Jamie L. Wagner

Comparison of fosfomycin to ertapenem for outpatient or step-down therapy of extended-spectrum β-lactamase urinary tract infections

Extended-spectrum β-lactamase (ESBL) enzymes cause resistance to common β-lactam antibiotics and are associated with poor outcomes. Management of ESBL urinary tract infections (UTIs) is challenging given the limited treatment options available outside the hospital setting. In this study, the primary endpoint of UTI-related 30-day hospital re-admission or emergency department/clinic revisit rates was compared for fosfomycin and ertapenem outpatient ESBL UTI treatments. A retrospective cohort study was performed on patients with ESBL UTIs treated with outpatient fosfomycin or ertapenem from January 2010 to February 2015. Inclusion criteria were age ≥18 years, outpatient treatment with fosfomycin or ertapenem for symptomatic ESBL UTI, and positive urine cultures with microbiologically proven ESBL-producing bacteria. A non-inferiority margin of 0.15 was selected to detect a difference in the primary endpoint. Patient and infection characteristics were compared. A sensitivity analysis with propensity score matching was performed. In total, 178 patients were included (89 fosfomycin-treated and 89 ertapenem-treated). Ertapenem-treated patients received longer outpatient antibiotic treatment (10 days vs. 6 days; P <0.001). ESBL isolates identified were 149 Escherichia coli (83.7%), 26 Klebsiella spp. (14.6%) and 3 other (1.7%). Common dosage regimens were oral dose of 3 g fosfomycin every 72 h (62%), oral dose of 3 g fosfomycin every 48 h (23%) and intravenous dose of 1 g ertapenem daily (76%). The thirty-day re-admission/revisit rates for fosfomycin and ertapenem were 14.6% vs. 13.5% (1.1% difference; 97.5% CI, -0.11 to 0.13). Fosfomycin was non-inferior to ertapenem for treating outpatient ESBL UTIs and should be considered as appropriate step-down therapy for these infections.

Elbasvir/Grazoprevir: A Review of the Latest Agent in the Fight against Hepatitis C

Hepatitis C virus (HCV) is estimated to affect up to 150 million people worldwide. Despite worldwide prevalence, treatment modalities prior to 2011 remained suboptimal, with low virologic response rates and intolerable side effect profiles. Fortunately, the landscape of treatment for chronic hepatitis C has rapidly evolved since the introduction of HCV NS3/4 protease inhibitors in 2011. Elbasvir, a NS5A inhibitor, combined with grazoprevir, a NS3/4A protease inhibitor, is the latest FDA-approved therapy for patients with genotype 1 or 4 chronic hepatitis C, with or without compensated cirrhosis. This review will focus on the current literature and clinical evidence supporting elbasvir/grazoprevir as first-line therapy in patients with genotypes 1 and 4 chronic hepatitis C.

Surgical prophylaxis with gram-negative activity for reduction of surgical site infections after microvascular reconstruction for head and neck cancer.

The purpose of this study was to determine the incidence of and risk factors for surgical site infections in microvascular reconstruction for patients with head and neck cancer.

Days of Therapy and Antimicrobial Days: Similarities and Differences Between Consumption Metrics

Benchmarks for antimicrobial consumption measured in antimicrobial days are beginning to emerge. The relationship between the traditional measure of days of therapy and antimicrobial days is unclear. We observed a high intermethod correlation (R2=0.99): antimicrobial days were 1.9-fold lower than days of therapy across agents. Individual institutions should correlate these measures. Infect Control Hosp Epidemiol 2016;37:971-973.

Intravenous Vancomycin Dosing in the Elderly: A Focus on Clinical Issues and Practical Application

The elderly population can be divided into three distinct age groups: 65–74 years (young-old), 75–84 years (middle-old), and 85+ years (old-old). Despite evidence of a shift in leading causes for mortality in the elderly from infectious diseases to chronic conditions, infections are still a serious cause of death in this population. These patients are at increased risk due to weakened immune systems, an increased prevalence of underlying comorbidities, and decreased physiologic reserves to fight infection. Additionally, elderly patients, especially adults in institutional settings, are at an increased risk of colonization and subsequent infection with methicillin-resistant Staphylococcus aureus at a rate that is five times higher than in younger individuals, causing an increase in empiric and definitive vancomycin use. Elderly patients have unique characteristics that make dosing vancomycin a challenge for clinicians, such as increased volume of distribution and decreased renal function. Using the best available evidence, it is recommended to initiate lower empiric maintenance doses and monitor vancomycin serum concentrations earlier than steady state to accurately calculate drug elimination and make appropriate dose adjustments.

Impact of an antifungal stewardship intervention on optimization of candidemia management

Background: Candidemia represents a leading cause of healthcare-associated bloodstream infections with significant morbidity and mortality. Previous studies have demonstrated that comprehensive care bundles improve candidemia management but are time-consuming. Objective: To determine the impact of a one-time targeted candidemia intervention on time to initiation of adequate therapy compared to standard of care. Methods: This Institutional Review Board (IRB)-approved, quasi-experiment evaluated a targeted candidemia intervention involving a single phone call to the primary team providing recommendations for care. Daily follow-up was provided by the infectious diseases (ID) consult service. Two time periods were evaluated: pre-intervention (01 August 2012 to 31 July 2014) and post-intervention (01 October 2014 to 30 September 2016). The primary endpoint was time to adequate antifungal therapy (TTx) in the business hours (6 a.m. to 6 p.m. Monday through Friday) population (BHP). Secondary endpoints were TTx in the total population as well as infection-related length of stay (IF-LOS) and compliance with quality indicators (composite endpoint: ophthalmology (OPH) consult, repeat cultures, and ⩾14 days of adequate therapy). Results: In all, 117 patients were included (pre-intervention = 50, post-intervention = 67, BHP = 51). TTx decreased from 2 h 57 m to 2 h 12 m (p = 0.094) in the BHP and 3 h 30 m to 2 h 9 m (p = 0.021) in the total population. There was no difference in IF-LOS (p = 0.797), compliance with quality indicators (p = 0.343), or in-hospital mortality (p = 0.761). Post-intervention, there were more ID and OPH consults (p < 0.001). Conclusions: Our one-time candidemia intervention did not statistically decrease time to adequate therapy in the BHP, but did in the total population. No differences were found for other clinical outcomes, except increases in ID and OPH consults. Further studies are needed to examine whether a one-time intervention is non-inferior to a more comprehensive care bundle.

Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic

The emergence and spread of antimicrobial resistance have led to a global public health emergency requiring development of new antimicrobial classes. Lefamulin (formally BC‐3781) is a novel pleuromutilin antibiotic currently undergoing Food and Drug Administration review for community‐acquired bacterial pneumonia (CABP) as intravenous (IV) and oral (PO) formulations. Although pleuromutilin antibiotics were first developed in the 1950s, lefamulin is the first to be used for systemic treatment of bacterial infections in humans. Lefamulin exhibits a unique mechanism of action through inhibition of protein synthesis by binding to the peptidyl transferase center of the 50S bacterial ribosome, thus preventing the binding of transfer RNA for peptide transfer. Lefamulin displays activity against gram‐positive and atypical organisms associated with CABP (i.e., Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae), with an expanded gram‐positive spectrum including Staphylococcus aureus (i.e., methicillin‐resistant, vancomycin‐intermediate, and heterogeneous strains) and vancomycin‐resistant Enterococcus faecium. Lefamulin was also shown to retain activity against multidrug‐resistant Neisseria gonorrhoeae and Mycoplasma genitalium. Lefamulin exhibits time‐dependent killing, and the pharmacodynamic target best associated with antibacterial activity is ƒAUC0–24/MIC (minimum inhibitory concentration [MIC]). Preclinical and phase II trials indicate that lefamulin concentrates in lung tissue are well tolerated at an IV dose of 150 mg twice/day over 1 hour or a PO dose of 600 mg twice/day, and preliminary phase III data suggest similar efficacy when compared with moxifloxacin with or without linezolid in CABP. Documented resistance and cross‐resistance with other gram‐positive antibacterials remains low. Additional published in vitro, in vivo, and preclinical trial data suggest further exploration of lefamulin in various infectious disease states (e.g., acute bacterial skin and skin structure infections, and sexually transmitted infections). This review discusses the pertinent bacterial spectrum of activity, preclinical and ongoing clinical data, and potential roles in therapy for lefamulin.

Omadacycline Enters the Ring: A New Antimicrobial Contender

Omadacycline is a novel aminomethylcycline approved for the treatment of community‐acquired bacterial pneumonia and acute bacterial skin and skin structure infections. This article reviews existing data pertaining to the biochemistry, mechanism of action, pharmacokinetics/pharmacodynamics, in vitro activity, and current progress with omadacycline in clinical trials. Omadacycline inhibits protein synthesis by binding to the 30S subunit of the bacterial ribosome at the tetracycline‐binding site with an affinity similar to glycylcyclines. It is able to bypass older tetracycline resistance mechanisms and demonstrates activity against bacterial strains that are tetracycline resistant. In addition, omadacycline displays broad‐spectrum activity against gram‐positive organisms (including methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant enterococci), gram‐negative organisms, atypical organisms, and anaerobes. It has been evaluated against infections in adults both intravenously and orally. Dosage adjustments are not required for patients with renal impairment. Omadacycline displays a comparable efficacy and safety profile to standard‐of‐care agents, with the most common side effects observed being gastrointestinal. Currently available data for omadacycline suggest that this is a promising agent added to our antimicrobial armamentarium.

Effect of elevated imipenem/cilastatin minimum inhibitory concentrations on patient outcomes in Gram-negative bloodstream infections

OBJECTIVES Carbapenem minimum inhibitory concentration (MICs) are known to predict outcomes for patients with Gram-negative bacteraemia. However, limited data exist on how MICs influence such outcomes when organisms are classified as carbapenem-resistant. The purpose of this study was to evaluate the effect of increasing imipenem/cilastatin MICs on mortality in patients with Gram-negative bloodstream infection (BSI). METHODS Patients with an imipenem/cilastatin-resistant (MIC>4mg/L) monomicrobial Gram-negative BSI were eligible for inclusion in the study and were assessed for baseline characteristics, organ function, microbiological data, timing and type of therapeutic treatment, and in-hospital mortality. RESULTS A total of 62 patients with imipenem/cilastatin-resistant bacterial isolates (MIC>4mg/L) were retrospectively studied. Time to event analyses found no difference between patients who received carbapenem therapy and those who did not (P=0.10). After adjustment, patients receiving directed therapy were less likely to die (adjusted hazard ratio=0.35, 95% confidence interval 0.15-0.83; P<0.01), whereas higher modified Acute Physiology and Chronic Health Evaluation (APACHE) II score and days to positive culture were associated with non-survival. CONCLUSION This study did not demonstrate a relationship between receipt of a carbapenem and mortality in patients with carbapenem-resistant Gram-negative BSI.

Ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus Bacteremia: A case series

Methicillin-susceptible Staphylococcus aureus (MSSA) causes 45% of S. aureus bloodstream infections (BSI) and is the most important cause of BSI-associated death. The standard of care therapy is an anti-staphylococcal penicillin or cefazolin, but dosing frequencies for these agents are often infeasible; multiple daily doses tie up infusion lines and are impractical for outpatient antibiotic infusion. Ceftriaxone represents a promising alternative, with once daily dosing and a short infusion time. Currently, treatment with ceftriaxone for invasive MSSA infections is infrequent, with minimal data supporting the clinical utility of ceftriaxone for MSSA BSI. In this case series, we identified 15 patients receiving ceftriaxone for treatment of MSSA BSI, either following standard of care therapy or as initial therapy. Patients were evaluated for clinical cure (CC)(clearance of BSI and normalization of white blood cell count) and microbiological cure (MC)(clearance of blood cultures and no recurrence of organism within 60 days). CC was observed in seven patients, with MC observed in all patients. Only one patient was readmitted to the hospital. This case series provides vital data to support ceftriaxone for treatment of MSSA BSI. With few readmissions and recurrences of infection, ceftriaxone was an effective option for maintenance therapy after resolution of the BSI. Ceftriaxone appears to be a viable alternative for the treatment of MSSA BSI.