Transition to Oral Antibiotic Therapy for Hospitalized Adults With Gram-Negative Bloodstream Infections.

Importance: Management of gram-negative bloodstream infections (GN-BSIs) with oral antibiotics is highly variable. Objective: To examine the transition from intravenous (IV) to oral antibiotics, including selection, timing, and associated clinical and microbial characteristics, among hospitalized patients with GN-BSIs. Design, Setting, and Participants: A retrospective cohort study was conducted of 4581 hospitalized adults with GN-BSIs at 24 US hospitals between January 1 and December 31, 2019. Patients were excluded if they died within 72 hours. Patients were excluded from the oral therapy group if transition occurred after day 7. Statistical analysis was conducted from July 2022 to October 2023. Exposures: Administration of antibiotics for GN-BSIs. Main Outcomes and Measures: Baseline characteristics and clinical parameters reflecting severity of illness were evaluated in groups receiving oral and IV therapy. The prevalence of transition from IV to oral antibiotics by day 7, median day of transition, sources of infection, and oral antibiotic selection were assessed. Results: Of a total of 4581 episodes with GN-BSIs (median age, 67 years [IQR, 55-77 years]; 2389 men [52.2%]), 1969 patients (43.0%) receiving IV antibiotics were transitioned to oral antibiotics by day 7. Patients maintained on IV therapy were more likely than those transitioned to oral therapy to be immunosuppressed (833 of 2612 [31.9%] vs 485 of 1969 [24.6%]; P < .001), require intensive care unit admission (1033 of 2612 [39.5%] vs 334 of 1969 [17.0%]; P < .001), have fever or hypotension as of day 5 (423 of 2612 [16.2%] vs 49 of 1969 [2.5%]; P < .001), require kidney replacement therapy (280 of 2612 [10.7%] vs 63 of 1969 [3.2%]; P < .001), and less likely to have source control within 7 days (1852 of 2612 [70.9%] vs 1577 of 1969 [80.1%]; P < .001). Transitioning patients from IV to oral therapy by day 7 was highly variable across hospitals, ranging from 25.8% (66 of 256) to 65.9% (27 of 41). A total of 4109 patients (89.7%) achieved clinical stability within 5 days. For the 3429 episodes (74.9%) with successful source control by day 7, the median day of source control was day 2 (IQR, 1-3 days) for the oral group and day 2 (IQR, 1-4 days) for the IV group (P < .001). Common infection sources among patients administered oral therapy were the urinary tract (1277 of 1969 [64.9%]), hepatobiliary (239 of 1969 [12.1%]), and intra-abdominal (194 of 1969 [9.9%]). The median day of oral transition was 5 (IQR, 4-6 days). Total duration of antibiotic treatment was significantly shorter among the oral group than the IV group (median, 11 days [IQR, 9-14 days] vs median, 13 days [IQR, 8-16 days]; P < .001]. Fluoroquinolones (62.2% [1224 of 1969]), followed by ß-lactams (28.3% [558 of 1969]) and trimethoprim-sulfamethoxazole (11.5% [227 of 1969]), were the most commonly prescribed oral antibiotics. Conclusions and Relevance: In this cohort study of 4581 episodes of GN-BSIs, transition to oral antibiotic therapy by day 7 occurred in fewer than half of episodes, principally with fluoroquinolones, although this practice varied significantly between hospitals. There may have been additional opportunities for earlier and more frequent oral antibiotic transitions because most patients demonstrated clinical stability by day 5.

Current Utilization of Antifungal Agents for Intra-abdominal Infections Categorized by Patient Risk Factors During Surgical Procedures: A Literature Review.

The high morbidity and mortality rates associated with invasive fungal infections have led to the overutilization of empiric antifungal therapies. With increasing antibiotic resistance, the careful consideration of prophylactic or empiric antifungal use is critical. The purpose of this review is to evaluate the available literature regarding the current practice of utilizing antifungal agents for intra-abdominal infections based on specific surgical procedures and patient risk factors. Relevant articles were identified through a comprehensive literature search of several databases using the keywords antifungal agents, postoperative period, preoperative care, surgical procedures, and intra-abdominal infections. Only articles that evaluated the use of empiric antifungals for suspected or confirmed intra-abdominal infections and surgical procedures were included in this review. Based on the available literature, antifungal prophylaxis is appropriate in patients who meet the criteria for high-risk invasive candidiasis, kidney or liver transplant recipients, severely-immunocompromised patients with perforated peptic ulcer, peritonitis, and patients on peritoneal dialysis who are failing on a therapeutic antibiotic regimen. We acknowledge that the evidence for using antifungal therapy empirically for all surgical procedures is lacking, and the following review is based on available literature and current guidelines.

Herpes zoster subunit vaccine for the prevention of herpes zoster.

PURPOSE: Published literature on the efficacy and safety of the herpes zoster (HZ) subunit vaccine (HZ/su vaccine) in reducing the risks of HZ and postherpetic neuralgia (PHN) in adults 50 years of age and older, as well as the vaccine's properties and efficacy relative to live attenuated vaccine, is reviewed. SUMMARY: HZ/su vaccine (Shingrix, GlaxoSmithKline) is a recently Food and Drug Administration (FDA)-approved vaccine indicated for the prevention of HZ in adults 50 years of age and older. Based on several Phase III trials, the Advisory Committee on Immunization Practices has preferentially recommended HZ/su vaccine over a live attenuated vaccine previously approved by FDA. Reported overall HZ/su vaccine efficacy in preventing HZ in Phase III trials ranged from 89.8% to 97.2%. Compared with placebo use, HZ/su vaccine in those trials was associated with higher rates of transient local and systemic adverse events (AEs) but similar rates of serious vaccine-related AEs. Other clinical trials of HZ/su vaccine have yielded favorable results in various populations, including adults with a history of HZ, older adults who previously received live attenuated zoster vaccine, adults with human immunodeficiency virus infection, and stem cell transplant recipients. CONCLUSION: HZ/su vaccine is a recently approved, preferred option to reduce the risks of HZ and PHN in adults 50 years of age or older. Pain at the injection site is the most common AE associated with use of the vaccine.

A Retrospective Study of Patient Factors That Indicate Provider Nonadherence to an Institutional Clostridium difficile Treatment Guideline.

BACKGROUND: Clostridium difficile infection (CDI) is treated most often with metronidazole or vancomycin. Both have been effective in treatment of mild to moderate infection. In more severe cases, vancomycin may be more effective. OBJECTIVES: The primary objectives were to quantify the severity of CDI and to describe overall adherence to the institutional CDI guideline. Secondary objectives were to assess factors associated with adherence to the guidelines. METHODS: Retrospective analysis of the electronic medical record was used to evaluate adherence to institutional guidelines. Data collected included demographics and other factors potentially contributing to adherence: Charlson comorbidity index, severity of infection, recurrence, intensive care unit (ICU) admission, infectious diseases (ID) consult, total duration and number of antibiotics, alternative therapies, and acid suppression. Descriptive statistics and bivariate analyses were used to describe and compare factors associated with guideline adherence; multivariate logistic regression assessed independent predictors of adherence. RESULTS: A total of 387 patients met the inclusion criteria. CDI severity was 55.8% mild/moderate cases, 42.4% severe, 0.5% fulminant, and 1.3% prophylaxis. Overall, institutional guideline adherence was 51.9%. In bivariate analyses, 5 factors were associated with nonadherence to guidelines: older age, ICU admission, duration of antibiotics, mild/moderate and severe infection (all P < .05). In the logistic regression model, severe infection ( P < .001) and longer duration of antibiotics ( P < .05) were independently associated with guideline nonadherence. CONCLUSION: In this study, 42.4% of the patients met criteria for severe infection. Providers for patients with severe infection and longer duration of antibiotic therapy were less likely to adhere to the institutional guideline.

Solithromycin (CEM-101): A New Fluoroketolide Antibiotic and Its Role in the Treatment of Gonorrhea.

Solithromycin is a macrolide antibiotic that has undergone review for the treatment of community-acquired bacterial pneumonia. Solithromycin is also being investigated and has shown promise for the treatment of gonorrhea. With increasing antibiotic resistance, the development of novel antibiotics to combat infections is essential. The unique ribosome-binding stability of solithromycin and mild side effect profile make this a promising new antibiotic. This article will provide an overview on the mechanism of action, clinical efficacy, and safety of this drug for the treatment of gonorrhea. Relevant data were identified through a comprehensive literature search using multiple databases using the keywords solithromycin, CEM-101, and gonorrhea.

Drug-Drug Interactions Among Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) Medications.

One-fourth of individuals diagnosed with the human immunodeficiency virus concomitantly have the hepatitis C virus infection. Since the discovery of highly active antiretroviral therapy, liver complications have become the leading cause of morbidity and mortality in HIV-HCV coinfected individuals. Optimal treatment in this patient population is critical, as coinfection has been linked to deterioration of both disease states. The objective of this review article is to highlight the current literature on drug-drug interactions between HIV and HCV treatments. The management of the treatment of coinfection patients has been covered extensively in numerous other publications.

Antiretroviral therapy : pharmacokinetic considerations in patients with renal or hepatic impairment.

Hepatic and renal insufficiency due to co-infection, alcoholism, diabetes mellitus, family history, adverse effects of antiretrovirals and other factors are commonly seen in HIV-infected patients. Therefore, the use of antiretrovirals in this patient setting requires attention to the pharmacokinetic issues that clinicians must consider when prescribing highly active antiretroviral therapy for these patients. This review summarizes the current knowledge of the use of antiretrovirals in patients with hepatic or renal impairment, and makes dosing recommendations for this subpopulation of HIV-infected patients.

Factors associated with altered pharmacokinetics in substance users and non-substance users receiving lopinavir and atazanavir.

Substance use is highly prevalent in HIV-infected individuals in the United States, and clinical management is complicated by the need for antiretroviral treatment, addiction therapy, variable medication adherence, and co-morbidities. The interrelation between HIV and substance use prompted our investigation to examine substance use and self-reported medication adherence in patients receiving the HIV-1 protease inhibitors, atazanavir (ATV) or lopinavir (LPV). ATV and LPV pharmacokinetics were determined by measuring plasma concentrations in subjects with active substance use (SU group) or with no active substance use (NSU group). No difference in adherence was observed between groups (p > 0.05). The mean SU ATV trough was 0.550+/-0.45 microg/mL; the mean NSU ATV trough was 0.780+/-0.590 microg/mL (p > 0.05). The mean SU LPV trough was 4.02+/-2.39 microg/mL; the mean NSU LPV trough was 6.67+/-0.910 microg/mL (p = 0.01). Co-factors found to be associated with variation in ATV and LPV concentrations included concurrent methadone use, cigarette smoking, and substance use status. These data indicate that chronic HIV treatment may be assisted with plasma concentration monitoring to identify those patients who may require dosage modification and/or regimen adjustment in order to optimize antiretroviral effects.

Assessing the impact of substance use and hepatitis coinfection on atazanavir and lopinavir trough concentrations in HIV-infected patients during therapeutic drug monitoring.

Atazanavir (ATV) and lopinavir (LPV) are widely used HIV-1 protease inhibitors. Like with other protease inhibitors, careful monitoring of potential drug-drug and drug-disease interactions in clinical practice is necessary. The aim of this study was to assess the impact of substance use and hepatitis virus coinfection on plasma ATV and LPV trough concentrations in HIV-positive substance users and nonusers. Individuals established on ATV (300 mg and 100 mg ritonavir daily) or LPV (400 mg and 100 mg ritonavir twice daily)-containing regimens completed two clinical visits (trough and directly observed therapy) during which dosing characteristics, concomitant medication, and substance use were recorded. Trough plasma concentrations (22-26 hours for ATV and 10-14 hours for LPV) were measured using LCMSMS. The influence of substance use was evaluated by Kruskal-Wallis test. Substance use was associated with a marked decrease in trough LPV concentrations during the trough visit (median, 5.536 and 3.791 microg/mL for nonsubstance users and substance users, respectively, P = 0.029). Significantly lower LPV trough levels were also noted among patients with active hepatitis C virus coinfection evaluated as an independent variable (median, 2.253 and 5.927 microg/mL for active and inactive/no hepatitis C virus infection, respectively, P = 0.032). Substance use and hepatitis virus coinfection had limited effects on ATV trough levels. In this cohort, despite the wide interindividual variability of ATV and LPV trough concentrations, significant associations between substance use and active hepatitis C virus infection and low LPV trough concentrations were observed. Further work is needed to assess the optimal dosing regimen when using LPV in HIV-infected substance users.

HIV pharmacotherapy issues, challenges, and priorities in sub-Saharan African countries.

The use of potent antiretroviral drugs has led to successful treatment of HIV infection in most high-income countries. However, therapy remains largely unaffordable to the resource-limited world, particularly to countries in sub-Saharan Africa. The disparity and subsequent disease burden are devastating to the poorly resourced countries, hence creating a greater demand for international collaboration. This review outlines key examples of emerging HIV pharmacotherapy issues, challenges, and priorities within resource-limited settings in order to lay groundwork for potential enchancement of international research collaboration efforts. The prevalence and distribution patterns of HIV infection and sociocultural factors found in sub-Saharan African settings are discussed. Challenges include drug financing, drug distribution infrastructure, and government commitment to responding to the HIV pandemic. Priorities include prevention of HIV transmission, management of pediatric patients, availability of affordable medicines, and addressing concerns over the quality of medicines. The potential for the effective international collaboration is enhanced when expertise and resources from the developed world are combined with an understanding of the unique priorities of resource-limited settings.

Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV.

INTRODUCTION: HIV-infected patients receiving protease inhibitors may benefit from therapeutic drug monitoring-assisted dose adjustment to achieve target plasma concentrations. However, efflux pumps such as permeability-glycoprotein, which is encoded by the multidrug resistance (MDR)1 gene, may decrease intracellular drug concentrations, thus reducing the amount of drug at the site of action. Plasma concentrations of protease inhibitors and CD4 cell count response have been associated with the T allele at the MDR1 C3435T locus. We examined MDR1 single nucleotide polymorphisms in a cohort of patients in whom therapeutic drug monitoring is ongoing through a research protocol. METHODS: In a multicenter study, genotypic analyses at two MDR1 loci, C3435T and G2677T, were performed by a real-time polymerase chain reaction method using DNA from 103 patients categorized as substance users or nonusers on atazanavir or lopinavir as the primary antiretrovirals. Allelic frequencies were determined as a function of racial/ethnic background, substance use status and trough concentrations of atazanavir and lopinavir. RESULTS: The C/T and G/T alleles at the MDR1 C3435T and G2677T loci were equally frequent in the Caucasian population, but the wild-type alleles were more prevalent in the African-American population (59% homozygous [CC] and 32% heterozygous [CT] for C3435T; 80% homozygous [GG] and 16% heterozygous [GT] for G2677T). The frequencies in the Hispanic population were 46% CC and 38% CT for C3435T, and 58% GG and 38% GT for G2677T. No significant differences were seen in allele frequencies for MDR1 polymorphisms in substance user versus nonuser groups. Trough plasma concentrations of atazanavir or lopinavir were not correlated with the variant T allele. CONCLUSIONS: These data confirm the higher prevalence of wild-type alleles of the MDR1 gene in African-Americans and the linkage disequilibrium between C3435T and G2677T loci. The T allele at the MDR1 C3435T and G2677T loci was not associated with higher atazanavir or lopinavir trough concentrations.

Pharmacokinetic drug interactions with non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that inhibit HIV Type 1 reverse transcriptase. Although possessing a common mechanism of action, the approved NNRTIs, delavirdine, efavirenz and nevirapine, differ in structural and pharmacokinetic characteristics. Each of the NNRTIs undergoes biotransformation by the cytochrome P450 (CYP) enzyme system, thus making them prone to clinically significant drug interactions when combined with other antiretrovirals. In addition, they interact with other concurrent medications and complementary/alternative medicines, acting as either inducers or inhibitors of drug-metabolising CYP enzymes. These drug interactions become an important consideration in the clinical use of these agents when designing combination regimens, as recommended by current guidelines. This review provides an updated summary of pharmacokinetic interactions with NNRTIs.

Drug interactions with antiretrovirals.

The recent development of new antiretroviral drugs, along with the evolution in clinical practice guidelines that include the recommendation of the use of three- to four-drug combination regimens for achieving optimal suppression of viral replication, has focused clinicians on the relevance of drug-drug interactions in the chronic care of HIV-infected individuals. However, the routine clinical management of drug interactions is complicated by our expanding knowledge of the physiologic mechanisms underlying pharmacokinetic interactions, particularly as they relate to drug transport and tissue distribution (eg, P-glycoprotein) and biotransformation (hepatic cytochrome p450 mono-oxygenase induction and inhibition). This review provides an updated summary of key drug interactions that have been reported since its initial publication.

A gentamicin pharmacokinetic population model and once-daily dosing algorithm for neonates.

STUDY OBJECTIVE: To develop a gentamicin pharmacokinetic population model and once-daily dosing algorithm for neonates younger than 10 days. DESIGN: Prospective, open-label study. SETTING: Neonatal intensive care unit. PATIENTS: One hundred thirty-nine neonates prescribed gentamicin. MEASUREMENTS AND MAIN RESULTS: Gentamicin peak and trough serum concentrations were collected from 139 neonates divided into three groups who were receiving one of the following intravenous 24-hour gentamicin regimens during the first 10 days of life, based on gestational age and birth weight (group 1, < 28 wks, 2.5 mg/kg; group 2, 28-34 wks, 3 mg/kg; and group 3, > 34 wks, 4 mg/kg). A structural model was developed in ADAPT II software using a MAP Bayesian approach. Final population parameter estimates were calculated using iterative two-stage analysis. The median (range) gestational age and birth weight, respectively, were 32 weeks (23-42 wks) and 1.92 kg (0.47-5.00 kg). The final one-compartmental linear model had a median (range) gentamicin total clearance, half-life, and volume of distribution of 0.0709 L/hour (0.0151-0.246 L/hr), 8.59 hours (4.88-16.9 hrs), and 0.262 L (0.0903-0.929 L), respectively. Total clearance increased as gestational age increased (p<0.001). Group 1 (10.2 hrs) had a significantly longer half-life than either group 2 (8.89 hrs, p<0.01) or group 3 (6.98 hrs, p<0.01). Total clearance was associated with gestational age and birth weight: clearance (L/hr) = (0.00504 + [0.00108 x gestational age]) x birth weight (coefficient of determination [r2] = 0.897), and volume of distribution was associated with birth weight (r2 = 0.700). The following dosing algorithm was designed to reach a therapeutic 24-hour area under the curve (87.5 mg/L x hr) in neonates during the first 10 days after birth: 24-hour gentamicin dose (mg) = (0.441 + [0.0945 x gestational age]) x birth weight. CONCLUSION: This dosing algorithm provides a new approach for determining initial gentamicin dosing regimens in neonates; however, clinical validation is required.