Search

Oral antimicrobials remain the mainstay of long-term treatment for many infections. Meanwhile, the use of oral agents is becoming commonplace for the treatment of several pediatric infections once managed exclusively with parenteral therapies. Unfortunately, antimicrobials are associated with several laboratory toxicities, particularly when high doses or combination therapies are used, but there is a paucity of data on optimal laboratory monitoring strategies. In this ID Consultant article, we offer a summary of the 3 most common laboratory-based toxicities seen with long-term use of oral antimicrobials-drug-induced kidney injury, liver injury, and hematological toxicities-and we provide our recommended approach to monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To examine associations of prenatal and early-life anti-infective exposures with obesity at 7 years., Methods: In this nationwide, registry-based, prevalence study, we included all children with an anthropometric assessment at age 7 years from the Children's Database and linked their data with Danish population-based registries from 2001 to 2018. We defined exposure to anti-infectives (anti-bacterials, anti-virals, and anti-fungals) by outpatient dispensings or by infection diagnoses at hospital encounters. The earliest date defined the exposure timing category: prenatal (-9 months- < 0 months), infancy (0- < 2 years), and early childhood (2- < 5 years). We computed prevalence ratios (aPRs) for associations of anti-infective exposure with obesity prevalence at 7 years of age, adjusting for maternal and perinatal factors., Results: We included 460 363 children (51% boys). Prevalence of obesity at 7 years of age was 38% higher (aPR = 1.38, 95% confidence interval (CI): 1.27-1.49) among children exposed to any anti-infective, 21% higher (aPR = 1.21, 95% CI: 1.12-1.31) among children exposed to anti-infectives in infancy, and 14% higher (aPR = 1.14, 95% CI: 1.03-1.26) among children exposed to anti-infectives in early childhood. Exposure to anti-bacterials was associated with obesity in a similar time-dependent pattern [prenatal: aPR = 1.39 (95% CI: 1.29-1.50), infancy: aPR = 1.21 (95% CI: 1.12-1.30), and early childhood: aPR = 1.14 (95% CI: 1.03-1.25)]. For anti-virals and anti-fungals, exposure during infancy and early childhood was associated with larger aPRs than prenatal exposure. Furthermore, obesity prevalence increased monotonically with number of the anti-infective prescriptions., Conclusion: These findings suggest that prenatal and early-life exposure to anti-infectives increases the risk of childhood obesity and that the magnitude of the associations depends on anti-infective type, timing, and dose., (© 2024 John Wiley & Sons Ltd.)

Objectives: Evidence on the optimal frequency of laboratory testing during outpatient parenteral antimicrobial therapy (OPAT) is lacking. Therefore, we investigated how often and when laboratory abnormalities occur during OPAT and which factors are associated with these abnormalities., Methods: We performed a multicenter cohort study in four Dutch hospitals among adult patients receiving OPAT and collected routinely obtained laboratory test results. Incidence and incidence rates were calculated for various laboratory abnormalities. Survival analysis was performed to visualize the time to the first occurrence of laboratory abnormalities and Poisson regression analysis to compare the number of abnormalities in the first and second 30 OPAT days among patients receiving OPAT for ≥60 days. Predictors were identified using a multivariable Cox proportional hazard regression model., Results: 45.1% of 1152 included patients developed laboratory abnormalities, but only 2% led to OPAT discontinuation. Hepatotoxicity was most common (33.9 events/1000 OPAT days), with a time-dependent decrease in the occurrence of the first hepatotoxic event, while hypokalemia was rare (1.7 events/1000 OPAT days). In the subgroup of patients receiving ≥60 days of OPAT, nephrotoxicity was more common in days 31-60. We observed partly toxicity-specific associations between antibiotic type, concomitant medication, baseline laboratory values, patient characteristics, and the occurrence of laboratory abnormalities., Conclusions: While laboratory abnormalities are frequently observed during OPAT, they rarely lead to discontinuation of OPAT. Specific patient, treatment and laboratory characteristics were associated with the occurrence of laboratory abnormalities. Based on our results, we recommend a more personalized laboratory monitoring policy with less blood sampling., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Antimicrobials are widely used in hospitals and are often associated with adverse drug reactions (ADRs). The objective of this study was to determine the incidence of ADRs caused by antimicrobials and classify them according to the type of reaction, the class of antimicrobials used, causality, severity and avoidability., Methods: A prospective cohort study was carried out with paediatric patients for 6 months. Causality was verified using the Naranjo and Liverpool algorithms, the severity was verified with the adapted scale of Hartwig and the avoidability was verified with the Liverpool Avoidability Assessment Tool., Results: A total of 303 patients were followed, and 18.2% (55/303) of them had one or more ADRs during the hospital stay. Just over half of the patients (28/55) had diarrhea. The most used antimicrobials were beta-lactams and second-generation cephalosporins. Suspicions were classified mainly as possible 78.6% (55/70) according to the Naranjo algorithm, and as probable 48.6% (34/70) according to the Liverpool algorithm. The antimicrobial most involved with ADRs was cefepime. The risk of manifesting ADR was greater with the use of some antimicrobials such as clindamycin (relative risk (RR) 3.0, CI 1.67 to 5.4), as well as with the increase in hospitalisation days (OR 1.022, CI 1.008 to 1.036) and in the number of antimicrobials prescribed (OR 1.649, CI 1.360 to 2.001)., Conclusion: ADRs were observed in approximately one-fifth of patients and were mostly gastrointestinal, moderate, unavoidable and with variable causality, depending on the algorithm used., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We aimed to assess how antimicrobial exposure affects Parkinson's disease (PD) risk., Methods: A nested case-control study was performed to examine the association between antimicrobial exposure and newly diagnosed PD using the Clinical Practice Research Datalink (CPRD). Each PD case was matched by age, sex, and year of diagnosis (index date) to up to 15 controls. Number of prescribed antimicrobial courses was assessed 1-5, 6-10, and 11-15 years prior to the index date. Logistic regression with generalized estimating equations (GEE) was used to estimate odds ratios (ORs) and false discovery rate-adjusted p-values between antimicrobial exposure and risk of PD., Results: We compared 12,557 PD cases with 80,804 matched controls. We found an inverse dose-response relationship between number of penicillin courses and PD risk across multiple time periods (5+ courses, 1-5 years prior: OR 0.85, 95 % CI 0.76-0.95, p = 0.043; 6-10 years prior: OR 0.84, 95 % CI: 0.73-0.95, p = 0.059; 11-15 years prior: OR 0.87, 95 % CI 0.74-1.02, p = 0.291). The number of macrolide courses was inversely but not significantly associated with PD risk 1-5 years prior to the index date (OR 0.89-0.91, 95 % CI: 0.79-0.99, adjusted p = 0.140-0.167). Exposure to ≥2 courses of antifungals 1-5 years prior was associated with an increased risk of PD (OR 1.16, 95 % CI: 1.06-1.27, p = 0.020)., Conclusions: In a large UK-representative population, the risk of PD was modestly lower among adults who had previously received multiple courses of penicillins in the last 15 years and modestly higher among those exposed to antifungal medicines in recent years., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gian Pal reports financial support was provided by Parkinson's Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Ambient air pollution and antimicrobial resistance pose significant global public health challenges. It is not known whether ambient air pollution is associated with increased consumption of antimicrobials., Objective: To assess whether a short-term association exists between ambient air pollution levels and antimicrobial consumption among the general population seeking primary care consultations for acute respiratory symptoms., Design, Setting, and Participants: This 2-stage cross-sectional ecological time series analysis study using data on daily ambient air pollution and antimicrobial consumption was conducted in the 11 largest cities in Catalonia, Spain, from June 23, 2012, to December 31, 2019, among all inhabitants aged 12 years or older. Statistical analysis was performed from November 2022 to December 2023., Exposures: Daily ambient air pollution (particulate matter of 10 μg/m3 [PM10], particulate matter of 2.5 μg/m3 [PM2.5], and nitrogen dioxide [NO2])., Main Outcomes and Measures: The main outcome was antimicrobial consumption associated with primary care consultations for acute respiratory symptoms in the 30 days before and after the dispensing of the antimicrobial. Antimicrobial consumption was measured as defined daily doses (DDDs) per 1000 inhabitants per day., Results: Among 1 938 333 inhabitants (median age, 48 years [IQR, 34-65 years]; 55% female participants), there were 8 421 404 antimicrobial dispensations, with a median of 12.26 DDDs per 1000 inhabitants per day (IQR, 6.03-15.32 DDDs per 1000 inhabitants per day). The median adjusted morbidity score was 2.0 (IQR, 1.0-5.0). For the 1 924 814 antimicrobial dispensations associated with primary care consultations for acute respiratory symptoms, there was a significant correlation between increases of 10 μg/m3 in the concentration of the 3 pollutants studied and heightened antimicrobial consumption at day 0 (PM10: relative risk [RR], 1.01 [95% CI, 1.01-1.02]; PM2.5: RR, 1.03 [95% CI, 1.01-1.04]; NO2: RR, 1.04 [95% CI, 1.03-1.05]). A delayed association emerged between increases in PM2.5 concentration and antimicrobial consumption between day 7 (RR, 1.00 [95% CI, 1.00-1.01]) and day 10 (RR, 1.00 [95% CI, 1.00-1.01]) after exposure., Conclusions and Relevance: In this 2-stage cross-sectional study using ecological time series analysis, short-term exposure to air pollution was associated with increased antimicrobial use associated with primary care consultations for acute respiratory symptoms in the general population. This finding could contribute to informing policy decisions aimed at reducing air pollution and its associated risks, thereby promoting respiratory health and reducing antimicrobial use.

Objective: To collect real-world data to demonstrate the safety and performance of Arrowg+ard Blue® /Arrowg+ard Blue Plus® (AGB/AGB+) central venous catheters (CVCs)., Methods: This observational, retrospective study involved patients who required AGB/AGB+ CVCs at designated general hospitals in USA (22), UK (19) and Germany (2). Data were extracted from electronic medical records. There were no specific inclusion/exclusion criteria. Primary endpoint was successful treatment without an adverse event (AE). Secondary endpoint was rate of AEs., Results: In total, 384 cases were included from 43 centres and most patients (74%) were >35 years of age. A success rate of 99%, and an overall AE rate of 0.8% were observed. Moreover, the overall infection rate was lower than typically reported for standard catheters. In addition, power injection of contrast media was successful in all 51 cases., Conclusions: This study indicates the AGB/AGB+ CVCs perform as intended with a high success rate and few AEs. Further large-scale, controlled studies are required to confirm our findings., Competing Interests: Declaration of conflicting interestT.P., A.B. and J.M. are employees of Teleflex Incorporated, the manufacturer of the study device.

Introduction: Metronidazole-induced encephalopathy is an uncommon but potentially severe complication of metronidazole treatment. Although the exact pathophysiology remains elusive, proposed hypotheses include RNA binding, neurotoxicity from free radicals, and modulation of neurotransmitter receptors. Most cases demonstrate improvement upon discontinuation of metronidazole, highlighting the importance of early recognition. Magnetic resonance imaging plays a critical role in diagnosing metronidazole-induced encephalopathy, with characteristic imaging findings frequently observed in the dentate nuclei and corpus callosum., Case Summary: A 63-year-old man treated with metronidazole for lumbar spondylodiscitis developed neurological symptoms consistent with metronidazole-induced encephalopathy., Images: Magnetic resonance imaging revealed characteristic bilateral hyperintense lesions in the cerebellar dentate nuclei, corpus callosum, and brainstem. Prompt recognition and discontinuation of metronidazole led to symptom resolution., Conclusion: This case underscores the importance of clinicians and radiologists being aware of this condition and emphasizes the pivotal role of magnetic resonance imagining in establishing the diagnosis.

Aims: This systematic review aimed to investigate the occurrence of moderate and severe adverse drug reactions (ADRs) to antimicrobials among hospitalized children., Methods: The PubMed/Medline, Cochrane Library, Embase, Web of Science, Scopus, Lilacs and CINAHL databases were searched in April 2023 to systematically review the published data describing the characteristics of moderate and severe ADRs to antimicrobials among hospitalized children. The search was carried out without date restrictions, up to the search date (April, 2023)., Results: At the end of the selection process, 30 articles met the inclusion criteria. Cutaneous reactions were the primary serious clinical manifestations in most articles (19/30), followed by erythema multiforme (71 cases), Stevens-Johnson syndrome (72 cases), and toxic epidermal necrolysis (22 cases). The main antimicrobials involved in moderate and severe ADRs were penicillins, cephalosporins and sulfonamides. Regarding the primary outcomes, 30% (9/30) of the articles reported deaths, and 46.7% (14/30) of studies reported increased lengths of hospital stay, need for intensive care, and transfer to another hospital. Regarding the main interventions, 10% (3/30) of the articles mentioned greater monitoring, suspension, medication substitution or prescription of specific medications for the symptomatology., Conclusions: The findings of this review could be used to identify areas for improvement and help health professionals and policymakers develop strategies. In addition, we emphasize the importance of knowing about ADRs so that there is adequate management to avoid undesirable consequences., (© 2024 British Pharmacological Society.)

Objectives: To validate the efficacy and safety of withholding antimicrobial therapy in a new cohort of children with cancer and febrile neutropenia (FN) having a demonstrated viral respiratory tract infection., Methods: Prospective, multicenter, noninferiority, randomized study, approved by the ethical committee, in children presenting with FN at seven hospitals in Chile, evaluated at admission for diagnosis of bacterial and viral pathogens. Children who were positive for a respiratory virus, negative for a bacterial pathogen, and had a favourable evolution after 48-72 hours of antimicrobial therapy were randomized to either maintain or withhold antimicrobial therapy. The primary endpoint was the percentage of episodes with an uneventful resolution, whereas the secondary endpoints were days of fever, days of hospitalization, requirement of antimicrobial treatment readministration, sepsis, paediatric intensive care unit admission, and death., Results: A total of 301 of 939 children with FN episodes recruited between March 2021 and December 2023 had a respiratory virus as a unique identified microorganism, of which 139 had a favourable evolution at 48-72 hours and were randomized, 70 to maintain and 69 to withdraw antimicrobial therapy. The median days of antimicrobial therapy was 5 (IQR 3-6) versus 3 (IQR 3-6) days (p < 0.001), with similar frequency of uneventful resolution 66/70 (94%) and 66/69 (96%); relative risk, 1.01; (95% CI, 0.93 to 1.09), absolute risk difference 0.01; (95% CI, -0.05 to 0.08) and similar number of days of fever and days of hospitalization. No cases of sepsis, paediatric intensive care unit admission, or death were reported., Discussion: We validated the strategy of withdrawal antimicrobial therapy in children with FN and viral respiratory tract infection based on clinical and microbiological/molecular diagnostic criteria. This will enable advances in antimicrobial stewardship strategies with a possible future impact on antimicrobial resistance., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Outpatient parenteral antimicrobial therapy (OPAT) offers an alternative to inpatient (hospital bed-based) treatment of infections that require intravenous administration of antimicrobials. This meta-analysis aimed to summarise the evidence available from randomised controlled trials (RCTs) regarding the efficacy and safety of OPAT compared to inpatient parenteral antimicrobial therapy., Methods: We searched the Cochrane Library, MEDLINE, Embase, PubMed, and Web of Sciences databases for RCTs comparing outpatient versus inpatient parenteral antimicrobial therapy. We included studies without restrictions on language or publication year. Eligibility was reviewed independently by two assessors, and data extraction was cross validated. We evaluated bias risk via the Cochrane tool and determined the evidence certainty using GRADE. Meta-analysis was conducted using a random effects model. The protocol of this review was registered on PROSPERO (CRD42023460389)., Result: Thirteen RCTs, involving 1,310 participants were included. We found no difference in mortality (Risk Ratio [RR] 0.54, 95% Confidence Interval [CI] 0.23 to 1.26; P = 0.93), treatment failure (RR 1.0, CI 0.59 to 1.72; P = 0.99), adverse reaction related to antimicrobials (RR 0.89, CI 0.69 to 1.15; P = 0.38), and administration device (RR 0.58, CI 0.17 to 1.98; P = 0.87) between outpatient and inpatient parenteral antimicrobial therapy. The overall body of evidence had a low level of certainty., Conclusion: Existing evidence suggests OPAT is a safe and effective alternative to inpatient treatment. Further RCTs are warranted for a thorough comparison of inpatient and outpatient parenteral antimicrobial therapy with a high level of certainty., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although antimicrobial medications are commonly prescribed to patients at the end of life (EOL), clinicians might not discuss the benefits and harms of antimicrobials with their patients in the advance care planning process. This commentary on a case discusses challenges and strategies in antimicrobial decision making for patients at the EOL. As antimicrobial use can harm some patients, and as antimicrobial resistance remains an urgent public health issue, this article advocates for ethical reasoning to guide antimicrobial decision making for patients at the EOL., (Copyright 2024 American Medical Association. All Rights Reserved.)

Background: Antimicrobials, especially antibiotics, are among the most widely used drugs in the pediatric intensive care unit. Pediatrics patients in intensive care unit are exposed to potential drug-drug interactions (PDDIs) and suffered from their adverse and side effects. The aim of this study is to evaluate the impact of antimicrobial use on PDDIs, as well as to examine the rate and the risk factors PDDIs, furthermore the management of PDDIs., Methods: The present retrospective cohort study included 179 patients under 18 years of age who were hospitalized in Pediatric Intensive Care Unit in Türkiye. Drug interactions were evaluated using the Lexicomp ® (Macedonia, OH, USA) drug interaction tool which provides evidence-based drug information., Results: Our study results showed that the frequency of the use of antimicrobial drugs (antibiotic, antifungal, antiviral) was found to be statistically significantly higher (P<0.05) in the group with PDDIs compared to the group without PDDIs. Especially, the use of carbapenem, cephalosporin among the antibiotic groups significantly increased the frequency of PDDIs (P<0.05). While the probability PDDIs statistically significantly increased 3.73 times (OR [odds ratio] = 3.73; 95% CI=1.47-9.50) in patients who used a single antibiotic compared to patients who did not use antibiotics (P=0.006), the probability of the occurrence of PDDIs by using more than one antibiotic was statistically significantly 8.5 times (95% CI=3.30-21.89) (P<0.001)., Conclusions: Our study results showed that the use of antimicrobial drugs (antibiotic, antifungal, antiviral) was found to be statistically significantly higher (P<0.05) in the group with PDDIs.

The identification of antimicrobial use patterns is essential for determining key targets for antimicrobial stewardship interventions and evaluating the effectiveness thereof. Accurately identifying antimicrobial use patterns requires quantitative evaluation, which focuses on measuring the quantity and frequency of antimicrobial use, and qualitative evaluation, which assesses the appropriateness, effectiveness, and potential side effects of antimicrobial prescriptions. This paper summarizes the quantitative and qualitative methods used to evaluate antimicrobials, drawing insights from overseas and domestic cases.

Purpose: Metronidazole, a widely used antimicrobial medication, has been linked to neurologic adverse drug reactions. This study investigates the association between metronidazole use and first-time neurologic events., Methods: We conducted a case-time-control study using data from the Danish National Patient Register and the National Prescription Register in years 2013 to 2021. Patients with a first-time diagnosis of encephalopathy, cerebellar dysfunction, or peripheral neuropathy were included. Conditional logistic regression analyses were performed to estimate the risk of neurologic events associated with metronidazole use., Findings: Out of 476,066 first-time metronidazole prescriptions, the 100-day cumulative incidence of peripheral neuropathy was 0.016%, and 0.002% for cerebellar dysfunction or encephalopathy. In the case-time control study, we identified 17,667 persons with a first-time neurologic event and were included for the analysis. The estimated odds ratio for the combined neurologic events was 0.98 (95% CI, 0.59-1.64, P = 0.95) with no statistically significant association across different subgroups and time windows., Implications: Our findings suggest that metronidazole-induced neurologic events may be rarer than previously described, and we did not find any consistent or statistically significant association between metronidazole exposure. Nonetheless, clinicians should remain vigilant to potential neurologic risks in patients receiving metronidazole, to ensure its safe and effective use., Competing Interests: Declaration of competing interest The authors declare no competing interests at the time of manuscript preparation and submission. Subsequent to manuscript finalization, author MAA has initiated employment with Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This Phase 1b study was designed to evaluate the safety and efficacy of pravibismane, a novel broad-spectrum topical anti-infective, in managing moderate or severe chronic diabetic foot ulcer (DFU) infections. This randomized, double-blind, placebo-controlled, multicenter study consisted of 39 individuals undergoing pravibismane treatment and 13 individuals in the placebo group. Assessment of safety parameters included clinical observations of tolerability and pharmacokinetics from whole blood samples. Pravibismane was well-tolerated and exhibited minimal systemic absorption, as confirmed by blood concentrations that were below the lower limit of quantitation (0.5 ng/mL) or in the low nanomolar range, which is orders of magnitude below the threshold of pharmacological relevance for pravibismane. Pravibismane treated subjects showed approximately 3-fold decrease in ulcer size compared to the placebo group (85% vs. 30%, p = 0.27). Furthermore, the incidence of ulcer-related lower limb amputations was approximately 6-fold lower (2.6%) in the pooled pravibismane group versus 15.4% in the placebo group (p = 0.15). There were no treatment emergent or serious adverse events related to study drug. The initial findings indicate that topical pravibismane was safe and potentially effective treatment for improving recovery from infected chronic ulcers by reducing ulcer size and facilitating wound healing in infected DFUs (ClinicalTrials.gov Identifier NCT02723539)., (© 2024 Microbion Corporation. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children., (© 2023 John Wiley & Sons Australia, Ltd.)

Background: Doxycycline postexposure prophylaxis (PEP) has been shown to prevent sexually transmitted infections (STIs) among cisgender men and transgender women, but data from trials involving cisgender women are lacking., Methods: We conducted a randomized, open-label trial comparing doxycycline PEP (doxycycline hyclate, 200 mg taken within 72 hours after condomless sex) with standard care among Kenyan women 18 to 30 years of age who were receiving preexposure prophylaxis against human immunodeficiency virus (HIV). The primary end point was any incident infection with Chlamydia trachomatis , Neisseria gonorrhoeae , or Treponema pallidum . Hair samples were collected quarterly for objective assessment of doxycycline use., Results: A total of 449 participants underwent randomization; 224 were assigned to the doxycycline-PEP group and 225 to the standard-care group. Participants were followed quarterly over 12 months. A total of 109 incident STIs occurred (50 in the doxycycline-PEP group [25.1 per 100 person-years] and 59 in the standard-care group [29.0 per 100 person-years]), with no significant between-group difference in incidence (relative risk, 0.88; 95% confidence interval [CI], 0.60 to 1.29; P = 0.51). Among the 109 incident STIs, chlamydia accounted for 85 (78.0%) (35 in the doxycycline-PEP group and 50 in the standard-care group; relative risk, 0.73; 95% CI, 0.47 to 1.13). No serious adverse events were considered by the trial investigators to be related to doxycycline, and there were no incident HIV infections. Among 50 randomly selected participants in the doxycycline-PEP group, doxycycline was detected in 58 of 200 hair samples (29.0%). All N. gonorrhoeae -positive isolates were resistant to doxycycline., Conclusions: Among cisgender women, the incidence of STIs was not significantly lower with doxycycline PEP than with standard care. According to hair-sample analysis, the use of doxycycline PEP among those assigned to receive it was low. (Funded by the National Institutes of Health; dPEP ClinicalTrials.gov number, NCT04050540.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Antimicrobial drug-associated diarrhea (AAD) is the most common adverse effect in horses receiving antimicrobials. Little information on how oral administration of antimicrobials alters intestinal microbiota in horses is available., Objective: Investigate changes of the fecal microbiota in response to oral administration of antimicrobials., Animals: Twenty healthy horses., Methods: Prospective, longitudinal study. Horses were randomly assigned to 4 groups comprising 4 horses each: group 1 (metronidazole); group 2 (erythromycin); group 3 (doxycycline); group 4 (sulfadiazine/trimethoprim, SMZ-TMP); and group 5 (control). Antimicrobials were administered for 5 days. Fecal samples were obtained before (day 0) and at 1, 2, 3, 4, 5, 6, and 30 days of the study period. Fecal microbiota was characterized by high throughput sequencing of the V4 region of the 16S rRNA., Results: Horses remained healthy throughout the study. Richness and diversity in doxycycline, erythromycin, and metronidazole, but not SMZ-TMP groups, was significantly lower (P < .05) at multiple time points after administration of antimicrobials compared with samples from day 0. Main changes in the microbiota were observed during the time of antimicrobial administration (day 2-5; weighted and unweighted UniFrac PERMANOVA P < .05). Administration of erythromycin, doxycycline and, to a lesser extent, metronidazole produced a pronounced alteration in the microbiota compared with day 0 samples by decreasing the abundance of Treponema, Fibrobacter, and Lachnospiraceae and increasing Fusobacterium and Escherichia-Shigella., Conclusions and Clinical Importance: Oral administration of antimicrobials alters the intestinal microbiota of healthy horses resembling horses with dysbiosis, potentially resulting in intestinal inflammation and predisposition to diarrhea., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

The potential association between antimicrobial mouthwash use and systemic health has gained attention in recent years with reports highlighting how some common systemic conditions are influenced by the use of different types of mouthwashes. In this context, links between mouthwash use and cardiovascular disease, diabetes mellitus, oral cancer, Alzheimer's disease, and preeclampsia have been proposed, albeit with limited levels of evidence. Chlorhexidine mouthwash in particular has been the most widely studied agent while available data on other types of over-the-counter mouthwashes are generally scarce. Furthermore, there is currently no evidence-based recommendations on the appropriate use of mouthwashes during pregnancy. This article will present the current evidence on the association between mouthwash use and the aforementioned conditions with emphasis on the mechanisms that may underlie such an association., Competing Interests: Conflict of interest None disclosed., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: TauroPace (Tauropharm, Bavaria Germany), a taurolidine solution for combating cardiac implantable electronic device (CIED) infection, was compared with a historical control of 3% hydrogen peroxide (H2O2) in a prospective observational study., Methods and Results: The device pocket was irrigated, and all hardware accessible within (leads, suture sleeves, pulse generator) was wiped with H2O2, TauroPace, or taurolidine in a galenic formulation during any invasive CIED procedure at the study centre. Only CIED procedures covered by TauroPace or H2O2 from 1 January 2017 to 28 February 2022 were included for analysis. Patients who underwent >1 procedure were censored for the last treatment group and reassigned at the next procedure. The primary endpoint was major CIED infection within 3 months. The secondary endpoints were CIED infection beyond 3 months, adverse events potentially related to the antimicrobial solutions, CIED system, procedure, and death, till the end of follow-up. TauroPace covered 654 procedures on 631 patients, and H2O2 covered 551 procedures on 532 patients. The TauroPace group had more patient risk factors for infection than the H2O2 group (P = 0.0058) but similar device and procedure-specific risk factors (P = 0.17). Cardiac implantable electronic device infection occurred in 0/654 (0%) of the TauroPace group and 6/551 (1.1%) of the H2O2 group (P = 0.0075). Death occurred in 23/654 (3.5%) of the TauroPace group and 14/551 (2.5%) of the H2O2 group (P = 0.33). Non-infection related adverse events were rarer in the TauroPace (3.8%) than the H2O2 (6.0%) group (P = 0.0802)., Conclusion: TauroPace is safe but more effective than H2O2 in reducing CIED infection., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT05576194., Competing Interests: Conflict of interest: B.B.: consultant/advisor: Abbott, Bioline Supply, Crosstec GmbH, Kapamed, Kimal PLC, M3 Medical/Ecclipse Medical, Medival SRL, Philips/Spectranetics, Sintec SRL, Tauro-Implant GmbH, Tauropharm GmbH, Transcutan; the other authors declare no conflict of interest in relation to this manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The risk of venous thromboembolism (VTE) in outpatient parenteral antimicrobial therapy (OPAT) is not fully understood and the optimal strategy for thromboprophylaxis remains unclear. This systematic review investigated the incidence of VTE in OPAT settings (PROSPERO CRD42022381523). MEDLINE, CINAHL, Emcare, Embase, Cochrane Library and grey literature were searched from earliest records to 18 January 2023. Primary studies reporting non-catheter-related VTE or catheter-related thromboembolism (CRT) events in adults who received parenteral antibiotics in home or outpatient settings were eligible. In total, 43 studies involving 23 432 patient episodes were reviewed, of which 4 studies reported non-catheter-related VTE and 39 included CRT. Based on generalised linear mixed-effects models, pooled risk estimates of non-catheter-related VTE and CRT were 0.2% [95% confidence interval (CI) 0.0-0.7%] and 1.1% [95% CI 0.8-1.5%; prediction interval (PI) 0.2-5.4%]. Heterogeneity was largely attributed to risk of bias by meta-regression (R 2  = 21%). Excluding high-risk-of-bias studies, CRT risk was 0.8% (95% CI 0.5-1.2%; PI 0.1-4.5%). From 25 studies, the pooled CRT rate per 1000 catheter-days was 0.37 (95% CI 0.25-0.55; PI 0.08-1.64). These findings do not support universal thromboprophylaxis or routine use of an inpatient VTE risk assessment model in the OPAT setting. However, a high index of suspicion should be maintained, especially for patients with known risk factors for VTE. An optimised protocol of OPAT-specific VTE risk assessment should be sought., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Introduction: The growing spread of infections caused by multidrug-resistant pathogens makes the need of tailoring antimicrobial therapies by means of a 'patient-centered' approach fundamental. In this scenario, therapeutic drug monitoring (TDM) of emerging antimicrobial candidates may be a valuable approach, but expert interpretation of TDM results should be granted for making them more clinically useful. The MD Clinical Pharmacologist may take over this task since this specialist may couple PK/PD expertise on drugs with a medical background and may provide expert interpretation of TDM results of antimicrobials for tailoring therapy on real-time in each single patient based on specific both drug/pathogen issues and patient issues., Areas Covered: This article aims to highlight the main key-points and organizational aspects for implementing a successful TDM-based expert clinical pharmacological advice (ECPA) program for tailoring antimicrobial therapies on real-time in different hospitalized patient special populations., Expert Opinion: TDM-based ECPA programs lead by the MD Clinical Pharmacologist may represent a way forward for maximizing clinical efficacy and for minimizing the risk of resistance developments and/or toxicity of antimicrobials. Stakeholders should be aware of the fact that this innovative approach may be cost-effective.

Objective: To investigate the impact of prenatal and early childhood antimicrobial use on autism spectrum disorders (ASD)., Data Sources: We searched PubMed and Embase databases for relevant studies from inception to August 2022., Study Selection and Data Extraction: Peer-reviewed, observational studies were all acceptable. Raw data were extracted into a predefined worksheet and quality analysis was performed using the Newcastle-Ottawa Scale., Data Synthesis: Nineteen studies were identified in the meta-analysis. Prenatal antimicrobial exposure was not associated with ASD ( P = 0.06 > 0.05), whereas early childhood antimicrobial exposure was associated with an increased odds ratio of ASD (OR = 1.17, 95% CI = [1.08-1.27], P value < 0.001). The sibling-matched analysis, with a very limited sample size, suggested that neither prenatal ( P = 0.47 > 0.05) nor early childhood ( P = 0.13 > 0.05) antimicrobial exposure was associated with ASD. Medical professionals may need to take the possible association into consideration when prescribing an antimicrobial in children., Conclusions: Early childhood antimicrobial exposure could increase the incidence of ASD. In future studies, it would be necessary to control for confounding factors, such as genetic factors, parenteral age at birth, or low birthweight, to further validate the association.

Drug-induced Stevens-Johnson syndrome (SJS) is a rare but life-threatening hypersensitivity reaction. Drug desensitization might be considered in drug-allergic patients with no therapeutic alternative. A 29-year-old man with a recent diagnosis of HIV and HBV (CD4 count: 4 cells/mm3) who has been receiving Trimethoprim/sulfamethoxazole (TMP/SMX) for Pneumocystis pneumonia (PCP) prophylaxis was admitted at Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, with the diagnosis of SJS due to TMP/SMX. After 45 days of supportive care, the patient was a candidate for TMP/SMX desensitization due to our region's unavailability of alternative agents. A 9-day desensitization protocol was used, but the patient complained about diarrhea with severe pain in the rectal mucosa, and macules developed over his lips again on the third day. As a result, the desensitization process immediately stopped, and after the signs and symptoms were resolved, the patient was discharged with Clindamycin tablet 600 mg TDS. Unfortunately, two weeks after discharge, the patient experienced acute kidney injury (AKI) and expired after two dialysis sessions., (© 2023. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

Background: Coronavirus Disease 2019 (COVID-19) is a highly infectious disease that can be treated with antivirals in addition to other antimicrobials in cases of secondary or concomitant infections. This creates potential for antimicrobials misuse, which increases antimicrobial resistance (AMR). Pharmacists are known to undertake prominent roles in combatting AMR., Aim: The aim of this review was to characterize pharmacist-driven interventions that have been performed in patients with COVID-19 globally and describe their impact on antimicrobial use., Method: We followed the Joanna Briggs Institutes manual framework for scoping reviews in our study. Studies that reported antimicrobial stewardship (AMS) interventions performed by pharmacists in COVID-19 patients were included. Articles that did not report outcomes or did not mention pharmacists in the intervention were excluded. Restrictions included English-only articles from inception date until June 2022. Articles were searched from four databases., Results: Eleven publications were included in the review. The most common AMS intervention was pharmacist-driven interventions reported in 63.2% of all studies, followed by guideline development and application (26.3%), and medication supply coordination (10.5%), respectively. The outcomes of the interventions were difficult to compare but showed a reduction in antimicrobial use and prevention of adverse drug reactions with a relatively high acceptance rate from physicians., Conclusion: Pharmacists played an important role in performing AMS-related interventions in COVID-19 patients and helped in the fight against the worsening of AMR during the pandemic. The impact of pharmacist-driven AMS interventions in patients with COVID-19 seemed to be positive and improved outcomes related to antimicrobial use., (© 2023. The Author(s).)

Older patients are at high risk of infections, which often present atypically and are associated with high morbidity and mortality. Antimicrobial treatment in older individuals with infectious diseases represents a clinical challenge, causing an increasing burden on worldwide healthcare systems; immunosenescence and the coexistence of multiple comorbidities determine complex polypharmacy regimens with an increase in drug-drug interactions and spread of multidrug-resistance infections. Aging-induced pharmacokinetic and pharmacodynamic changes can additionally increase the risk of inappropriate drug dosing, with underexposure that is associated with antimicrobial resistance and overexposure that may lead to adverse effects and poor adherence because of low tolerability. These issues need to be considered when starting antimicrobial prescriptions. National and international efforts have been made towards the implementation of antimicrobial stewardship (AMS) interventions to help clinicians improve the appropriateness and safety of antimicrobial prescriptions in both acute and long-term care settings. AMS programs were shown to decrease consumption of antimicrobials and to improve safety in hospitalized patients and older nursing home residents. With the abundance of antimicrobial prescriptions and the recent emergence of multidrug resistant pathogens, an in-depth review of antimicrobial prescriptions in geriatric clinical practice is needed. This review will discuss the special considerations for older individuals needing antimicrobials, including risk factors that shape risk profiles in geriatric populations as well as an evidence-based description of antimicrobial-induced adverse events in this patient population. It will highlight agents of concern for this age group and discuss interventions to mitigate the effects of inappropriate antimicrobial prescribing., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Serious cases of allergic contact dermatitis (ACD) caused by exposure to 3,5,6-tetrachloro-4-(methylsulfonyl)pyridine (TCMSP; CAS no. 13108-52-6) used as an antimicrobial agent for desk mats have been reported in Japan., Objective: A quantitative risk assessment (QRA) of TCMSP contained in desk mats was performed retrospectively., Materials and Methods: A local lymph node assay (LLNA): BrdU-ELISA was conducted to determine a reliable EC1.6 value for TCMSP. The acceptable exposure level (AEL) for TCMSP was derived from the EC1.6 value by applying sensitization assessment factors (SAFs). The exposure level was estimated based on the assumption referring to the use conditions of thiabendazole in the same purpose. Then, the estimated exposure level was compared with the AEL to evaluate the skin sensitization risk., Results: The AEL was calculated as 0.00458 μg/cm 2 based on the EC1.6 value (0.011%, 2.75 μg/cm 2 ) by applying a composite SAF of 600. The estimated TCMSP exposure level from the desk mat was 500 times greater than the AEL, indicating a serious skin sensitization risk., Conclusions: Assessments of skin sensitization potencies of chemicals to be used in consumer products are strongly recommended, and QRAs should be performed at the pre-marketing stage to avoid the skin sensitization risk in consumers., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Outpatient parenteral antimicrobial therapy (OPAT) is a cost-effective method of administering intravenous antimicrobial therapy. Although OPAT is well established in the UK and US healthcare systems, few centres in Europe perform it. Here we analysed OPAT for the treatment of patients with spinal infections at our institution. In this retrospective study, patients with spinal infection who required intravenous (i.v.) antimicrobial treatment between 2018 and 2021 were analysed. The duration of short-term antimicrobial treatment for skin and soft tissue infections and complex infections requiring long-term antimicrobial treatment, such as spinal bone or joint infections, were analysed. All patients were discharged with a peripherally inserted central catheter (PICC) line. Prior to discharge, all patients received training in the safe administration of their medications via the PICC line. The duration of OPAT and the rate of readmission after OPAT were analysed. For this study a total of 52 patients who were treated via OPAT due to spinal infections were analyzed. In 35 cases (69.2%) complex spinal infection was reason for i.v. antimicrobial therapy. Surgery was required in 23 of these 35 patients (65.7%). The average hospital stay for these patients was 12 ± 6 days. The remaining 17 patients were treated for an infection of the soft tissue or the skin and hospital stay for these patients was on average 8 ± 4 days. Gram-positive organisms were isolated in 64.4%. Staphylococcus aureus followed by other Staphylococcus species, was the most common detected organism. After discharging i.v. antimicrobial treatment was given for an average of 20 ± 14 days. The duration of antimicrobial treatment for soft tissue was 10.8 ± 8 days, and for complex infections 25.1 ± 18 days. The mean follow-up was 21 ± 14 months. There was one case of readmission due to treatment failure. There were no difficulties encountered in implementing OPAT. OPAT is a feasible and effective option for delivering intravenous antimicrobial therapy to patients with spinal infections who can be managed without hospitalisation. OPAT offers patient-centred treatment at home while avoiding the risks associated with hospitalisation, with high levels of patient satisfaction., (© 2023. The Author(s).)

Background: Which antimicrobial agents provide the optimal efficacy, safety, and tolerability for the empirical treatment of complicated intra-abdominal infection (cIAI) remains unclear but is paramount in the context of evolving antimicrobial resistance. Therefore, updated meta-analyses on this issue are warranted., Methods: We systematically searched four major electronic databases from their inception through October 2022. Randomized controlled trials examining antimicrobial agents for cIAI treatment were included. Two reviewers independently assessed the quality of included studies utilizing the Cochrane Collaboration's risk of bias tool as described in the updated version 1 of the Cochrane Collaboration Handbook and extracted data from all manuscripts according to a predetermined list of topics. All meta-analyses were conducted using R software. The primary outcome was clinical success rate in patients with cIAIs., Results: Forty-five active-controlled trials with low to medium methodological quality and involving 14,267 adults with cIAIs were included in the network meta-analyses. The vast majority of patients with an acute physiology and chronic health evaluation II score < 10 had low risk of treatment failure or death. Twenty-one regimens were investigated. In the network meta-analyses, cefepime plus metronidazole was more effective than tigecycline and ceftolozane/tazobactam plus metronidazole (odds ratio [OR] = 1.96, 95% credibility interval [CrI] 1.05 ~ 3.79; OR = 3.09, 95% CrI 1.02 ~ 9.79, respectively). No statistically significant differences were found among antimicrobial agents regarding microbiological success rates. Cefepime plus metronidazole had lower risk of all-cause mortality than tigecycline (OR = 0.22, 95% CrI 0.05 ~ 0.85). Statistically significant trends were observed favoring cefotaxime plus metronidazole, which exhibited fewer discontinuations because of adverse events (AEs) when compared with eravacycline, meropenem and ceftolozane/tazobactam plus metronidazole (OR = 0.0, 95% CrI 0.0 ~ 0.8; OR = 0.0, 95% CrI 0.0 ~ 0.7; OR = 0.0, 95% CrI 0.0 ~ 0.64, respectively). Compared with tigecycline, eravacycline was associated with fewer discontinuations because of AEs (OR = 0.17, 95% CrI 0.03 ~ 0.81). Compared with meropenem, ceftazidime/avibactam plus metronidazole had a higher rate of discontinuation due to AEs (OR = 2.09, 95% CrI 1.0 ~ 4.41). In pairwise meta-analyses, compared with ceftriaxone plus metronidazole, ertapenem and moxifloxacin (one trial, OR = 1.93, 95% CI 1.06 ~ 3.50; one trial, OR = 4.24, 95% CI 1.18 ~ 15.28, respectively) were associated with significantly increased risks of serious AEs. Compared with imipenem/cilastatin, tigecycline (four trials, OR = 1.57, 95%CI 1.07 ~ 2.32) was associated with a significantly increased risk of serious AEs. According to the surface under the cumulative ranking curve, Cefepime plus metronidazole was more likely to be optimal among all treatments in terms of efficacy and safety, tigecycline was more likely to be worst regimen in terms of tolerability, and eravacycline was more likely to be best tolerated., Conclusion: This study suggests that cefepime plus metronidazole is optimal for empirical treatment of patients with cIAIs and that tigecycline should be prescribed cautiously considering the safety and tolerability concerns. However, it should be noted that data currently available on the effectiveness, safety, and tolerability of antimicrobial agents pertain mostly to lower-risk patients with cIAIs., (© 2023. The Author(s).)

Parabens, triclosan (TCS), and triclocarban (TCC) are antimicrobial additives that are widely used in personal care products (PCPs) and may dysregulate infant gut microbiota and induce a series of chronic diseases. Dietary intake may be an underestimated exposure route of such antimicrobial additives in infants, but relevant data remain scarce. Therefore, this study determined five common preservatives, including methyl- (MeP), ethyl- (EtP), propyl- (PrP), butyl- (BuP), and benzyl-paraben (BeP), and two antimicrobials TCS and TCC, in major infant food sources (breastmilk, milk-based infant formula [MIF], and cereal-based complementary food [CCF]) in southern China. The health risks associated with dietary exposure among infants across different months of age were also evaluated. The results demonstrated a high incidence of MeP, EtP, PrP, and BeP in processed infant food products, while TCS and TCC were mainly detected in maternal breastmilk. Notably, MeP and EtP were found in all of the MIFs tested, while MeP, EtP, and BeP were detected in 85.6 %-100 % of the CCFs. By incorporating the human equivalent dose and an additional 10-fold margin of safety for infants into the health risk assessment, the 95th percentile hazard quotient of PrP via the ingestion of breastmilk among neonates exceeded 1. For the first time, the results showed that exposure to PrP via breastmilk intake may pose a considerable health risk to urban neonates in southern China. The health risks caused by antimicrobial exposure via ingesting MIF and CCF among infants were negligible. Thus, we recommend breastfeeding women reduce their consumption of PCPs and processed food, especially during the first month after delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome., (© 2023. The Author(s).)

Among several environmental factors, exposure to antimicrobials has been in the spotlight as a cause of profound and long-term disturbance of the intestinal microbiota. Antimicrobial-induced dysbiosis is a general term and includes decreases in microbial richness and diversity, loss of beneficial bacterial groups, blooms of intestinal pathogens and alterations in the metabolic functions and end-products of the microbiota. Mounting evidence from human and experimental animal studies suggest an association between antimicrobial-induced dysbiosis and susceptibility to gastrointestinal, metabolic, endocrine, immune and neuropsychiatric diseases. These associations are commonly stronger after early life exposure to antimicrobials, a period during which maturation of the microbiota and immune system take place in parallel. In addition, these associations commonly become stronger as the number of antimicrobial courses increases. The repeatability of these findings among different studies as well as the presence of a dose-dependent relationship between antimicrobial exposure and disease development collectively require careful consideration of the need for antimicrobial use. There are limited studies are available in dogs and cats regarding the long-term effects of antimicrobials on the microbiota and subsequent susceptibility to diseases. This review discusses the effects of antimicrobials on the gastrointestinal microbiota and the most important associations between antimicrobial-induced dysbiosis and diseases in humans, dogs, and cats., Competing Interests: Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Bacterial infections such as osteomyelitis and endocarditis routinely require several weeks of treatment with intravenous (IV) antimicrobials. Outpatient parenteral antimicrobial therapy (OPAT) programs allow patients to receive IV antimicrobials in an outpatient clinic or at home. The outcomes and costs of such treatments remain uncertain., Methods: We conducted a retrospective observational cohort study over a 5-year study interval (1 June 2012 to 31 March 2018) using population-based linked administrative data from British Columbia, Canada. Patients receiving OPAT following a hospitalization for bacterial infection were matched based on infection type and implied duration of IV antimicrobials to patients receiving inpatient parenteral antimicrobial therapy (IPAT). Cumulative adverse events and direct healthcare costs were estimated over a 90-day outcome interval., Results: In a matched cohort of 1842 patients, adverse events occurred in 35.6% of OPAT patients and 39.0% of IPAT patients (adjusted odds ratio, 1.04 [95% confidence interval {CI}, .83-1.30; P = .61). Relative to IPAT patients, OPAT patients were significantly more likely to experience hospital readmission (30.5% vs 23.0%) but significantly less likely to experience Clostridioides difficile diarrhea (1.2% vs 3.1%) or death (2.0% vs 8.8%). Estimated mean direct healthcare costs were $30 166 for OPAT patients and $50 038 for IPAT patients (cost ratio, 0.60; average cost savings with OPAT, $17 579 [95% CI, $14 131-$21 027]; P < .001)., Conclusions: Outpatient IV antimicrobial therapy is associated with a similar overall prevalence of adverse events and with substantial cost savings relative to patients remaining in hospital to complete IV antimicrobials. These findings should inform efforts to expand OPAT use., Competing Interests: Potential conflicts of interest. D. F. was the past president of the British Columbia Infectious Diseases Society (elected unpaid position) and reports advisory board honoraria from Gilead Sciences and AbbVie. J. M. S. reports support for attending meetings from the government of Canada, the government of Australia, the Province of Alberta, the Province of Ontario, and Cancer Care Ontario. J. H. reports receiving research funding to examine similar topics and grants or contracts unrelated to this work from the Vancouver Coastal Health Research Institute (Team Grant, 2021) for the project “Community-based antibiotic therapy for persons with severe bacterial infections and substance use disorders in a low-barrier, home-like, skilled nursing facility: an evaluation of the CTCT model of care.” All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown., Objective: To evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19., Design, Setting, and Participants: ACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US., Interventions: Participants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774)., Main Outcomes and Measures: Time to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28., Results: Among 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5])., Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Background: Bacillus anthracis, the causative agent for anthrax, poses a potential bioterrorism threat and is capable of causing mass morbidity and mortality. Antimicrobials are the mainstay of postexposure prophylaxis (PEP) and treatment of anthrax. We conducted this safety review of 24 select antimicrobials to identify any new or emerging serious or severe adverse events (AEs) to help inform their risk-benefit evaluation for anthrax., Methods: Twenty-four antimicrobials were included in this review. Tertiary data sources (e.g. Lactmed, Micromedex, REPROTOX) were reviewed for safety information and summarized to evaluate the known risks of these antimicrobials. PubMed was also searched for published safety information on serious or severe AEs with these antimicrobials; AEs that met inclusion criteria were abstracted and reviewed., Results: A total of 1316 articles were reviewed. No consistent observations or patterns were observed among the abstracted AEs for a given antimicrobial; therefore, the literature review did not reveal evidence of new or emerging AEs that would add to the risk-benefit profiles already known from tertiary data sources., Conclusions: The reviewed antimicrobials have known and/or potential serious or severe risks that may influence selection when recommending an antimicrobial for PEP or treatment of anthrax. Given the high fatality rate of anthrax, the risk-benefit evaluation favors use of these antimicrobials for anthrax. The potential risks of antimicrobials should not preclude these reviewed antimicrobials from clinical consideration for anthrax but rather guide appropriate antimicrobial selection and prioritization across different patient populations with risk mitigation measures as warranted., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

A woman in her 30s presented to our emergency department with vomiting and lethargy after an intentional ingestion of unknown antimicrobial pills which was later found to be dapsone. The patient developed cyanosis, hypoxia and tachycardia due to acute methaemoglobinaemia (level of 30.9% on venous blood gas analysis). As dapsone is notorious for prolonged and rebound methaemoglobinaemia, she was managed with repeated doses of intravenous methylene blue and oral multidose activated charcoal which warranted elective intubation and intensive care unit admission. Subsequent drug-induced hepatitis and delayed dapsone-induced haemolysis were managed conservatively. She was discharged in a stable condition with outpatient follow-ups. Physician familiarity with the nuances of this rare condition and its complications contributes to better patient care., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Outpatient parenteral antimicrobial therapy (OPAT) delivery using peripherally inserted central catheters is associated with a risk of catheter related thrombosis (CRT). Individualised preventative interventions may reduce this occurrence, however patient selection is hampered by a lack of understanding of risk factors. We aimed to identify patient, infection or treatment related risk factors for CRT in the OPAT setting., Methods: Retrospective case control study (1:3 matching) within OPAT services at two tertiary hospitals within Australia., Results: Over a 2 year period, encompassing OPAT delivery to 1803 patients, there were 19 cases of CRT, giving a prevalence of 1.1% and incidence of 0.58/1000 catheter days. Amongst the cases of CRT, there were nine (47%) unplanned readmissions and two (11%) pulmonary emboli. Compared to controls, cases had a higher frequency of malposition of the catheter tip (4/19 (21%) vs 0/57 (0%), p  = 0.003) and complicated catheter insertion (3/19 (16%) vs 1/57 (2%), p  = 0.046)., Conclusions: Although CRTs during OPAT are infrequent, they often have clinically significant sequelae. Identification of modifiable vascular access related predictors of CRT should assist with patient risk stratification and guide risk reduction strategies.

Background: Skin and soft tissue infections (SSTIs) carry significant economic burden, as well as morbidity and mortality, especially when caused by methicillin-resistant Staphylococcus aureus. This study aims to investigate the efficacy and safety of optional antimicrobial therapy for the treatment of complicated SSTIs (cSSTIs)., Methods: We searched PubMed, Medline (Via Ovid SP), Embase (Via Ovid SP), and the Cochrane Central Register of Controlled Trials from their inception to March 22, 2021 for randomized controlled trials (RCTs) that studied the use of optional antimicrobial therapy for cSSTIs. Citations' screening, study selection, data extraction, and risk of bias assessment were independently performed by 2 authors. The primary outcomes were clinical and microbiological treatment success, and adverse events (AEs) were also assessed., Results: A total of 48 trials covering 24,381 patients assessing 20 types of antimicrobial treatment modalities were included. Overall, omadacycline was associated with the highest beneficial effect on clinical and microbiological treatment success and with the largest rank probability based on surface under the cumulative ranking curve values, avarofloxacin was closely followed. Both had, however, omadacycline was related to moderately safety profiles. Lefamulin ranked as the best option was associated with the lowest risk of severe AEs. Subgroup analysis showed similar results. The quality of primary outcomes was moderate to low., Conclusions: The use of omadacycline was associated with higher rates of clinical and microbiological treatment success for the treatment of cSSTIs, with a relative low risk of AEs. Due to the limitations of the included RCTs, high-quality and well-designed RCTs are needed to further confirm the results., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The lack of therapeutic options to fight Covid-19 has contributed to the current global pandemic. Despite the emergence of effective vaccines, development of broad-spectrum antiviral treatment remains a significant challenge, in which antimicrobial photodynamic therapy (aPDT) may play a role, especially at early stages of infection. aPDT of the nares with methylene blue (MB) and non-thermal light has been successfully utilized to inactivate both bacterial and viral pathogens in the perioperative setting. Here, we investigated the effect of MB-aPDT to inactivate human betacoronavirus OC43 and SARS-CoV-2 in vitro and in a proof-of-principle COVID-19 clinical trial to test, in a variety of settings, the practicality, technical feasibility, and short-term efficacy of the method. aPDT yielded inactivation of up to 6-Logs in vitro, as measured by RT-qPCR and infectivity assay. From a photo-physics perspective, the in vitro results suggest that the response is not dependent on the virus itself, motivating potential use of aPDT for local destruction of SARS-CoV-2 and its variants. In the clinical trial we observed variable effects on viral RNA in nasal-swab samples as assessed by RT-qPCR attributed to aPDT-induced RNA fragmentation causing falsely-elevated counts. However, the viral infectivity in clinical nares swabs was reduced in 90% of samples and undetectable in 70% of samples. This is the first demonstration based on quantitative clinical viral infectivity measurements that MB-aPDT is a safe, easily delivered and effective front-line technique that can reduce local SARS-CoV-2 viral load., (© 2022. The Author(s).)

Mass drug administration (MDA) of antimicrobials has shown promise in the reduction and potential elimination of a variety of neglected tropical diseases (NTDs). However, with antimicrobial resistance (AMR) becoming a global crisis, the risks posed by widespread antimicrobial use need to be evaluated. As the role of the environment in AMR emergence and dissemination has become increasingly recognized, it is likewise crucial to establish the role of MDA in environmental AMR pollution, along with the potential impacts of such pollution. This review presents the current state of knowledge on the antimicrobial compounds, resistant organisms, and antimicrobial resistance genes in MDA trials, routes of these determinants into the environment, and their persistence and ecological impacts, particularly in low and middle-income countries where these trials are most common. From the few studies directly evaluating AMR outcomes in azithromycin MDA trials, it is becoming apparent that MDA efforts can increase carriage and excretion of resistant pathogens in a lasting way. However, research on these outcomes for other antimicrobials used in MDA trials is sorely needed. Furthermore, while paths of AMR determinants from human waste to the environment and their persistence thereafter are supported by the literature, quantitative information on the scope and likelihood of this is largely absent. We recommend some mitigative approaches that would be valuable to consider in future MDA efforts. This review stands to be a valuable resource for researchers and policymakers seeking to evaluate the impacts of MDA., (© 2022. The Author(s).)

Background: Inappropriate antibiotic use can cause harm and promote antimicrobial resistance, which has been declared a major health challenge by the World Health Organization. In Australian residential aged care facilities (RACFs), the most common indications for antibiotic prescribing are for infections of the urinary tract, respiratory tract and skin and soft tissue. Studies indicate that a high proportion of these prescriptions are non-compliant with best prescribing guidelines. To date, a variety of interventions have been reported to address inappropriate prescribing and overuse of antibiotics but with mixed outcomes. This study aims to identify the impact of a set of sustainable, multimodal interventions in residential aged care targeting three common infection types., Methods: This protocol details a 20-month stepped-wedge cluster-randomised trial conducted across 18 RACFs (as 18 clusters). A multimodal multi-disciplinary set of interventions, the 'AMS ENGAGEMENT bundle', will be tailored to meet the identified needs of participating RACFs. The key elements of the intervention bundle include education for nurses and general practitioners, telehealth support and formation of an antimicrobial stewardship team in each facility. Prior to the randomised sequential introduction of the intervention, each site will act as its own control in relation to usual care processes for antibiotic use and stewardship. The primary outcome for this study will be antibiotic consumption measured using defined daily doses (DDDs). Cluster-level rates will be calculated using total occupied bed numbers within each RACF during the observation period as the denominator. Results will be expressed as rates per 1000 occupied bed days. An economic analysis will be conducted to compare the costs associated with the intervention to that of usual care. A comprehensive process evaluation will be conducted using the REAIM Framework, to enable learnings from the trial to inform sustainable improvements in this field., Discussion: A structured AMS model of care, incorporating targeted interventions to optimise antimicrobial use in the RACF setting, is urgently needed and will be delivered by our trial. The trial will aim to empower clinicians, residents and families by providing a robust AMS programme to improve antibiotic-related health outcomes., Trial Registration: US National Library of Medicine Clinical Trials.gov ( NCT04705259 ). Prospectively registered in 12th of January 2021., (© 2022. The Author(s).)

Background: The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear., Methods: We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization., Results: A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events., Conclusions: Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.)., (Copyright © 2022 Massachusetts Medical Society.)

Introduction: Antibiotic prescription is a challenging issue in critical care settings. Different pharmacokinetic and pharmacodynamic properties, polypharmacy, drug interactions, and high incidence of multidrug-resistant microorganisms in this population can influence the selection, safety, and efficacy of prescribed antibiotics., Areas Covered: In the current article we searched PubMed, Scopus and Google Scholar for neurotoxicities, hematologic toxicity and fluid stewardship in intensive care units., Expert Opinion: Critically ill patients who receive antimicrobial agents should be monitored for neurological, hematologic toxicities especially seizure, thrombocytopenia, and clostridioides infections. Other toxicities including QTc prolongation, electrolyte disturbances, liver enzyme elevation, and infusion-related reactions were being considered. Other changes, including fluid overload, hypoalbuminemia, augmented renal clearance, increased cardiac outputs in septic shock, and acute kidney injury, may influence treatment efficiency and patient outcome.

Background In the Netherlands, home treatment with intravenous antimicrobial therapy is a relatively new concept. Although several studies have shown that outpatient parenteral antimicrobial therapy (OPAT) can be administered safely, people receiving antimicrobials at home remain at risk for adverse events, including readmission. Aim The aim of our retrospective study was to identify risk factors for readmission in patients discharged with OPAT. Method Patients who were at least 18 years or older, discharged with OPAT between January 2016-December 2018 were included. Variables that were collected consisted of baseline demographics, complications, readmission within 30 days and treatment failure. Multivariate logistic regression analysis was performed to identify risk factors for readmission. Results A total of 247 patients were included; the most common reason for OPAT was bone and joint infections (17%). Penicillin (37%), cephalosporin (26%) and vancomycin/aminoglycoside (15%) were the most commonly prescribed antimicrobials. Among patients receiving medication subject to therapeutic drug monitoring (i.e. aminoglycosides or vancomycin), 51% (19/37) received weekly therapeutic drug monitoring. Receiving aminoglycosides or vancomycin (adjusted OR 2.05; 95% CI 1.30-3.25, p < 0.05) and infection of prosthetic material (adjusted OR 2.92, 95% CI 1.11-7.65, p < 0.05) were independent risk factors associated with readmission. Conclusion Although patients receiving medication subject to therapeutic drug monitoring are at higher risk of readmission, only half of the patients discharged with aminoglycosides or vancomycin were monitored according to IDSA guidelines. A specialized team in charge of monitoring patients with OPAT is more likely to increase the rate of monitoring to prevent readmissions and complications., (© 2022. The Author(s).)