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The massive dissemination of carbapenemase-producing Enterobacterales poses a global threat to public health. Carbapenem antibiotics remain the last line of defense against highly resistant Enterobacterales. Carbapenemases have been identified in [...]

Background Klebsiella pneumoniae is the most common pathogen causing neonatal infections, leading to high mortality worldwide. Along with increasing antimicrobial use in neonates, carbapenem-resistant K. pneumoniae (CRKP) has emerged as a severe challenge for infection control and treatment. However, no comprehensive systematic review is available to describe the global epidemiology of neonatal CRKP infections. We therefore performed a systematic review of available data worldwide and combined a genome-based analysis to address the prevalence, clonal diversity, and carbapenem resistance genes of CRKP causing neonatal infections. Methods and findings We performed a systematic review of studies reporting population-based neonatal infections caused by CRKP in combination with a genome-based analysis of all publicly available CRKP genomes with neonatal origins. We searched multiple databases (PubMed, Web of Science, Embase, Ovid MEDLINE, Cochrane, bioRxiv, and medRxiv) to identify studies that have reported data of neonatal CRKP infections up to June 30, 2022. We included studies addressing the prevalence of CRKP infections and colonization in neonates but excluded studies lacking the numbers of neonates, the geographical location, or independent data on Klebsiella or CRKP isolates. We used narrative synthesis for pooling data with JMP statistical software. We identified 8,558 articles and excluding those that did not meet inclusion criteria. We included 128 studies, none of which were preprints, comprising 127,583 neonates in 30 countries including 21 low- and middle-income countries (LMICs) for analysis. We found that bloodstream infection is the most common infection type in reported data. We estimated that the pooled global prevalence of CRKP infections in hospitalized neonates was 0.3% (95% confidence interval [CI], 0.2% to 0.3%). Based on 21 studies reporting patient outcomes, we found that the pooled mortality of neonatal CRKP infections was 22.9% (95% CI, 13.0% to 32.9%). A total of 535 neonatal CRKP genomes were identified from GenBank including Sequence Read Archive, of which 204 were not linked to any publications. We incorporated the 204 genomes with a literature review for understanding the species distribution, clonal diversity, and carbapenemase types. We identified 146 sequence types (STs) for neonatal CRKP strains and found that ST17, ST11, and ST15 were the 3 most common lineages. In particular, ST17 CRKP has been seen in neonates in 8 countries across 4 continents. The vast majority (75.3%) of the 1,592 neonatal CRKP strains available for analyzing carbapenemase have genes encoding metallo-[beta]-lactamases and NDM (New Delhi metallo-[beta]-lactamase) appeared to be the most common carbapenemase (64.3%). The main limitation of this study is the absence or scarcity of data from North America, South America, and Oceania. Conclusions CRKP contributes to a considerable number of neonatal infections and leads to significant neonatal mortality. Neonatal CRKP strains are highly diverse, while ST17 is globally prevalent and merits early detection for treatment and prevention. The dominance of bla.sub.NDM carbapenemase genes imposes challenges on therapeutic options in neonates and supports the continued inhibitor-related drug discovery., Author(s): Ya Hu 1,2, Yongqiang Yang 2,3, Yu Feng 2,3, Qingqing Fang 1,2, Chengcheng Wang 1,2, Feifei Zhao 1,2, Alan McNally 4, Zhiyong Zong 1,2,3,* Introduction Neonatal mortality is a [...]

In some enterobacterial pathogens, but not in Escherichia coli, loss-of-function mutations are a common route to clinically relevant [beta]-lactam antibiotic resistance. We previously constructed an assay system for studying enterobacterial [beta]-lactam resistance mutations using the well-developed genetics of E. coli by integrating enterobacterial ampRC genes into the E. coli chromosome. Like the cells of other enterobacteria, E. coli cells acquire [beta]-lactam resistance by ampD mutation. Here we show that starvation and stress responses provoke ampD [beta]-lactam resistance mutagenesis. When starved on lactose medium, [Lac.sup.-] strains used in mutagenesis studies accumulate ampD [beta]-lactam resistance mutations independent of Lac reversion. DNA double-strand break repair (DSBR) proteins and the SOS and RpoS stress responses are required for this mutagenesis, in agreement with the results obtained for lac reversion in these cells. Surprisingly, the stress-induced ampD mutations require DinB (DNA polymerase IV) and partially require error-prone DNA polymerase V, unlike lac mutagenesis, which requires only DinB. This assay demonstrates that real-world stressors, such as Starvation, can induce clinically relevant resistance mutations. Finally, we used the ampD system to observe the true forward-mutation sequence spectrum of DSBR-associated stress-induced mutagenesis, for which previously only frameshift reversions were studied. We found that base substitutions outnumber frameshift mutations, as seen in other experimental systems showing stress-induced mutagenesis. The important evolutionary implication is that not only loss-of-function mutations but also change-of-function mutations can be generated by this mechanism. doi: 10.1128/JB.00732-09

Byline: Julia Langgartner (1), Antje Vasold (1), Thomas Gluck (2), Michel Reng (3), Frieder Kees (4) Keywords: Meropenem; Beta-lactam antibiotics; Continuous infusion; Pharmacokinetics; CVVHD; Renal replacement therapy; Pharmacodynamics Abstract: Objective The clinical effect of beta-lactam antibiotics depends on the time of drug concentration above the minimal inhibitory concentration (MIC) for a susceptible bacterium. Continuous infusion (CI) of ss-lactams such as meropenem may therefore be a more rational approach than intermittent bolus injections (IB). The aim of this study was to test whether CI of meropenem achieves effective drug concentrations comparable to IB in patients treated by continuous renal replacement therapy (CRRT). Design Prospective, randomised cross-over study. Setting Twelve-bed medical intensive care unit (ICU). Patients and interventions Six ICU patients were randomised to receive either meropenem 1a-g IB every 12a-h or a 0.5a-g i.v. loading dose followed by 2a-g i.v. CI over 24a-h. After 2 days, regimens were crossed over. Meropenem pharmacokinetics were determined on days 2 and 4. Measurements and results Peak serum concentration [median (25% and 75% quartiles)] after short infusion of 1a-g meropenem were 62.8 (51.4 85.0) mg/l, trough levels at 12a-h were 8.1 (4.5 18.7) mg/l, and serum half-life was 5.3 (5.1 7.0) h. Steady-state concentrations during CI were 18.6 (13.3 24.5) mg/l. The AUCs during either treatment were comparable and determined as 233 (202 254) mg/l*h (IB) and 227 (182 283) mg/l*h (CI), respectively. Four hours after IB, drug concentrations dropped below CI steady-state concentrations. Conclusion Appropriate antibacterial concentrations of meropenem in patients with CRRT are easily achievable with CI. CI may be an effective alternative dosing regimen to IB. A prospective comparison of the clinical efficacy of the two dosage regimens is warranted. Author Affiliation: (1) Department of Internal Medicine I, University of Regensburg, 93042, Regensburg, Germany (2) Department of Internal Medicine, General Hospital Traunstein, Postfach 1820, 83276, Traunstein, Germany (3) Department of Internal Medicine, General Hospital Bogen, Mussinanstr. 8, 94327, Bogen, Germany (4) Department of Pharmacology, University of Regensburg, 93053, Regensburg, Germany Article History: Registration Date: 28/01/2008 Received Date: 20/09/2007 Accepted Date: 24/12/2007 Online Date: 23/02/2008 Article note: The authors wrote this article in cooperation with the TAHI section of the ESICM.

Background. Intrapartum antibiotic prophylaxis against group B Streptococcus (GBS) has reduced the occurrence of serious bacterial infections (SBI) in young infants caused by GBS. Recommendations for initial antibiotic therapy for the febrile infant 1 to 90 days old were developed when infections with GBS were common and antibiotic resistance was rare. Objective. To document the pathogens responsible for SBI in recent years in febrile infants 1 to 90 days old and the antibiotic susceptibility of these organisms. Methods. The results of bacterial cultures from infants 1 to 90 days old evaluated for fever at Primary Children's Medical Center in Salt Lake City, Utah, between July 1999 and April 2002 were analyzed. Antibiotic susceptibility profiles were collected and patient records were reviewed to determine if initial antibiotic therapy was changed following the identification of the organism. Results. Of 1298 febrile infants enrolled from the Primary Children's Medical Center emergency department, 105 (8%) had SBI. The mean age of the infants with SBI was 39 days (range 2-82 days) and 2 (2%) were Of the 105 pathogens, 56 (53%) were resistant to ampicillin. Of the pathogens causing meningitis, UTI, and bacteremia, 78%, 53%, and 50%, respectively, were resistant to ampicillin. Antibiotic therapy was changed in 54% of cases of SBI following identification of the organism. Conclusions. In Utah, ampicillin-resistant Gram-negative bacteria are the most common cause of SBI in febrile infants, ABBREVIATIONS. GBS, group B Streptococcus; SBI, serious bacterial infection; UTI, urinary tract infection; ESBL, extended spectrum [beta]-lactamases; ampC, ampC [beta]-lactamases; PCMC, Primary Children's Medical Center; ED, emergency department; CSF, cerebrospinal [...]