Michael Veve

Predictors of Clinically Significant Drug-Drug Interactions Among Patients Treated with Nonnucleoside Reverse Transcriptase Inhibitor-, Protease Inhibitor-, and Raltegravir-Based Antiretroviral Regimens

Background: The Department of Health and Human Services (DHHS) HIV treatment guidelines recommend that antiretroviral regimens for treatment-naïve individuals include at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus either (1) a nonnucleoside reverse transcriptase inhibitor (NNRTI), (2) a protease inhibitor (PI), or (3) raltegravir, an integrase strand transfer inhibitor. Differences in drug-drug interaction potential may represent an important differentiating feature when choosing between these regimen types. Objective: To identify risk factors for clinically significant drug-drug interactions (CSDDIs) among patients on NNRTI-, PI-, and raltegravir-based antiretroviral regimens; compare CSDDI risks between these regimen types; and develop a clinical prediction tool for antiretroviral CSDDIs Methods: In this cross-sectional study, outpatient medical records from the HIV clinic at Albany Medical Center Hospital were randomly selected to review patients’ current antiretroviral regimens. Patients treated with NNRTI-, PI-, or raltegravir-based regimens were included. Drug therapies were analyzed for interactions using Lexi-Comp drug interaction software. The CSDDIs were defined as either (1) a drug combination that is contraindicated or accompanied by strong precautions per DHHS antiretroviral guidelines or (2) a drug combination that necessitates a medication dose adjustment. Results: Of the 500 patient records screened. 229 were included. Baseline characteristics were similar between regimen groups, with the exception of comorbidities. In multivariate analyses, variables independently associated with CSDDIs were use of >5 non-antiretroviral medications (prevalence ratio [PR] 1.86; 95% CI 1.31 to 2.64: p< 0.001) and regimen type (NNRTI: PR 2.48, PI: PR 4.96, and rallegravir [referent]: PR 1.00; 95% CI 1.79 to 3.44; p < 0.001). Conclusions: Use of >5 non-antiretroviral medications or a non-raltegravir-based antiretroviral regimen increased the risk of a CSDDI. Our findings help clarify drug interaction risks among NNRTI-. PI-, and raltegravir-based regimen types that should be considered when prescribing antiretroviral therapy.

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.

Comparison of Etest to Broth Microdilution for Testing of Susceptibility of Pseudomonas aeruginosa to Ceftolozane-Tazobactam

The emergence and spread of multidrug-resistant (MDR) Pseudomonas aeruginosa are a significant burden to health care systems due to poor patient outcomes, serious infection control implications, and limited antibiotic effectiveness ([1][1], [2][2]). Ceftolozane-tazobactam is a novel beta-lactam–

Frequency of electrocardiogram testing among HIV-infected patients at risk for medication-induced QTc prolongation.

HIV‐infected patients are commonly prescribed several medications and are thus at risk for drug interactions that may result in QTc prolongation. We sought (1) to identify the frequency of electrocardiogram (ECG) monitoring (2), to determine the prevalence of drug interactions involving QTc‐prolonging medications, and (3) to quantify the prevalence of QTc prolongation.

Prevalence and Predictors of Important Telaprevir Drug Interactions Among Patients Coinfected With Hepatitis C and Human Immunodeficiency Virus

Background: Among patients with HIV and hepatitis C (HCV) coinfection, drug–drug interactions involving nonstructural protein 3/4 (NS3/4A) serine protease inhibitors for HCV infection are an important concern because these drugs affect cytochrome P450 metabolism and p-glycoprotein transporters. Objectives: The primary objective was to determine the prevalence of clinically significant drug–drug interactions (CSDDIs) in HIV/HCV coinfected patients if telaprevir-based HCV therapy is added to patients’ medication regimens. Secondary objectives were to identify antiretroviral therapy (ART) regimens associated with the lowest risk of CSDDI and determine the clinical risk factors. Methods: A cross-sectional study was performed among adult HIV/HCV coinfected patients. Demographics, comorbidities, social history, and medication lists were extracted from medical records. For each patient, CSDDIs were identified by entering all medications and pegylated interferon, ribavirin, and telaprevir into Lexi-Interact drug interaction software. The number and nature of CSDDIs were recorded before and after addition of telaprevir-based therapy. Results: There were 335 patients included. Prior to the addition of telaprevir-based HCV therapy, there was a high frequency (82.1%) of any CSDDI. After the addition of telaprevir-based HCV therapy, the frequency of any CSDDI increased to 97% (P < .001). Contraindicated interactions rose from 20.0% to 38.2% of patients after addition of telaprevir-based therapy. Use of ≥10 non-HIV medications, dyslipidemia, and HIV protease inhibitors were independently associated with the occurrence of a contraindicated interaction. Conclusions: Clinicians considering initiating telaprevir in HIV/HCV coinfected patients should be vigilant of drug–drug interactions, particularly among patients with dyslipidemia, those using ≥10 non-HIV medications, and those using HIV protease inhibitors.

Considerations for antibiotic prophylaxis in head and neck cancer surgery

Peri/post-operative antibiotic prophylaxis (POABP) has become standard practice for preventing surgical site infections (SSI) in head and neck cancer patients undergoing microvascular reconstruction, but few data exist on optimal POABP regimens. Current surgical prophylaxis guideline recommendations fail to account for the complexity of microvascular reconstruction relative to other head and neck procedures, specifically regarding wound classification and antibiotic duration. Selection of POABP spectrum is also controversial, and must balance the choice between too narrow, risking subsequent infection, or too broad, and possible unwanted effects (e.g. antibiotic resistance, Clostridium difficile-associated diarrhea). POABP regimens should retain activity against bacteria expected to colonize the upper respiratory/salivary tracts, which include Gram-positive organisms and facultative anaerobes. However, Gram-negative bacilli also contribute to SSI in this setting. POABP doses should be optimized in order to achieve therapeutic tissue concentrations at the surgical site. Antibiotics targeted towards methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa are not warranted for all patients. Prolonged POABP durations have shown no differences in SSI when compared to short POABP durations, but prolonged durations provide unnecessarily antibiotic exposure and risk for adverse effects. Given the lack of standardization behind antibiotic POABP in this setting and the potential for poor patient outcomes, this practice necessitates an additional focus of surgeons and antimicrobial stewardship programs. The purpose of this review is to provide an overview of POABP evidence and discuss pertinent clinical implications of appropriate use.

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.

Multicenter Assessment of Antibiotic Prophylaxis Spectrum on Surgical Infections in Head and Neck Cancer Microvascular Reconstruction

Objective To characterize and identify risk factors for 30-day surgical site infections (SSIs) in patients with head and neck cancer who underwent microvascular reconstruction. Study Design Cross-sectional study with nested case-control design. Setting Nine American tertiary care centers. Subjects and Methods Hospitalized patients were included if they underwent head and neck cancer microvascular reconstruction from January 2003 to March 2016. Cases were defined as patients who developed 30-day SSI; controls were patients without SSI at 30 days. Postoperative antibiotic prophylaxis (POABP) regimens were categorized by Gram-negative (GN) spectrum: no GN coverage, enteric GN coverage, and enteric with antipseudomonal GN coverage. All POABP regimens retained activity against anaerobes and Gram-positive bacteria. Thirty-day prevalence of and risk factors for SSI were evaluated. Results A total of 1307 patients were included. Thirty-day SSI occurred in 189 (15%) patients; median time to SSI was 11.5 days (interquartile range, 7-17). Organisms were isolated in 59% of SSI; methicillin-resistant Staphylococcus aureus (6%) and Pseudomonas aeruginosa (9%) were uncommon. A total of 1003 (77%) patients had POABP data: no GN (17%), enteric GN (52%), and antipseudomonal GN (31%). Variables independently associated with 30-day SSI were as follows: female sex (adjusted odds ratio [aOR], 1.6; 95% CI, 1.1-2.2), no GN POABP (aOR, 2.2; 95% CI, 1.5-3.3), and surgical duration ≥11.8 hours (aOR, 1.9; 95% CI, 1.3-2.7). Longer POABP durations (≥6 days) or antipseudomonal POABP had no association with SSI. Conclusions POABP without GN coverage was significantly associated with SSI and should be avoided. Antipseudomonal POABP or longer prophylaxis durations (≥6 days) were not protective against SSI. Antimicrobial stewardship interventions should be made to limit unnecessary antibiotic exposures, prevent the emergence of resistant organisms, and improve patient outcomes.

Retraction for Flynt et al., “Comparison of Etest to Broth Microdilution for Testing of Susceptibility of Pseudomonas aeruginosa to Ceftolozane-Tazobactam”

Volume 55, no. 1, p. 334 –335, 2017, https://doi.org/10.1128/JCM.01920-16. We hereby retract this article. In our paper we described discrepant results between ceftolozane-tazobactam Etests and broth microdilution. However, when repeat testing on the same isolates was done for a second, larger study recently published by R. M. Humphries, J. A. Hindler, P. Magnano, A. Wong Beringer, R. Tibbetts, and S. A. Miller (J Clin Microbiol 56:e01633-17, 2018, https://doi.org/10.1128/JCM.01633-17) we could not replicate the initial results. Upon review of the procedure used for broth microdilution it was determined that the tazobactam concentrations were not prepared according to CLSI guidelines (Clinical Laboratory Standards Institute, Performance Standards for Antimicrobial Susceptibility Testing, 26th ed, CLSI supplement M100S, 2016). We hypothesized that this may have contributed to the high MICs and very major errors. In order to test this hypothesis, we repeated the broth microdilution in the original laboratory using the same procedure as initially performed; however, we could not replicate the errors. Based on this outcome, a second hypothesis was that perhaps the bacteria possessed a resistance mechanism at the time of initial testing but that upon repeated subculture the mechanism was lost; however, we are unable to test this hypothesis.

Trowels and Tribulations: Review of Antimicrobial‐Impregnated Bone Cements in Prosthetic Joint Surgery

Antimicrobial‐impregnated bone cement (AIBC) is a staple of contemporary orthopedic surgery and has been used to either treat or prevent prosthetic joint infection. Applied intraoperatively during primary arthroplasty or prosthetic joint exchange, this drug‐delivery vehicle has become a popular means of maximizing drug concentrations within a joint space while minimizing systemic exposure. Antimicrobial characteristics conducive to cement loading include availability of a crystalline powder formulation, molecular characteristics, minimal impact on cement integrity, and other variables promoting drug elution. Antimicrobials most commonly incorporated into cements are vancomycin and aminoglycosides, usually in combination due to synergistic antibacterial activity and enhanced cement elution. Other classes include the β‐lactams, lipopeptides, oxazolidinones, and antifungals. With the exception of several commercially available AIBCs, most products are compounded extemporaneously without a formal safety or efficacy assessment. Few randomized controlled trials have been conducted to assess the benefit or optimal use of these cement preparations, and variable methodology renders cross‐study comparison challenging. Given the lack of standardization and multidisciplinary oversight often seen with practical AIBC use, additional data are needed. This review presents information intended to guide AIBC preparation, selection, dosing, and safe use. In addition, opportunities for best practice development, antimicrobial stewardship, and future research are discussed.