Virologic outcomes of antiretroviral therapy in patients with HIV-1 following bariatric surgery: A case series and review of the literature.

BACKGROUND: Selection of an antiretroviral regimen for people living with HIV (PLWH) involves various clinical considerations, such as comorbidities, archived drug resistance mutations, concomitant medications, and potential drug interactions and side effects. Alterations in the surface area and pH of the gastrointestinal tract following bariatric surgery may alter absorption, antiretroviral pharmacokinetics and viral suppression. Data on the efficacy of antiretroviral (ARV) therapy in PLWH who have undergone bariatric surgery are limited or lacking for new antiretrovirals, such as dolutegravir and bictegravir. METHODS: This case series reports virologic outcomes and side effects in eight cases of PLWH receiving ARV therapy who underwent bariatric surgery. A systematic literature review was performed to review the available literature on the efficacy and safety of antiretroviral regimens in PLWH who have undergone bariatric surgery. RESULTS: Virologic suppression was not impacted for obese PLWH who underwent bariatric surgery following failure of life-style modifications and pharmacological therapy. CONCLUSIONS: There were no deleterious effects on HIV progression for PLWH that underwent bariatric surgery. More prospective research is required to validate the effects of bariatric surgery on immunologic and virologic function outcomes. Close involvement of HIV and surgical specialists is recommended to manage ARV therapy in patients undergoing bariatric surgery.

Oral antibiotic step-down therapy for nonstaphylococcal gram-positive bloodstream infections.

Bloodstream infections traditionally are treated with intravenous (IV) therapy. This study's purpose is to evaluate if oral step-down therapy is noninferior to IV therapy for gram-positive bloodstream infections (GP-BSIs). This retrospective cohort study included patients who received IV therapy and those who received oral step-down therapy for a nonstaphylococcal GP-BSI from 2017 to 2019. The primary endpoint was a composite outcome of 90-day all-cause mortality and clinical failure. A total of 308 patients were included (n = 94, oral; n = 214, IV). The oral step-down group had a lower incidence of 90-day clinical failure (9% vs 14%; P < 0.001). The IV group had a longer hospital stay (4 vs 6 days, P < 0.001); however, there were no significant differences in secondary outcomes. Bivariate analysis found no predictors of 90-day clinical failure. Oral step-down therapy was found to be noninferior to IV therapy.

Aminopenicillins for treatment of ampicillin-resistant enterococcal urinary tract infections.

PURPOSE: The purpose of this review is to describe the theory behind and data supporting use of aminopenicillins in the treatment of ampicillin-resistant enterococcal urinary tract infections. SUMMARY: Aminopenicillin concentrations in the urine may be high enough to achieve bacterial eradication and clinical cure for infections affecting the lower genitourinary tract, even in the context of in vitro resistance based on established susceptibility breakpoints. A literature search was conducted to identify original research articles describing the use of aminopenicillins in the treatment of urinary tract infections caused by ampicillin-resistant Enterococcus species. Three published retrospective cohort studies were identified, all of which reported that aminopenicillins had similar rates of clinical cure as other antibiotic classes prescribed for the treatment of enterococcal urinary tract infections. CONCLUSION: Both pharmacokinetic/pharmacodynamic principles and limited retrospective clinical data support the use of aminopenicillins in the treatment of lower urinary tract infections caused by Enterococcus species, even when the isolates have a minimum inhibitory concentration that exceeds the susceptibility breakpoint.

Association Between Estimated Pharmacokinetic/Pharmacodynamic Predictions of Efficacy and Observed Clinical Outcomes in Obese and Nonobese Patients With Enterobacteriaceae Bloodstream Infections.

BACKGROUND: Evidence on pharmacokinetic/pharmacodynamic (PK/PD) alterations and clinical outcomes in obese patients with serious infections remains limited. This study aimed to evaluate predicted PK/PD indices of efficacy and observed clinical outcomes between obese and nonobese patients receiving cefepime or piperacillin-tazobactam for Enterobacteriaceae bacteremia. METHODS: This was a retrospective study of adult inpatients from 1/2012 to 9/2015 with Enterobacteriaceae bacteremia who received empiric cefepime or piperacillin-tazobactam. The primary outcome was clinical cure. First-dose free-drug exposure was estimated via predicted concentrations generated from population PK analyses and used to assess PD target attainment (>50% fT > minimum inhibitory concentration [MIC]) for the specific Enterobacteriaceae isolate. Multivariable logistic regression was utilized to identify independent predictors of clinical cure. RESULTS: One hundred forty-two patients were included, 57 obese and 85 nonobese. Clinical cure was achieved in 68.4% of obese and 62.4% of nonobese patients (P = .458). No significant difference in outcomes was observed when evaluated by World Health Organization (WHO) obesity classes. The PK/PD target was achieved in 98.2% of obese and 91.8% of nonobese patients (P = .144). Independent predictors of clinical cure were immunosuppression and a shorter duration of bacteremia. Obesity was not identified as a significant predictor of clinical outcomes. CONCLUSIONS: Neither predicted PK/PD parameters nor clinical outcomes differed significantly between obese and nonobese patients treated with piperacillin-tazobactam or cefepime. As the majority of patients received extended-infusion piperacillin-tazobactam for bacteremia due to pathogens with low MICs, the potentially detrimental pathophysiologic derangements caused by obesity may not have been realized. Further studies are warranted to establish the optimal treatment of serious infections in obese patients.

Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants.

The pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n = 11) and urine (n = 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 µg/ml, time to Cmax (Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0-24) = 151.6 ± 35.6 versus 156.6 ± 42.5 µg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 µg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%; P < 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.).

Effectiveness of Probiotic for Primary Prevention of Clostridium difficile Infection: A Single-Center Before-and-After Quality Improvement Intervention at a Tertiary-Care Medical Center.

OBJECTIVETo evaluate probiotics for the primary prevention of Clostridium difficile infection (CDI) among hospital inpatients.DESIGNA before-and-after quality improvement intervention comparing 12-month baseline and intervention periods.SETTINGA 694-bed teaching hospital.INTERVENTIONWe administered a multispecies probiotic comprising L. acidophilus (CL1285), L. casei (LBC80R), and L. rhamnosus (CLR2) to eligible antibiotic recipients within 12 hours of initial antibiotic receipt through 5 days after final dose. We excluded (1) all patients on neonatal, pediatric and oncology wards; (2) all individuals receiving perioperative prophylactic antibiotic recipients; (3) all those restricted from oral intake; and (4) those with pancreatitis, leukopenia, or posttransplant. We defined CDI by symptoms plus C. difficile toxin detection by polymerase chain reaction. Our primary outcome was hospital-onset CDI incidence on eligible hospital units, analyzed using segmented regression.RESULTSThe study included 251 CDI episodes among 360,016 patient days during the baseline and intervention periods, and the incidence rate was 7.0 per 10,000 patient days. The incidence rate was similar during baseline and intervention periods (6.9 vs 7.0 per 10,000 patient days; P=.95). However, compared to the first 6 months of the intervention, we detected a significant decrease in CDI during the final 6 months (incidence rate ratio, 0.6; 95% confidence interval, 0.4-0.9; P=.009). Testing intensity remained stable between the baseline and intervention periods: 19% versus 20% of stools tested were C. difficile positive by PCR, respectively. From medical record reviews, only 26% of eligible patients received a probiotic per the protocol.CONCLUSIONSDespite poor adherence to the protocol, there was a reduction in the incidence of CDI during the intervention, which was delayed ~6 months after introducing probiotic for primary prevention.Infect Control Hosp Epidemiol 2018;765-770.

Impact of Clinical and Laboratory Standards Institute breakpoint changes on susceptibility rates of cephalosporins in uncomplicated urinary tract infections caused by Enterobacteriaceae.

Breakpoint changes may impact cephalosporin susceptibility rates in uncomplicated urinary tract infections (uUTIs). Applying the ≤16-mg/L breakpoint to urine cultures from adult women in an academic health system resulted in cefazolin being the most active uUTI antimicrobial, with 86.9% susceptibility, compared to levofloxacin (80%), nitrofurantoin (76.5%), and sulfamethoxazole-trimethoprim (72.6%).

Clinical use of the polymyxins: the tale of the fox and the cat.

BACKGROUND: There is a need to identify practice patterns of polymyxin use, quantify gaps in knowledge, and recognize areas of persistent confusion. METHODS: A structured electronic survey was distributed to physicians, pharmacists and microbiologists. Demographic information was obtained, along with data regarding availability, stewardship principles, therapeutic usage, dosing, microbiological testing, and knowledge, attitudes and beliefs regarding the polymyxins. RESULTS: In total, there were 420 respondents with a median of 8 (interquartile range 4-15) years of experience in infectious diseases (52.5%) and critical care (35%). Of the respondents who reported that only one polymyxin was available for use, 17.1% used polymyxin B. Over half (52.5%) of the respondents utilized a loading dose very often/always, and 66.8% dosed both polymyxins in milligrams, with the most common doses of colistin and polymyxin B being 2.5 mg/kg twice daily (60.3%) and 1.5 mg/kg twice daily (65%), respectively, for patients with normal renal function. Polymyxins were most often used for respiratory infections (63%) in combination with a carbapenem (63.6%). Approximately 85% of respondents reported their knowledge level to be fair, good or very good, although 34.9% answered two of the three knowledge questions incorrectly. More than 70% of respondents agreed that confusion exists in all surveyed areas of polymyxin use. Almost all respondents (91.2%) agreed that a polymyxin guideline would be a helpful resource. CONCLUSIONS: This survey revealed objective and subjective variability in the use and perception of the polymyxins, and identified several areas in which they were being used contrary to the available evidence. The information provided herein lays the framework to harmonize clinical practice, guide future research and shape consensus guidelines.

Pharmacokinetics of Telavancin at Fixed Doses in Normal-Body-Weight and Obese (Classes I, II, and III) Adult Subjects.

A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects (n = 32) received a single, weight-stratified, fixed dose of 500 mg (n = 4), 750 mg (n = 8), or 1,000 mg (n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC0-∞) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC0-∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.).

Immunologic and Virologic Outcomes of Obese and Nonobese Incarcerated Adults on Antiretroviral Therapy for HIV Infection.

BACKGROUND: Obesity is common among patients with HIV. The objective of this study was to characterize response to antiretroviral therapy (ART) in a cohort of obese incarcerated adults compared to a nonobese cohort. METHODS: A retrospective matched cohort study was conducted in an HIV telemedicine clinic. Patients with body mass index (BMI) >30 kg/m2 who received the same ART with >95% adherence for at least 6 months were matched to nonobese patients by age, gender, ART, CD4 count, and viral load at baseline. RESULTS: Twenty pairs were included, with an average BMI of 24 kg/m2 in the nonobese cohort and 35 kg/m2 in the obese cohort. No difference was observed in the proportion of patients who achieved virologic suppression or the change in CD4 count from baseline to 6 to 12 months. CONCLUSION: This study revealed no differences in immunologic recovery or virologic suppression between obese and nonobese patients in an adult correctional population.

Clinical and economic impact of the introduction of a nucleic acid amplification assay for Clostridium difficile.

BACKGROUND: The clinical outcomes and cost implications of a diagnostic shift from an EIA- to PCR-based assay for Clostridium difficile infection (CDI) have not been completely described in the literature. METHODS: The impact of the PCR-based assay on the incidence and duration of CDI therapy was compared to the EIA assay for patients with a negative CDI diagnostic result. Secondary clinical and economic outcomes were also evaluated. Independent predictors of receipt of antibiotic therapy were assessed via logistic regression. RESULTS: 141 EIA and 140 PCR patients were included. Significantly more patients were started or continued on anti-CDI antibiotic therapy after a known negative assay result in the EIA group (26 patients vs. 8 patients, P = 0.002). Duration of antibiotic therapy after a known negative result was significantly shorter in the PCR group (1 vs. 4 days, P = 0.029) and a 23% reduction in the number of tests obtained per patient was observed (1.41 ± 0.86 vs. 1.82 ± 1.35, P = 0.007). The over fourfold difference in per-test cost of the EIA assay ($8.33 vs. $42.86, P < 0.0001) was offset by the overall medication costs required for the increased treatment in the EIA group ($546.60 vs. $188.96, P = 0.191). Utilization of the EIA-based CDI assay was associated with increased odds of CDI treatment after a negative test (aOR 4.71, 95% CI 1.93-11.46, P = 0.001). CONCLUSION: The transition from an EIA to PCR-based assay for diagnosing CDI resulted in a significant decrease in the number of patients treated and the duration of treatment in response to a negative test result. This significant decrease in treatment resulted in decreased costs offsetting the utilization of a more expensive molecular test for patients with a negative CDI diagnostic result.

Economic Barriers in the Treatment of Clostridium difficile Infection With Oral Vancomycin.

Vancomycin is an increasingly important option for the treatment of Clostridium difficile infection, but economic barriers to its use remain significant in the outpatient setting. Generic vancomycin capsules are still inexplicably expensive and not universally covered by insurers. This report highlights the potential adverse consequences of cost-related nonadherence to vancomycin therapy and the challenges that clinicians face when prescribing oral vancomycin.

Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration.

Ceftazidime-avibactam administered at 1.25 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa bacteremia in a critically ill patient on continuous venovenous hemofiltration (CVVH). Prefiltration plasma drug concentrations of ceftazidime and avibactam were measured at 0, 1, 2, 4, 6, and 8 h along with postfiltration and ultrafiltrate concentrations at h 2 and h 6. Plasma pharmacokinetic parameters of ceftazidime and avibactam, respectively, were as follows: maximum plasma concentration (Cmax), 61.10 and 14.54 mg/liter; minimum plasma concentration (Cmin), 31.96 and 8.45 mg/liter; half-life (t1/2), 6.07 and 6.78 h; apparent volume of distribution at the steady state (Vss), 27.23 and 30.81 liters; total clearance at the steady state (CLss), 2.87 and 2.95 liters/h; area under the concentration-time curve from 0 to 8 h (AUC0-8), 347.87 and 85.69 mg · h/liter. Concentrations of ceftazidime in plasma exceeded the ceftazidime-avibactam MIC (6 mg/liter) throughout the 8-h dosing interval. Mean CVVH extraction ratios for ceftazidime and avibactam were 14.44% and 11.53%, respectively, and mean sieving coefficients were 0.96 and 0.93, respectively. The calculated mean clearance of ceftazidime by CVVH was 1.64 liters/h and for avibactam was 1.59 liters/h, representing 57.1% of the total clearance of ceftazidime and 54.3% of the total clearance of avibactam. Further data that include multiple patients and dialysis modes are needed to verify the optimal ceftazidime-avibactam dosing strategy during critical illness and CVVH.

Methicillin-Resistant Staphylococcus aureus Pneumonia in Critically Ill Trauma and Burn Patients: A Retrospective Cohort Study.

BACKGROUND: The timing and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in trauma patients are not well characterized. This information is critical for the selection of appropriate empiric antibiotics. The objective of this study was to determine the incidence of MRSA pneumonia in early-onset and late-onset pneumonia and to identify risk factors for MRSA in the trauma-burn intensive care unit (ICU). PATIENTS AND METHODS: We conducted a retrospective cohort study from January 2012 to March 2015 of patients in the trauma and burn ICU with clinical and microbiologic evidence of pneumonia. Demographics, injury type and severity, co-morbidities, antimicrobial agents, and MRSA nasal colonization at ICU admission were extracted from the medical record. A multi-variable exact logistic regression was performed to assess predictors of MRSA pneumonia. RESULTS: Eighty patients with 88 episodes of pneumonia were included in the cohort. Ten patients had MRSA pneumonia, an overall incidence of 11.4% of pneumonia episodes with a median onset of seven days. The proportion of MRSA pneumonia episodes was not significantly different in early-onset (<5 days) or late-onset pneumonia, and there were no statistically significant risk factors for developing MRSA pneumonia. The majority of patients with MRSA had at least one known risk factor including homelessness, substance abuse, and receipt of broad-spectrum antibiotic agents. CONCLUSIONS: The 11.4% overall incidence of MRSA pneumonia in this trauma-burn cohort was similar to what has been reported in other trauma populations, although MRSA was equally likely to be identified in early- and late-onset pneumonia. Our results suggest that risk factors other than duration of hospitalization may be important considerations in the decision to initiate MRSA-active empiric therapy for pneumonia in the trauma-burn ICU.

Nephrotoxicity Associated with Concomitant Use of Ledipasvir-Sofosbuvir and Tenofovir in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection.

Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection, with superior efficacy and safety compared to interferon-based therapies. Despite these improvements, drug interactions with DAAs exist and may be clinically relevant in human immunodeficiency virus (HIV)-coinfected patients. We present a case of nephrotoxicity associated with concomitant use of tenofovir disoproxil fumarate (TDF) and ledipasvir-sofosbuvir (LDV-SOF). A 56-year-old woman with HIV infection who had been taking efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) for 6 years developed acute kidney injury 8 weeks after initiating LDV-SOF for the treatment of HCV infection. Her serum creatinine concentration peaked at 10 mg/dL, compared with her baseline concentration of 0.9-1 mg/dL. Kidney biopsy revealed acute tubular necrosis and acute interstitial nephritis. Both LDV-SOF and TDF were discontinued, and the patient's serum creatinine concentration decreased to 1.3 mg/dL over the following 6 weeks. We postulate that this adverse drug reaction may have been secondary to the known interaction between ledipasvir and TDF, which results in increased TDF exposure. Despite knowledge of this interaction, LDV-SOF is commonly prescribed in patients with HIV-HCV coinfection, as patients who received LDV-SOF- and TDF-containing regimens in trials have not demonstrated adverse clinical consequences related to this interaction. This case highlights the rare but potentially serious nephrotoxicity that can result from TDF toxicity and serves as a reminder to clinicians to implement close renal function monitoring in patients receiving both LDV-SOF and TDF. Clinicians prescribing LDV-SOF to HCV-HIV-coinfected patients receiving TDF should be cautious about use with concomitant nephrotoxic medications and monitor markers of tubular dysfunction, including urinary phosphorus excretion, and renal injury at baseline and week 4 of therapy. Tenofovir alafenamide and alternative DAAs may also have a role in the management of patients at high risk for renal adverse effects from TDF.

Levetiracetam-induced neutropenia following traumatic brain injury.

BACKGROUND: Levetiracetam is being increasingly utilized for post-traumatic brain injury seizure prophylaxis, in part because of its more favourable adverse effect profile compared to other anti-epileptics. This report highlights an unusual, clinically significant adverse drug reaction attributed to levetiracetam use in a patient with blunt traumatic brain injury. METHODS: This study describes a case of isolated neutropenia associated with levetiracetam in a 52-year-old man with traumatic brain injury. RESULTS: The patient developed neutropenia on day 3 of therapy with levetiracetam, with an absolute neutrophil count nadir of 200. There were no other medications that may have been implicated in the development of this haematological toxicity. Neutropenia rapidly resolved upon cessation of levetiracetam therapy. CONCLUSIONS: Clinicians should be aware of potentially serious adverse reactions associated with levetiracetam in patients with neurological injury.

Exposure of cyclosporin A in whole blood, cerebral spinal fluid, and brain extracellular fluid dialysate in adults with traumatic brain injury.

Cyclosporin A (CsA), an immunosuppressive medication traditionally used in the prevention of post-transplant rejection, is a promising neuroprotective agent for traumatic brain injury (TBI). Preliminary studies in animals and humans describe the efficacy and safety of CsA when administered following neurotrauma. The objective of this study is to describe CsA exposure in adults with severe TBI by assessing concentrations in whole blood, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) dialysate as measured by brain microdialysis. Severe TBI patients were enrolled in a randomized controlled trial following the written informed consent of their legal guardians. Patients received either CsA 5 mg/kg as a continuous infusion over 24 h, or matching placebo. Noncompartmental exposure analyses were performed using CsA concentrations in whole blood, CSF, and ECF dialysate. There were 37 patients randomized to the CsA arm of the trial and included in this exposure analysis. CsA was detected in the ECF dialysate and CSF at a fraction of the whole blood concentration. Mean CsA maximum concentrations were achieved at 24 and 30 h from the start of the 24 h infusion, in the CSF and ECF dialysate, respectively. A correlation was found between ECF dialysate and CSF concentrations. CsA was detected in the blood, CSF, and brain ECF dialysate. CsA exposure characteristic differences exist for whole blood, CSF, and ECF dialysate in severe TBI patients when administered as a continuous intravenous infusion. These exposure characteristics should be used for safer CsA dose optimization to achieve target CsA concentrations for neuroprotection in future TBI studies.