Antibiotics for treatment of leptospirosis.

BACKGROUND: Leptospirosis is a disease transmitted from animals to humans through water, soil, or food contaminated with the urine of infected animals, caused by pathogenic Leptospira species. Antibiotics are commonly prescribed for the management of leptospirosis. Despite the widespread use of antibiotic treatment for leptospirosis, there seems to be insufficient evidence to determine its effectiveness or to recommend antibiotic use as a standard practice. This updated systematic review evaluated the available evidence regarding the use of antibiotics in treating leptospirosis, building upon a previously published Cochrane review. OBJECTIVES: To evaluate the benefits and harms of antibiotics versus placebo, no intervention, or another antibiotic for the treatment of people with leptospirosis. SEARCH METHODS: We identified randomised clinical trials following standard Cochrane procedures. The date of the last search was 27 March 2023. SELECTION CRITERIA: We searched for randomised clinical trials of various designs that examined the use of antibiotics for treating leptospirosis. We did not impose any restrictions based on the age, sex, occupation, or comorbidities of the participants involved in the trials. Our search encompassed trials that evaluated antibiotics, regardless of the method of administration, dosage, and schedule, and compared them with placebo or no intervention, or compared different antibiotics. We included trials regardless of the outcomes reported. DATA COLLECTION AND ANALYSIS: During the preparation of this review, we adhered to the Cochrane methodology and used Review Manager. The primary outcomes were all-cause mortality and serious adverse events (nosocomial infection). Our secondary outcomes were quality of life, proportion of people with adverse events considered non-serious, and days of hospitalisation. To assess the risk of bias of the included trials, we used the RoB 2 tool, and for evaluating the certainty of evidence we used GRADEpro GDT software. We presented dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD), both accompanied by their corresponding 95% confidence intervals (CI). We used the random-effects model for all our main analyses and the fixed-effect model for sensitivity analyses. For our primary outcome analyses, we included trial data from the longest follow-up period. MAIN RESULTS: We identified nine randomised clinical trials comprising 1019 participants. Seven trials compared two intervention groups and two trials compared three intervention groups. Amongst the trials comparing antibiotics versus placebos, four trials assessed penicillin and one trial assessed doxycycline. In the trials comparing different antibiotics, one trial evaluated doxycycline versus azithromycin, one trial assessed penicillin versus doxycycline versus cefotaxime, and one trial evaluated ceftriaxone versus penicillin. One trial assessed penicillin with chloramphenicol and no intervention. Apart from two trials that recruited military personnel stationed in endemic areas or military personnel returning from training courses in endemic areas, the remaining trials recruited people from the general population presenting to the hospital with fever in an endemic area. The participants' ages in the included trials was 13 to 92 years. The treatment duration was seven days for penicillin, doxycycline, and cephalosporins; five days for chloramphenicol; and three days for azithromycin. The follow-up durations varied across trials, with three trials not specifying their follow-up periods. Three trials were excluded from quantitative synthesis; one reported zero events for a prespecified outcome, and two did not provide data for any prespecified outcomes. Antibiotics versus placebo or no intervention The evidence is very uncertain about the effect of penicillin versus placebo on all-cause mortality (RR 1.57, 95% CI 0.65 to 3.79; I2 = 8%; 3 trials, 367 participants; very low-certainty evidence). The evidence is very uncertain about the effect of penicillin or chloramphenicol versus placebo on adverse events considered non-serious (RR 1.05, 95% CI 0.35 to 3.17; I2 = 0%; 2 trials, 162 participants; very low-certainty evidence). None of the included trials assessed serious adverse events. Antibiotics versus another antibiotic The evidence is very uncertain about the effect of penicillin versus cephalosporin on all-cause mortality (RR 1.38, 95% CI 0.47 to 4.04; I2 = 0%; 2 trials, 348 participants; very low-certainty evidence), or versus doxycycline (RR 0.93, 95% CI 0.13 to 6.46; 1 trial, 168 participants; very low-certainty evidence). The evidence is very uncertain about the effect of cefotaxime versus doxycycline on all-cause mortality (RR 0.18, 95% CI 0.01 to 3.78; 1 trial, 169 participants; very low-certainty evidence). The evidence is very uncertain about the effect of penicillin versus doxycycline on serious adverse events (nosocomial infection) (RR 0.62, 95% CI 0.11 to 3.62; 1 trial, 168 participants; very low-certainty evidence) or versus cefotaxime (RR 1.01, 95% CI 0.15 to 7.02; 1 trial, 175 participants; very low-certainty evidence). The evidence is very uncertain about the effect of doxycycline versus cefotaxime on serious adverse events (nosocomial infection) (RR 1.01, 95% CI 0.15 to 7.02; 1 trial, 175 participants; very low-certainty evidence). The evidence is very uncertain about the effect of penicillin versus cefotaxime (RR 3.03, 95% CI 0.13 to 73.47; 1 trial, 175 participants; very low-certainty evidence), versus doxycycline (RR 2.80, 95% CI 0.12 to 67.66; 1 trial, 175 participants; very low-certainty evidence), or versus chloramphenicol on adverse events considered non-serious (RR 0.74, 95% CI 0.15 to 3.67; 1 trial, 52 participants; very low-certainty evidence). Funding Six of the nine trials included statements disclosing their funding/supporting sources and three trials did not mention funding source. Four of the six trials mentioning sources received funds from public or governmental sources or from international charitable sources, and the remaining two, in addition to public or governmental sources, received support in the form of trial drug supply directly from pharmaceutical companies. AUTHORS' CONCLUSIONS: As the certainty of evidence is very low, we do not know if antibiotics provide little to no effect on all-cause mortality, serious adverse events, or adverse events considered non-serious. There is a lack of definitive rigorous data from randomised trials to support the use of antibiotics for treating leptospirosis infection, and the absence of trials reporting data on clinically relevant outcomes further adds to this limitation.

Bacterial Isolates and Characteristics of Children With Febrile Neutropenia on Treatment for Cancer at a Tertiary Hospital in Western Kenya.

PURPOSE: This study aimed to identify the patient characteristics of children with febrile neutropenia, the associated bacterial organisms, and their sensitivity patterns. MATERIALS AND METHODS: A descriptive cross-sectional study was conducted at the Moi Teaching and Referral Hospital (MTRH) pediatric oncology ward, from June 2021 to April 2022. A total of 110 children who developed fever and neutropenia during chemotherapy were enrolled. Blood samples for culture were collected aseptically. Patient characteristics were presented in frequency tables. Antimicrobial sensitivity patterns were plotted in tables against the bacterial isolates cultured. Chi-square/Fisher's exact test was used to determine any association between patient characteristics, bacterial growth, and antimicrobial sensitivity. RESULTS: The majority (n = 66; 60%) were males. The median age was 6.3 years (standard deviation, 3.7). The majority of patients 71 (64.5%) had hematologic malignancies, the most common being AML. There was a significant association between severity of neutropenia and hematologic malignancies (P = .028). In total, 31/110 (28.2%) blood cultures were positive for bacterial growth. Gram-positive bacteria were more frequent (n = 20; 58.1%). The most common organism was Escherichia coli (n = 6; 18.2%), followed by Staphylococcus aureus (n = 5; 15.2%). All the isolates were sensitive to linezolid and vancomycin and also showed good sensitivity toward meropenem (n = 10/11; 90.9%). High resistance to cephalosporins was noted with ceftriaxone (n = 5/6; 83.3%), cefepime (n = 4/7; 57.1%), and ceftazidime (n = 3/4; 75%). CONCLUSION: The most common malignancy associated with febrile neutropenia was AML. Gram-positive bacteria were the most common isolates. There was high resistance to cephalosporins.

Ceftriaxone-induced encephalopathy in a patient with a normal renal function.

Ceftriaxone-induced encephalopathy is an exceptionally rare adverse effect of this commonly used cephalosporin and is generally observed in patients undergoing haemodialysis or suffering from severe renal failure. We present a case of a fit woman in her mid-80s with a normal renal function who developed severe fluctuating neurological symptoms (aphasia, loss of contact, chorea-like tongue movements) while being treated with ceftriaxone for a urinary tract infection with bacteraemia. The symptoms began on day 4 of treatment and an adverse drug reaction was suspected on day 7, after exhaustive investigations failed to reveal another cause. A complete recovery was observed 3 days after discontinuing ceftriaxone. Our case highlights the need to consider the diagnosis of ceftriaxone encephalopathy, even if the traditional risk factors are lacking. In this article, we also provide a brief overview of the pathophysiology as well as a literature review concerning the subject.

Assessing Pediatric Cephalosporin Allergic Reactions Through Direct Graded Oral Challenges.

BACKGROUND: Cephalosporins, ß-lactam antibiotics, commonly cause allergic reactions. OBJECTIVE: To assess the clinical characteristics and management of pediatric patients with suspected cephalosporin allergy using direct graded oral challenges (GOCs). METHODS: Children referred for suspected cephalosporin allergy at 4 Canadian clinics were recruited over 10 years. Data on demographics, clinical reaction characteristics, and management were collected through a questionnaire. Patients underwent a direct GOC (initially 10% of the treatment dose, then 90% after 20 min), and reactions were monitored 1 week postchallenge. Families were contacted annually for up to 5 years to detect subsequent antibiotic reactions. Logistic regression analysis identified factors associated with positive GOC reactions. RESULTS: Among the 136 patients reporting cephalosporin allergy, 75 (55.1%) were males with a median age of 3.9 years (interquartile range 2.3-8.7). Cefprozil represented the most common cephalosporin linked to the index reaction (67.6% of cases). Of the 136 direct GOCs, 5.1% had an immediate and 4.4% a nonimmediate reaction, respectively. Positive GOCs conducted in children with a history of skin-limited nonsevere rashes were classified as mild, benign skin rashes. Positive GOCs were more likely in children with food allergies (adjusted odds ratio 1.14; 95% confidence interval [95% CI] 1.00-1.29). CONCLUSIONS: Direct GOCs are safe and effective for diagnosing pediatric cases that report nonvesicular skin-limited symptoms while being treated with cephalosporins.

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.

Safety and effectiveness of fifth generation cephalosporins for the treatment of methicillin-resistant staphylococcus aureus bloodstream infections: a narrative review exploring past, present, and future.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a major issue in healthcare, since it is often associated with endocarditis or deep site foci. Relevant morbidity and mortality associated with MRSA-BSIs forced the development of new antibiotic strategies; in particular, this review will focus the attention on fifth-generation cephalosporins (ceftaroline/ceftobiprole), that are the only ß-lactams active against MRSA. AREAS COVERED: The review discusses the available randomized controlled trials and real-world observational studies conducted on safety and effectiveness of ceftaroline/ceftobiprole for the treatment of MRSA-BSIs. Finally, a proposal of MRSA-BSI treatment flowchart, based on fifth-generation cephalosporins, is described. EXPERT OPINION: The use of anti-MRSA cephalosporins is an acceptable choice either in monotherapy or combination therapy for the treatment of MRSA-BSIs due to their relevant effectiveness and safety. Particularly, their use may be advisable in combination therapy in case of severe infections (including endocarditis or persistent bacteriemia) or in monotherapy in subjects at higher risk of drugs-induced toxicity with older regimens. On the contrary, caution should be taken in case of suspected/ascertained central nervous system infections due to inconsistent data regarding penetration of these drugs in cerebrospinal fluid and brain tissues.

Cefiderocol-associated brown chromaturia.

Cefiderocol is a novel siderophore cephalosporin antibiotic. In the present case report, a woman in her 70s presented with a 1-week history of altered mental status and progressive purulent discharge from a non-healing diabetic foot ulcer on her right heel. MRI of the right foot revealed chronic osteomyelitis of the calcaneum. Surgical debridement was performed, and the tissue cultures grew extensively drug resistant (XDR) Pseudomonas aeruginosa, XDR Acinetobacter baumannii and Enterococcus faecalis The patient received ampicillin-sulbactam and cefiderocol. The antibiotic treatment course was complicated by brown urine discolouration. Investigations were unrevealing for haemoglobinuria, myoglobinuria and bilirubinuria. A side effect from cefiderocol was suspected and subsequently discontinued. Her urine colour returned to its normal colour within 3 days of discontinuation of cefiderocol.

Different antibiotic treatments for group A streptococcal pharyngitis.

BACKGROUND: Antibiotics provide only modest benefit in treating sore throat, although their effectiveness increases in people with positive throat swabs for group A beta-haemolytic streptococci (GABHS). It is unclear which antibiotic is the best choice if antibiotics are indicated. This is an update of a review first published in 2010, and updated in 2013, 2016, and 2021. OBJECTIVES: To assess the comparative efficacy of different antibiotics in: (a) alleviating symptoms (pain, fever); (b) shortening the duration of the illness; (c) preventing clinical relapse (i.e. recurrence of symptoms after initial resolution); and (d) preventing complications (suppurative complications, acute rheumatic fever, post-streptococcal glomerulonephritis). To assess the evidence on the comparative incidence of adverse effects and the risk-benefit of antibiotic treatment for streptococcal pharyngitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2023, Issue 2), MEDLINE Ovid, Embase Elsevier, and Web of Science (Clarivate) up to 19 March 2023. SELECTION CRITERIA: Randomised, double-blind trials comparing different antibiotics, and reporting at least one of the following: clinical cure, clinical relapse, or complications and/or adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials for inclusion and extracted data using standard methodological procedures recommended by Cochrane. We assessed the risk of bias in the included studies according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions, and used the GRADE approach to assess the overall certainty of the evidence for the outcomes. We reported the intention-to-treat analysis, and also performed an analysis of evaluable participants to explore the robustness of the intention-to-treat results. MAIN RESULTS: We included 19 trials reported in 18 publications (5839 randomised participants): six trials compared penicillin with cephalosporins; six compared penicillin with macrolides; three compared penicillin with carbacephem; one compared penicillin with sulphonamides; one compared clindamycin with ampicillin; and one compared azithromycin with amoxicillin in children. All participants had confirmed acute GABHS tonsillopharyngitis, and ages ranged from one month to 80 years. Nine trials included only, or predominantly, children. Most trials were conducted in an outpatient setting. Reporting of randomisation, allocation concealment, and blinding was poor in all trials. We downgraded the certainty of the evidence mainly due to lack of (or poor reporting of) randomisation or blinding, or both, heterogeneity, and wide confidence intervals. Cephalosporins versus penicillin We are uncertain if there is a difference in symptom resolution (at 2 to 15 days) for cephalosporins versus penicillin (odds ratio (OR) for absence of symptom resolution 0.79, 95% confidence interval (CI) 0.55 to 1.12; 5 trials, 2018 participants; low-certainty evidence). Results of the sensitivity analysis of evaluable participants differed (OR 0.51, 95% CI 0.27 to 0.97; 5 trials, 1660 participants; very low-certainty evidence). Based on an analysis of evaluable participants, we are uncertain if clinical relapse may be lower for cephalosporins compared with penicillin (OR 0.55, 95% CI 0.30 to 0.99; number needed to treat for an additional beneficial outcome (NNTB) 50; 4 trials, 1386 participants; low-certainty evidence). Very low-certainty evidence showed no difference in reported adverse events. Macrolides versus penicillin We are uncertain if there is a difference between macrolides and penicillin for resolution of symptoms (OR 1.11, 95% CI 0.92 to 1.35; 6 trials, 1728 participants; low-certainty evidence). Sensitivity analysis of evaluable participants resulted in an OR of 0.79 (95% CI 0.57 to 1.09; 6 trials, 1159 participants). We are uncertain if clinical relapse may be different (OR 1.21, 95% CI 0.48 to 3.03; 6 trials, 802 participants; low-certainty evidence). Children treated with macrolides seemed to experience more adverse events than those treated with penicillin (OR 2.33, 95% CI 1.06 to 5.15; 1 trial, 489 participants; low-certainty evidence). However, the test for subgroup differences between children and adults was not significant. Azithromycin versus amoxicillin Based on one unpublished trial in children, we are uncertain if resolution of symptoms is better with azithromycin in a single dose versus amoxicillin for 10 days (OR 0.76, 95% CI 0.55 to 1.05; 1 trial, 673 participants; very low-certainty evidence). Sensitivity analysis for per-protocol analysis resulted in an OR of 0.29 (95% CI 0.11 to 0.73; 1 trial, 482 participants; very low-certainty evidence). We are also uncertain if there was a difference in relapse between groups (OR 0.88, 95% CI 0.43 to 1.82; 1 trial, 422 participants; very low-certainty evidence). Adverse events were more common with azithromycin compared to amoxicillin (OR 2.67, 95% CI 1.78 to 3.99; 1 trial, 673 participants; very low-certainty evidence). Carbacephem versus penicillin There is low-certainty evidence that compared with penicillin, carbacephem may provide better symptom resolution post-treatment in adults and children (OR 0.70, 95% CI 0.49 to 0.99; NNTB 14.3; 3 trials, 795 participants). Studies did not report on long-term complications, so it was unclear if any class of antibiotics was better at preventing serious but rare complications. AUTHORS' CONCLUSIONS: We are uncertain if there are clinically relevant differences in symptom resolution when comparing cephalosporins and macrolides with penicillin in the treatment of GABHS tonsillopharyngitis. Low-certainty evidence in children suggests that carbacephem may be more effective than penicillin for symptom resolution. There is insufficient evidence to draw conclusions regarding the other comparisons in this review. Data on complications were too scarce to draw conclusions. Antibiotics have a limited effect in the treatment of GABHS pharyngitis and the results do not demonstrate that other antibiotics are more effective than penicillin. In the context of antimicrobial stewardship, penicillin can be used if treatment with an antibiotic is indicated. All studies were conducted in high-income countries with a low risk of streptococcal complications, so there is a need for trials in low-income countries and disadvantaged populations, where the risk of complications remains high.

Stevens-Johnson syndrome: a case report of possible cephalosporin-induced cutaneous adverse reaction.

A severe medical condition known as Stevens-Johnson syndrome (SJS) is marked by a cutaneous and mucosal reaction from the use of specific medications. The prodromal illness is followed by severe mucocutaneous symptoms in this immune-mediated disease. We describe the clinical history of a 55-year-old Caucasian woman who was exposed to cephalosporins. In resource-constrained countries and hospitals where cutaneous biopsy is not readily available, it is not easy to diagnose Steven Johnson Syndrome. This is particularly true in countries where the incidence of infectious diseases such as scarlet fever and measles is high and the early symptoms of SJS can be mistaken for these conditions. We used the Naronjo scale to confirm the probable association of the drug with the syndrome. Physicians while writing prescriptions for their patients need to warn them of potential side effects and they should keep in mind conditions like Stevens-Johnson syndrome. This case report highlights the need for improved knowledge and understanding of SJS among healthcare practitioners in resource-limited communities where the prevalence of infectious diseases is high.

Systematic review of ceftaroline fosamil in the management of patients with methicillin-resistant Staphylococcus aureus pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for an array of problematic community- and healthcare-acquired infections, including pneumonia, and is frequently associated with severe disease and high mortality rates. Standard recommended treatments for empiric and targeted coverage of suspected MRSA in patients with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), are vancomycin and linezolid. However, adverse events such as acute kidney injury and Clostridium difficile infection have been associated with these antibiotics. Ceftaroline fosamil is a ß-lactam/extended-spectrum cephalosporin approved for the treatment of adults and children with CAP and complicated skin and soft tissue infections. Ceftaroline has in vitro activity against a range of common Gram-positive bacteria and is distinct among the ß-lactams in retaining activity against MRSA. Due to the design of the pivotal randomised controlled trials of ceftaroline fosamil, outcomes in patients with MRSA CAP were not evaluated. However, various reports of real-world outcomes with ceftaroline fosamil for pneumonia caused by MRSA, including CAP and HAP/VAP, been published since its approval. A systematic literature review and qualitative analysis of relevant publications was undertaken to collate and summarise relevant published data on the efficacy and safety of ceftaroline fosamil in patients with MRSA pneumonia. While relatively few real-world outcomes studies are available, the available data suggest that ceftaroline fosamil is a possible alternative to linezolid and vancomycin for MRSA pneumonia. Specific scenarios in which ceftaroline fosamil might be considered include bacteraemia and complicating factors such as empyema.

Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria.

BACKGROUND: Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For ß-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). OBJECTIVES: To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. METHODS: Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition. RESULTS: Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. CONCLUSIONS: The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.

Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia.

BACKGROUND: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus. METHODS: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed. RESULTS: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole. CONCLUSIONS: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).

Association Between Fluoroquinolone Use and Hospitalization With Aortic Aneurysm or Aortic Dissection.

Importance: Fluoroquinolone use has been associated with increased hospitalization with aortic aneurysm or dissection in noninterventional studies, but the reason for this observed association is unclear. Objective: To determine the association between fluoroquinolone use and aortic aneurysm or dissection using multiple study designs and multiple databases to increase the robustness of findings. Design, Setting, and Participants: Cohort and case-crossover studies were conducted separately in 2 databases of UK primary care records. Clinical Practice Research Datalink Aurum and GOLD primary care records were linked to hospital admissions data. Adults with a systemic fluoroquinolone or cephalosporin prescription between April 1997 and December 2019 were included in the cohort study. Adults hospitalized with aortic aneurysm or dissection within the eligibility period were included in the case-crossover study. Individuals meeting inclusion criteria in the case-crossover study were matched 1:3 to control individuals on age, sex, index date, and clinical practice to adjust for calendar trends in prescribing. Data were analyzed from January to July 2022. Exposures: Systemic fluoroquinolone or comparator antibiotic. Main Outcomes and Measures: Hazard ratios (HRs) were estimated in the cohort study for the association between prescription of fluoroquinolones and hospitalization with aortic aneurysm or dissection using stabilized inverse probability of treatment-weighted Cox regression. Odds ratios (OR) were estimated in the case-crossover study for the association between systemic fluoroquinolone use and hospitalization with aortic aneurysm or dissection using a conditional logistic regression model. Estimates were pooled across databases using fixed-effects meta-analysis. Results: In the cohort study, we identified 3 134 121 adults in Aurum (mean [SD] age, 52.5 [20.3] years; 1 969 257 [62.8%] female) and 452 086 in GOLD (mean [SD] age, 53.9 [20.2] years; 286 502 [63.4%] female) who were prescribed fluoroquinolones or cephalosporins. In crude analyses, fluoroquinolone relative to cephalosporin use was associated with increased hospitalization with aortic aneurysm or dissection (pooled HR, 1.28; 95% CI, 1.13-1.44; P < .001) but after adjustment for potential confounders, this association disappeared (pooled adjusted HR, 1.03; 95% CI, 0.91-1.17; P = .65). In the case-crossover study, we identified 84 841 individuals hospitalized with aortic aneurysm or dissection in Aurum (mean [SD] age, 75.5 [10.9]; 23 551 [27.8%] female) and 10 357 in GOLD (mean [SD] age, 75.6 [10.5]; 2809 [27.1%] female). Relative to nonuse, fluoroquinolone use was associated with an increase in hospitalization with aortic aneurysm or dissection, but no association was found relative to other antibiotics (vs cephalosporin pooled OR, 1.05; 95% CI, 0.87-1.27; vs trimethoprim, 0.89; 95% CI, 0.75-1.06; vs co-amoxiclav, 0.98; 95% CI, 0.82-1.18). Conclusions and Relevance: The results in this study suggest that estimates of association of fluoroquinolones with aortic aneurysm or dissection may be affected by confounding. When such confounding is accounted for, no association was evident, providing reassurance on the safety of fluoroquinolones with respect to aortic aneurysm or dissection.

The state and consideration for skin test of ß-lactam antibiotics in pediatrics.

ß-lactam antibiotics are the most frequently used drugs and the most common drugs that cause allergic reactions in pediatrics. The occurrence of some allergic reactions can be predicted by skin testing, especially severe adverse reactions such as anaphylactic shock. Thus, penicillin and cephalosporin skin tests are widely used to predict allergic reactions before medication in pediatrics. However, false-positive results from skin tests were more often encountered in pediatrics than in adults. In fact, many children labeled as allergic to ß-lactam are not allergic to the antibiotic, leading to the use of alternative antibiotics, which are less effective and more toxic, and the increase of antibiotic resistance. There has been controversy over whether ß-lactam antibiotics should be tested for skin allergies before application in children. Based on the great controversy in the implementation of ß-lactam antibiotic skin tests, especially the controversial cephalosporin skin tests in pediatrics, the mechanism and reasons of anaphylaxis to ß-lactam antibiotics, the significance of ß-lactam antibiotic skin tests, the current state of ß-lactam antibiotic skin tests at home and abroad, and the problems of domestic and international skin tests were analyzed to determine a unified standard of ß-lactam antibiotic skin tests in pediatrics to prevent and decrease adverse drug reactions, avoid waste of drugs, and a large amount of manpower and material resource consumption.

The safety of ceftolozane/tazobactam for the treatment of complicated urinary tract infections.

INTRODUCTION: Ceftolozane is a cephalosporin similar to ceftazidime in its structure, which is marketed in combination with tazobactam, a well-known ß-lactamase inhibitor. AREAS COVERED: After a brief introduction on the drug characteristics and efficacy, we focused on available data from randomized controlled trials and post-marketing observational studies pertaining to the safety of ceftolozane/tazobactam (C/T) for the treatment of complicated urinary tract infections (cUTI). A search was conducted in PubMed from January 2010 to February 2023. EXPERT OPINION: The use of C/T for the treatment of cUTI is supported by solid efficacy and safety data, especially for the treatment of those pathogens where it can represent a first-line approach due to some peculiar characteristics: (i) treatment of cUTI caused by multidrug-resistant Pseudomonas aeruginosa, in view of its frequent activity against carbapenem-resistant isolates when resistance mechanisms other than production of carbapenemases are concerned; (ii) treatment of cUTI caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales in those settings where the selective pressure for carbapenem resistance needs to be relieved, as a suitable and effective carbapenem-sparing option. Although development of resistance to C/T during or after treatment has been reported, this has been reported very rarely in patients receiving C/T for the treatment of cUTI.

Piperacillin-Tazobactam Versus Anti-Pseudomonal Cephalosporins and Renal and Neurologic Outcomes in Critically Ill Adults: A Secondary Analysis of the SMART Trial.

Background: Prior studies suggest associations between receipt of piperacillin-tazobactam and development of acute kidney injury and receipt of anti-pseudomonal cephalosporins and neurotoxicity. We compared clinically-relevant renal and neurologic outcomes in critically ill patients who received piperacillin-tazobactam versus anti-pseudomonal cephalosporins. Methods: We conducted a secondary analysis of data from the Isotonic Solutions and Major Adverse Renal Events Trial examining patients who received piperacillin-tazobactam or an anti-pseudomonal cephalosporin within 24 h of intensive care unit admission. We performed multivariable analysis using a proportional odds model to examine the association between the first antibiotic received and the outcomes of Major Adverse Kidney Events within 30 days (MAKE30) and days alive and free of delirium and coma to day 28. Results: 3199 were included in the study; 2375 (74%) receiving piperacillin-tazobactam and 824 (26%) receiving anti-pseudomonal cephalosporin. After adjustment for prespecified confounders, initial receipt of piperacillin-tazobactam, compared to anti-pseudomonal cephalosporins, was not associated with higher incidence of MAKE30 (adjusted odds ratio, 1.03; 95% CI, 0.83-1.27; P = .80) but was associated with a greater number of days alive and free of delirium and coma (adjusted odds ratio, 1.18; 95% CI, 1.00-1.38; P = .04). In a sensitivity analysis adjusting for baseline receipt of medications which may impact neuro function, this finding was not significant. Conclusion: Among critically ill adults, receipt of piperacillin-tazobactam was not associated with an increased incidence of death, renal replacement therapy, or persistent renal dysfunction or a greater number of days alive and free of delirium and coma. Randomized trials are needed to inform the choice of antibiotics for empiric treatment infection in critically ill adults.

Nephrotoxicity of Amoxicillin and Third-Generation Cephalosporins: An Updated Review.

Because of their broad-spectrum bactericidal activity, amoxicillin (AMX) and third-generation cephalosporins (TGC) are widely used for the prophylaxis and treatment of established infections. They are considered relatively safe, but several recent reports have suggested substantial nephrotoxicity, especially with AMX use. Considering the importance of AMX and TGC for clinical practice, we conducted this up-to-date review, using the PubMed database, which focuses specifically on the nephrotoxicity of these molecules. We also briefly review the pharmacology of AMX and TGC. Nephrotoxicity of AMX may be driven by several pathophysiological mechanisms, such as a type IV hypersensitivity reaction, anaphylaxis, or intratubular and/or urinary tract drug precipitation. In this review, we focused on the two main renal adverse effects of AMX, namely acute interstitial nephritis and crystal nephropathy. We summarize the current knowledge in terms of incidence, pathogenesis, factors, clinical features, and diagnosis. The purpose of this review is also to underline the probable underestimation of AMX nephrotoxicity and to educate clinicians about the recent increased incidence and severe renal prognosis associated with crystal nephropathy. We also suggest some key elements on the management of these complications to avoid inappropriate use and to limit the risk of nephrotoxicity. While renal injury appears to be rarer with TGC, several patterns of nephrotoxicity have been reported in the literature, such as nephrolithiasis, immune-mediated hemolytic anemia, or acute interstitial nephropathy, which we detail in the second part of this review.

Impact of an Inpatient Allergy Guideline on ß-Lactam and Alternative Antibiotic Use.

BACKGROUND: A guideline identifying when inpatients with penicillin or cephalosporin antibiotic allergy labels (PCAAL) can receive ß-lactam antibiotics increased ß-lactam receipt at a large northeastern US health care system. OBJECTIVE: To report outcomes of implementing a similar guideline and electronic order set (OS) at an independent academic health care system. METHODS: Penicillin/cephalosporin receipt (percentage of inpatients receiving full doses) and alternative antibiotic use (days of therapy per 1000 patient-days [DOT/1000PD]) were compared over 3 periods before (February 1, 2017, to January 31, 2018) and after guideline implementation (February 1, 2018, to January 31, 2019), and after OS implementation (February 1, 2019, to January 31, 2020) among inpatients with PCAAL admitted on medical services with access to guideline/OS and education (Medical-PCAAL, n = 8721), surgical services with access to guideline/OS without education (Surgical-PCAAL, n = 5069), and obstetrics/gynecology services without interventions (Ob/Gyn-PCAAL, n = 798) and inpatients without PCAAL admitted on the same services (Medical-No-PCAAL, n = 50,840; Surgical-No-PCAAL, n = 29,845; Ob/Gyn-No-PCAAL, n = 6109). χ2 tests were used to compare categorical variables, and analysis of variance was used to compare continuous and interrupted time series analyses (ITSA) to investigate the guideline/OS implementation effect on penicillin/cephalosporin receipt. RESULTS: In the Medical-PCAAL group, penicillin/cephalosporin receipt increased (58%-68%, P < .001), specifically for cefazolin (8%-11%, P = .02) and third- to fifth-generation cephalosporins (43%-48%, P = .04), and aztreonam use decreased (12 DOT/1000PD, P = .03). In the Medical-No-PCAAL group, penicillin/cephalosporin receipt increased (88%-90%, P = .004), specifically for penicillin (40%-44%, P < .001), without changes in aztreonam use. Significant changes were not observed in these outcomes on surgical or obstetrics/gynecology services. Per ITSA, guideline/OS implementation was associated with increased penicillin/cephalosporin receipt in the Medical-PCAAL group only. CONCLUSION: Guideline and OS implementation was associated with improved antibiotic stewardship on inpatient services that also received allergy education.