Risk factors for acute kidney injury in adult patients receiving vancomycin.

BACKGROUND AND OBJECTIVE: Questions have been raised regarding nephrotoxicity from vancomycin. A few small studies have shown that higher trough concentrations of vancomycin result in more nephrotoxicity. The purpose of this study was to evaluate risk factors that may predispose patients to nephrotoxicity in those concomitantly receiving vancomycin. METHODS: This was a single-center retrospective chart review conducted on adult subjects 18 years and older who received at least three doses of vancomycin. Exclusion criteria included sepsis, septic shock, or acute renal failure or stage 5 chronic kidney disease. Subjects were divided into two groups: those who developed nephrotoxicity and those who did not. Data collected included co-morbidities (diabetes mellitus, hypertension, congestive heart failure), creatinine clearance (CLCR), concomitant treatment with potentially nephrotoxic drugs, vancomycin trough concentrations, total daily dose, and duration of therapy. RESULTS: Seventy-seven subjects were included in the nephrotoxic group and 149 were in the control group. The proportion of men in the nephrotoxic group was higher (68 vs. 50 %, p = 0.0135). Hypertension (74 vs. 51 %, p = 0.0009), diabetes (49 vs. 30 %, p = 0.0046), and furosemide use (65 vs. 39 %, p = 0.0009) were more common in the nephrotoxic group. The proportion of subjects with baseline CLCR ≤63.5 mL/min was higher in the nephrotoxic group. Furosemide use (odds ratio [OR] 2.91, 95 % CI 1.64-5.15), hypertension (OR 2.74, 95 % CI 1.5-5.0), and vancomycin trough concentration ≥16.2 µg/mL (OR 2.33, 95 % CI 1.25-4.44) were each associated with nephrotoxicity during vancomycin therapy. CONCLUSIONS: In summary, the patient profile exhibiting the greatest risk (OR 4.99) of developing kidney injury is one who has hypertension, is receiving furosemide therapy, and has vancomycin trough concentrations ≥16.2 µg/mL.

Evaluating the impact of a pharmacist's absence from an antimicrobial stewardship team.

PURPOSE: Results of a study to determine the impact of a clinical pharmacist's temporary absence from a hospital's antimicrobial stewardship team are presented. METHODS: A retrospective chart review was conducted to compare the appropriateness of the use of selected antimicrobial medications with and without regular pharmacist involvement on the hospital's antimicrobial stewardship team. The charts of two samples of patients were evaluated: (1) 119 patients who had received prolonged (≥72 hours) imipenem-cilastatin, linezolid, or micafungin therapy over a three-month period during which a clinical pharmacist routinely provided interventions to help ensure the drugs were used according to institutional guidelines and (2) 111 patients treated with one of the three drugs during a three-month period when the clinical pharmacist did not serve on the stewardship team. RESULTS: Relative to the period of active pharmacist involvement in antimicrobial stewardship, rates of inappropriate use of imipenem-cilastatin, linezolid, and micafungin during the pharmacist's absence were deemed to have increased by 27, 39, and 35 percentage points, respectively, with corresponding increases in the average duration of therapy of 0.7, 4.0, and 3.2 days; in addition, the number of cases of Clostridium difficile infection increased more than threefold (from 8 to 25) during the pharmacist's absence. CONCLUSION: The temporary absence of a pharmacist from the antimicrobial stewardship team was associated with increased rates of inappropriate use of restricted antimicrobial agents and consequent increases in average durations of therapy.

The Retrospective Cohort of Extended-Infusion Piperacillin-Tazobactam (RECEIPT) study: a multicenter study.

STUDY OBJECTIVE: To compare the effectiveness of extended-infusion piperacillin-tazobactam with that of similar-spectrum, nonextended-infusion [H9252]-lactam antibiotics in the treatment of gram-negative infections. DESIGN: Multicenter, retrospective medical record review. SETTING: Fourteen hospitals throughout the United States. PATIENTS: A total of 359 adults treated for gram-negative infections between January 1, 2007, and February 28, 2010, with either 4-hour extended-infusion piperacillin-tazobactam (186 patients) or nonextended-infusion comparator antibiotics (173 patients), which consisted of cefepime, ceftazidime, imipenem-cilastatin, meropenem, doripenem, or piperacillin-tazobactam. MEASUREMENTS AND MAIN RESULTS: Deidentified data were collected on demographics, renal function, Acute Physiology and Chronic Health Evaluation II score, chronic health conditions, source of infection and type of organism, intensive care unit (ICU) length of stay, total length of stay, type and duration of antimicrobial therapy, and in-hospital mortality. The primary outcome was mortality rate of the patients receiving extended-infusion piperacillin-tazobactam versus those receiving nonextended-infusion comparator antibiotics. Secondary outcomes were hospital length of stay, ICU length of stay, and total duration of antibiotic therapy. Baseline characteristics were similar between groups, except a significantly lower proportion of patients in the extended-infusion group were treated with a concomitant intravenous aminoglycoside (5.9% vs 16.2%, p<0.01), were infected with Pseudomonas species (22.6% vs 39.9%, p<0.01), or had positive respiratory cultures (30.7% vs 43.4%, p=0.01). Antibiotic duration, hospital length of stay, and ICU length of stay were similar between groups. In-hospital mortality was significantly decreased in the extended-infusion piperacillin-tazobactam group versus those receiving comparator antibiotics (9.7% vs 17.9%, p=0.02). Multivariate analysis confirmed that extended-infusion piperacillin-tazobactam prolonged survival by 2.77 days (p<0.01) and reduced the risk of mortality (odds ratio 0.43, p=0.05). CONCLUSION: Pharmacodynamic dosing using extended-infusion piperacillintazobactam demonstrated favorable outcomes, including mortality, when compared with nonextended-infusion, similar-spectrum [H9252]-lactams in the treatment of patients with documented gram-negative infections. Prospective, randomized trials are needed to further corroborate these findings.

Anidulafungin and its role in candida infections.

Candida infections continue to play a significant role not only in critically ill and immunocompromised patients but also in non-compromised patients. The incidence of systemic fungal infections in the United States has been on the rise for the past 30 years. Anidulafungin and all echinocandins inhibit glucan synthase thus inhibiting the formation of 1,3-ß-D-glucan which is an essential component of the fungal cell wall. The decrease in 1,3-ß-D-glucan results in the osmotic lysis of the cell, resulting in fungicidal activity against candida. Anidulafungin is active against most species of candida and resistance to it is very rare. Two potential mechanisms conferring reduced susceptibility to the echinocandins are efflux and target alteration. The efflux pump associated with fluconazole resistance in Candida albicans can confer higher minimum inhibitory concentrations to caspofungin. The second mechanism of resistance is via mutations in the genes which code for 1,3 ß-D-glucan synthase, specifically FKS1. Because of its spectrum of activity, fungicidal nature, and tolerability it is an attractive first-line therapeutic choice for treating candidemia in both non-neutropenic and neutropenic patients. Because it is available only parenterally its role in treating mucocutaneous candidiasis is primarily in patients unable to take oral therapy.

The echinocandins.

The changing pattern in fungal infections has driven the need to expand the targets of antifungal activity. The echinocandins are the newest addition to the arsenal against fungal infections. Three echinocandins have been approved by the United States Food and Drug Administration: caspofungin, micafungin, and anidulafungin. These agents have a broad spectrum of activity and are similar to each other with respect to in vitro activity against Candida sp, with micafungin and anidulafungin having similar minimum inhibitory concentrations (MICs) that are generally lower than the MIC of capsofungin. The MICs of the echinocandins are highest against Candida parapsilosis; however, whether this will affect clinical outcomes is unknown. Several case reports have identified clinical failure due to elevated MICs with caspofungin or micafungin against Candida albicans, Candida krusei, and C. parapsilosis. Resistance to the echinocandin class was present in some but not all of the isolates. Empiric therapy with one of the echinocandins for candidemia or invasive candidiasis in patients with neutropenia and those without neutropenia appears to be appropriate when one factors in mortality rate, the increasing frequency of non-albicans Candida infections, and the broad spectrum, safety, and fungicidal effect of the echinocandins. After speciation of the organism, continued therapy with an echinocandin can and should be reevaluated. The echinocandins demonstrate similar in vitro and in vivo activity against Aspergillus sp, but only caspofungin is approved for treatment in patients who are intolerant of or refractory to other therapies. Voriconazole and amphotericin B have demonstrated synergy with the echinocandins. The clinical response to combination therapy has been variable; however, the mortality rate appears to be lower with combination therapy than monotherapy. Large controlled trials are needed to determine the role of combination therapy for invasive aspergillosis. Micafungin and anidulafungin generally have a lower frequency of adverse reactions compared with caspofungin. Phlebitis (3.5-25% of patients) and elevated liver enzyme levels (1-15%) occur more often with caspofungin compared with micafungin and anidulafungin (< 8%). Overall, the three echinocandins are relatively safe and effective agents for the treatment of Candida infections.

Evaluation of an intracellular pharmacokinetic in vitro infection model as a tool to assess tuberculosis therapy.

In vitro intracellular infection models have been used to evaluate drug therapy against Mycobacterium tuberculosis; however, they do not simulate human pharmacokinetics. This study demonstrates the intracellular and extracellular killing activity of antimycobacterial drugs in a pharmacokinetic intracellular in vitro model. The pharmacokinetic parameters of levofloxacin, rifampicin and isoniazid were controlled in the central chamber; drug passively diffused into the cell culture inserts and then into the macrophages. In the pharmacokinetic model, the rates of killing observed were faster than other in vitro methods and allowed for a higher initial inoculum to be utilised. The pharmacokinetic model more closely mimics in vivo conditions than other in vitro systems and is a new instrument for evaluating the activity of antimycobacterial agents.

Assessment of differences in antimicrobial effect determined with two in vitro pharmacodynamic models: impact of surface area to volume ratio.

STUDY OBJECTIVE: To measure the influence of different surface area:volume ratios (SA:Vs) on antibiotic penetration and subsequent antibacterial effect. DESIGN: In vitro laboratory experiment. SETTING: Two academic research laboratories. INTERVENTION: The two models with effective SA:Vs of 5.34 and 4.80 cm(-1) were evaluated by conducting a time-kill experiment with Pseudomonas aeruginosa ATCC 27853 and ceftazidime. MEASUREMENTS AND MAIN RESULTS: Ceftazidime was administered by constant infusion into the central compartment. Its penetration into the peripheral compartment and bacterial counts were determined over 24 hours, and antibacterial effect was quantified. Antibiotic penetration, calculated using central compartment and peripheral compartment area under the concentration-time curves, and effect, quantified as the relationship between the areas under growth and kill curves, differed between the models. Antibiotic penetration into the peripheral compartment was 53% greater over the first 4 hours of the experiment in the model with the larger SA:V. This was associated with antibacterial effects that were 64% and 38% greater in the 0-4-hour and 0-24-hour time periods, respectively. CONCLUSION: Differences in antibiotic penetration and effect observed between these models are likely explained by differences in SA:V