane-tazobactam, and ceftazidime-avibactam for the treatment of ESBL infections.

A Seven-Day Course of TMP-SMX May Be as Effective as a Seven-Day Course of Ciprofloxacin for the Treatment of Pyelonephritis.

BACKGROUND: The Infectious Diseases Society of America guidelines recommend either 14 days of trimethoprim-sulfamethoxazole (TMP-SMX) or 7 days of ciprofloxacin for the treatment of pyelonephritis. Antibiotic courses of 7 days of TMP-SMX vs 7 days of ciprofloxacin for pyelonephritis have not been previously compared. We evaluated the odds of a subsequent, symptomatic urinary tract infection (UTI) for women with Escherichia coli pyelonephritis receiving a 7-day course of TMP-SMX vs a 7-day course of ciprofloxacin. METHODS: Women ages 16 years and older with E. coli pyelonephritis presenting to 5 health care facilities in the greater Maryland area between 2010 and 2016 receiving either TMP-SMX or ciprofloxacin were included. Patients were excluded if they met any of the following criteria: (a) pregnancy, (b) dialysis dependency, (c) E. coli not susceptible to the treatment prescribed, (d) polymicrobial urine culture, or (e) >48 hours of antibiotic therapy other than TMP-SMX or ciprofloxacin. RESULTS: Of 272 women meeting eligibility criteria, 81 (30%) and 191 (70%) received 7 days of TMP-SMX and 7 days of ciprofloxacin, respectively. In an adjusted model, the likelihood of a recurrent UTI within 30 days for the TMP-SMX and ciprofloxacin groups was similar (adjusted odds ratio 2.30; 95% confidence interval, 0.72-7.42). CONCLUSIONS: Our findings suggest that 7 days of TMP-SMX therapy may result in similar clinical outcomes compared with 7 days of ciprofloxacin for the treatment of pyelonephritis. Considering the frequency of pyelonephritis and risks of antibiotic resistance and associated toxicities, decreasing the duration of antibiotic therapy for pyelonephritis may impact a large number of women.

The Use of a Combination Antibiogram to Assist with the Selection of Appropriate Antimicrobial Therapy for Carbapenemase-Producing Enterobacteriaceae Infections.

Combination antibiograms can be used to evaluate organism cross-resistance among multiple antibiotics. As combination therapy is generally favored for the treatment of carbapenemase-producing Enterobacteriaceae (CPE), combination antibiograms provide valuable information about the combination of antibiotics that achieve the highest likelihood of adequate antibiotic coverage against CPE.

Risk Factors for Resistance to ß-Lactam/ß-Lactamase Inhibitors and Ertapenem in Bacteroides Bacteremia.

The objective of this study was to determine risk factors for the development of resistance to ß-lactams/ß-lactamase inhibitors (ßL/ßLIs) and ertapenem among Bacteroides species bacteremia. We conducted a retrospective case-control study of 101 adult patients with Bacteroides species bacteremia at a 1,051-bed tertiary care medical center. The duration of exposure to ßL/ßLIs (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.08 to 2.31) was the only independent risk factor for resistance.

Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum ß-lactamase bacteremia.

BACKGROUND: The effectiveness of piperacillin-tazobactam (PTZ) for the treatment of extended-spectrum ß-lactamase (ESBL) bacteremia is controversial. We compared 14-day mortality of PTZ vs carbapenems as empiric therapy in a cohort of patients with ESBL bacteremia who all received definitive therapy with a carbapenem. METHODS: Patients hospitalized between January 2007 and April 2014 with monomicrobial ESBL bacteremia were included. A decrease of >3 doubling dilutions in the minimum inhibitory concentration for third-generation cephalosporins tested in combination with 4 µg/mL of clavulanic acid was used to confirm ESBL status. The primary exposure was empiric therapy, defined as antibiotic therapy administered to a patient before ESBL status was known. Patients were excluded if they did not receive a carbapenem after ESBL production was identified. The primary outcome was time to death from the first day of bacteremia. Propensity scores using inverse probability of exposure weighting (IPW) were used to estimate the probability that a patient would receive PTZ vs carbapenems empirically. We calculated overall hazard ratios for mortality censored at 14 days using Cox proportional hazards models on an IPW-adjusted cohort. RESULTS: A total of 331 unique patients with ESBL bacteremia were identified. One hundred three (48%) patients received PTZ empirically and 110 (52%) received carbapenems empirically. The adjusted risk of death was 1.92 times higher for patients receiving empiric PTZ compared with empiric carbapenem therapy (95% confidence interval, 1.07-3.45). CONCLUSIONS: PTZ appears inferior to carbapenems for the treatment of ESBL bacteremia. For patients at high risk of invasive ESBL infections, early carbapenem therapy should be considered. Our findings should not be extended to ß-lactam/ß-lactamase inhibitor combinations in development, as limited clinical data are available for these agents.

Challenges in the management of infections due to carbapenem-resistant Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae (CRE) infections are increasing and are associated with considerable morbidity and mortality. Members of the Emerging Infections Network treating CRE encountered difficulties in obtaining laboratory results and struggled with limited treatment options. In addition, many treated patients experienced an alarming degree of drug toxicity from CRE therapies.

Treatment of multidrug-resistant Gram-negative infections in children.

Antibiotic resistance in conjunction with the erosion of the drug development pipeline may lead us into a bleak future, a "post-antibiotic era." Because of a shortage of studies addressing treatment options for multidrug-resistant Gram-negative (MDRGN) infections in children, data must be extrapolated from the adult literature. However, even adult studies are limited by significant methodological flaws. We are in urgent need of pediatric specific pharmacokinetic/pharmacodynamic data for agents with activity against MDRGN infections as well as improved clinical outcomes studies. For the time being, we must rely on in vitro studies, observational data, and clinical experience to guide our therapeutic decisions. In this review, we discuss treatment considerations for infections caused by extended-spectrum ß-lactamase-producing organisms, AmpC ß-lactamase-producing organisms, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii in the pediatric population.