Clinical outcomes of linezolid and vancomycin in patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus stratified by baseline renal function: a retrospective, cohort analysis.

BACKGROUND: The primary objective of this study is to assess whether baseline renal function impacts treatment outcomes of linezolid and vancomycin (with a dose-optimized regimen) for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. METHODS: We conducted a retrospective cohort analysis of data generated from a prospective, randomized, controlled clinical trial (NCT 00084266). The analysis included 405 patients with culture-proven MRSA pneumonia. Baseline renal function was stratified based on creatinine clearance. Clinical and microbiological success rates and presence of nephrotoxicity were assessed at the end of treatment (EOT) and end of study (EOS). Multivariate logistic regression analyses of baseline patient characteristics, including treatment, were performed to identify independent predictors of efficacy. Vancomycin concentrations were analyzed using a nonlinear mixed-effects modeling approach. The relationships between vancomycin exposures, pharmacokinetic-pharmacodynamic index (trough concentration, area under the curve over a 24-h interval [AUC0-24], and AUC0-24/MIC) and efficacy/nephrotoxicity were assessed in MRSA pneumonia patients using univariate logistic regression or Cox proportional hazards regression analysis approach. RESULTS: After controlling for use of vasoactive agents, choice of antibiotic therapy and bacteremia, baseline renal function was not correlated with clinical and microbiological successes in MRSA pneumonia at either end of treatment or at end of study for both treatment groups. No positive association was identified between vancomycin exposures and efficacy in these patients. Higher vancomycin exposures were correlated with an increased risk of nephrotoxicity (e.g., hazards ratio [95% confidence interval] for a 5 µg/ml increase in trough concentration: 1.42 [1.10, 1.82]). CONCLUSIONS: In non-dialysis patients, baseline renal function did not impact the differences in efficacy or nephrotoxicity with treatment of linezolid versus vancomycin in MRSA pneumonia.

Clinical population pharmacokinetics and toxicodynamics of linezolid.

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of <100 ×10(9)/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.

Experience implementing a university-based mass immunization program in response to a meningococcal B outbreak.

Neisseria meningitidis serogroup B (MenB) has caused several recent outbreaks of meningococcal disease on US college campuses. In January 2015, a case of MenB was reported at a university in Oregon, culminating in an outbreak with a total of 7 cases (including 1 fatality) identified over a 5-month period. In response to the outbreak, the university organized a mass immunization campaign with 4 "opt-in" immunization clinics. The preparation, challenges, and resources required for organization and implementation of a mass immunization program in response to an outbreak at a large public university are discussed herein. Based on the logistical challenges as well as resource expenditures associated with planning and executing a mass immunization effort, this experience illustrates that proactive, routine immunization of incoming students is the best strategy for MenB outbreak prevention.

Suboptimal aminoglycoside dosing in critically ill patients.

Maximal aminoglycoside (AG) killing requires that the ratio of peak serum concentrations (Cmax) to the minimum inhibitory concentration (MIC) of the pathogen exceeds by > or =10. This has been shown to hasten resolution of infection in the general patient population. It was postulated that critically ill patients, likely to have larger intravascular volumes, are underdosed. The primary aim was to determine Cmax to MIC target attainment rate in medical intensive care unit (MICU) patients. A retrospective review of MICU patients who received at least 1 intravenous dose and serum concentration of either gentamicin or tobramycin was performed. A population pharmacokinetic model was developed, and MIC distributions for AG were used in determining the Cmax/MIC and in calculating the probability of attaining the pharmacodynamic (PD) target. One hundred two unique patients with 211 AG concentrations were analyzed to determine population pharmacokinetic parameters. Mean maximum clearance (CL) was 3.14L/h (95% confidence interval: 1.26-4.54 L/h), and mean volume of distribution (V) was 53 L (95% confidence interval: 38-66.8 L/h). Glomerular filtration rate and standardized body weight were identified as significant covariates for clearance in the final model. Standardized body weight also significantly affected V. There was only a 20% and 40% probability that patients receiving 7 mg/kg of gentamicin and tobramycin, respectively, will achieve PD target over the range of MIC distributions. Based on these data, the majority of critically ill patients would not be predicted to achieve the PD target under current dosing regimens. This may be a result of intensive care unit patients having a larger volume of distribution than reported in the literature. Future recommendations for treating gram-negative infections in the MICU population include using initial doses of 7 mg/kg of either gentamicin or tobramycin, measuring Cmax after the first dose, and determining MIC for the pathogen(s) with adjustment of subsequent doses to achieve the PD target.

Pseudomonas aeruginosa infections in the Intensive Care Unit: can the adequacy of empirical beta-lactam antibiotic therapy be improved?

Inadequate empirical antibiotic therapy for serious Pseudomonas aeruginosa infections has been linked to increased mortality. We performed a retrospective cohort study of consecutive patients with ventilator-associated pneumonia, bacteraemia or other sterile-site infections caused by P. aeruginosa occurring during Intensive Care Unit admissions. One hundred and fifty-eight episodes of serious infection with P. aeruginosa occurred in 140 patients. Empirical antibiotic therapy was microbiologically adequate in 67% of episodes of infection. Patients with P. aeruginosa isolates resistant to piperacillin/tazobactam or cefepime were more likely to have received these antibiotics in the month prior to the P. aeruginosa infection or to have had a Gram-negative bacillus resistant to these antibiotics isolated in the month prior to the P. aeruginosa infection. From these data, we have developed simple algorithms for empirical antibiotic choice in seriously ill patients with suspected P. aeruginosa infections based on prior antibiotic exposure and prior isolation of antibiotic-resistant organisms. Application of these algorithms would have improved the adequacy of empirical antibiotic therapy from 67% to 80-84%. Routine empirical addition of amikacin to the beta-lactam would have increased the adequacy of the antibiotics to 96%. We conclude that knowledge of the prior receipt of beta-lactam antibiotics with activity against P. aeruginosa and the isolation of Gram-negative bacilli resistant to such antibiotics in the recent past can readily increase the adequacy of empirical antibiotic therapy for suspected P. aeruginosa infections.

Epidemiological profile of linezolid-resistant coagulase-negative staphylococci.

BACKGROUND: Surveillance studies have shown that <0.1% of coagulase-negative staphylococci are linezolid resistant; however, at our institution, 4% of such organisms were found to be resistant. We investigated the risk factors for and the epidemiological profile of linezolid-resistant coagulase-negative staphylococci. METHODS: Susceptibility testing and pulsed-field gel electrophoresis were performed to analyze the genetic relatedness of both linezolid-resistant and linezolid-susceptible isolates. Clinical data were retrieved from medical records, and a case-case-control study was performed to identify unique risk factors for linezolid resistance. RESULTS: Isolates recovered from 25 patients with linezolid-resistant coagulase-negative staphylococci were examined; all but 1 of the isolates were identified as Staphylococcus epidermidis, and all but 1 had a minimum inhibitory concentration of linezolid of >256 microg/mL. Pulsed-field gel electrophoresis showed that 21 (84%) of 25 linezolid-resistant isolates exhibited genetic relatedness, whereas linezolid-susceptible isolates were of diverse clones. Unique, independent predictors of linezolid resistance included receipt of linezolid in the 3 months preceding isolation of the coagulase-negative staphylococci (odds ratio, 20.6; 95% confidence interval, 5.8-73.0). CONCLUSION: Linezolid-resistant coagulase-negative staphylococci have emerged at our institution and are predominately of a single clone. We believe that the most likely scenario to explain this emergence is that person-to-person spread of linezolid-resistant coagulase-negative staphylococci led to establishment of skin colonization with the strain. Subsequent use of linezolid was followed by selection of the linezolid-resistant strain, which then became the dominant skin flora. The potential for a parallel scenario involving clonal dissemination followed by selection of linezolid-resistant methicillin-resistant Staphylococcus aureus is a real possibility.

Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults.

STUDY OBJECTIVE: To determine the steady-state, extracellular, and intracellular pulmonary disposition of moxifloxacin (MXF), levofloxacin (LEVO), and azithromycin (AZI) relative to that of the plasma over a 24-h dosing interval. DESIGN: Randomized, multicenter, open-label investigation. PATIENTS: Forty-seven older adults (mean [+/- SD] age, 62 +/- 13 years) undergoing diagnostic bronchoscopy. INTERVENTIONS: Oral administration of MXF, 400 mg, LEVO, 500 mg daily for five doses, or AZI, 500 mg for one dose, then 250 mg daily for four doses. BAL and venipuncture were completed at 4, 8, 12, or 24 h following the administration of the last dose. MEASUREMENTS AND RESULTS: Steady-state MXF, LEVO, and AZI concentrations were determined in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs). The concentrations of all three agents were greatest in the AMs followed by the ELF compared to the plasma. Plasma concentrations were similar to those previously reported with these agents. The mean ELF concentrations at 4, 8, 12, and 24 h were as follows: MXF, 11.7 +/- 11.9, 7.8 +/- 5.1, 10.5 +/- 3.7, and 5.7 +/- 6.3 micro g/mL, respectively; LEVO, 15.2 +/- 4.5, 10.2 +/- 6.7, 6.9 +/- 4.4, and 2.9 +/- 1.7 micro g/mL, respectively; and AZI, 0.6 +/- 0.4, 0.7 +/- 0.4, 0.9 +/- 0.5, and 0.9 +/- 0.7 micro g/mL, respectively. The AM concentrations at 4, 8, 12, and 24 h were as follows: MXF, 47.7 +/- 47.6, 123.3 +/- 126.4, 26.2 +/- 19.4, and 32.8 +/- 16.5 micro g/mL, respectively; LEVO, 28.5 +/- 30.2, 26.1 +/- 15.7, 28.3 +/- 12.6, and 8.2 +/- 6.1 micro g/mL, respectively; and AZI, 71.8 +/- 50.1, 73.8 +/- 75.3, 155.9 +/- 81.3, and 205.2 +/- 256.3 micro g/mL, respectively. CONCLUSIONS: The intrapulmonary concentrations of MXF, LEV, and AZI were superior to those obtained in the plasma. The AM concentrations of all agents studied were more than adequate relative to the minimum concentration required to inhibit 90% of the organism population (MIC(90)) of the common intracellular pathogens (< 1 micro g/mL). These data indicate that attainable extracellular concentrations of AZI are insufficient to reliably eradicate Streptococcus pneumoniae, based on the agent's current minimum inhibitory concentration profile, whereas the mean concentrations of MXF and LEVO in the ELF exceed the MIC(90) of the S pneumoniae population. Moreover, MXF concentrations exceeded the S pneumoniae susceptibility breakpoint (1.0 micro g/mL) at all time points, while 2 of 15 concentrations (13%) failed to maintain LEVO concentrations above the breakpoint (2.0 micro g/mL) throughout the dosing interval.

Cost effect of managing methicillin-resistant Staphylococcus aureus in a long-term care facility.

OBJECTIVES: The purpose of this study was to measure the total consumption of resources involved in the care of a long-term care facility (LTCF) resident infected with methicillin-resistant Staphylococcus aureus (MRSA). DESIGN: A retrospective cohort study. SETTING: A 375-bed LTCF that provides two levels of care. PARTICIPANTS: Ninety LTCF residents infected with Staphylococcus aureus (mean age +/- standard deviation for methicillin-sensitive Staphylococcus aureus (MSSA) patients = 85 +/- 8.8, for MRSA patients = 82 +/- 9.5, P =.127; 49 MSSA and 41 MRSA patients). Inclusion criteria consisted of identification of a positive S. aureus culture in addition to symptoms/signs consistent with infection. Patients colonized with S. aureus were excluded. MEASUREMENTS: A standardized data collection tool was used to conduct chart and database review throughout the defined infection period. The type of information collected included demographic, infection characterization, antibiotic regimen, resource assessment, and cost data. The cost data were further categorized into total pharmaceutical, infection management, physician care, nursing care, and total infection cost. RESULTS: One hundred eleven cases were identified, with 90 cases eligible for evaluation. No difference in population demographics was noted between groups. A significantly higher number of patients in the MRSA group had an indwelling device (P <.001), pressure ulcer(s) (P =.028), or diabetes mellitus (P =.007). There was a significantly higher number of patients with congestive heart failure in the MSSA group (P =.047), but no difference existed in the primary infection site (P =.297) or the incidence of patients with more than two comorbidities (P =.509). The infection characterization variables included were also similar between groups. The most prevalent infection site was the urinary tract (48%) followed by skin/skin structure (38%). Because the majority of patients (82%) developed infection at least 30 days after their LTCF admission, the infections may be considered to have been largely LTCF acquired. The median infection management cost of an MRSA infection was six times greater than that of a MSSA infection (P <.001), whereas the median associated nursing care cost was two times greater (P =.001). The median overall infection cost associated with MRSA was 1.95 times greater than that of MSSA (median (range): MSSA 1,332 US dollars (268-7,265 US dollars) vs MRSA 2,607 US dollars (849-8,895 US dollars), P <.001). Nursing care cost constituted the major portion of the overall infection cost in both groups (MSSA 51%, MRSA 48%). Evaluation of antimicrobial management revealed that infected residents were treated with a wide array of combination therapies (65% of patients received combination therapy). CONCLUSIONS: The management of a resident infected with MRSA was much more costly to the LTCF than that of an MSSA-infected patient. The general care of the patient and not the specific antibiotic regimen influenced the large difference in cost between groups. The approach to the antibiotic management of these patients was variable. A more streamlined approach to infection management that facilitates a faster cure rate may dramatically lower resource consumption and improve patient outcomes.

Efficacy of clarithromycin against Streptococcus pneumoniae expressing mef(A)-mediated resistance.

As a result of macrolide resistance rates of 25% for pneumococci in the US, the clinical use of this class as empirical therapy has been questioned. However, macrolides continue to be used with clinical success. Using an immunocompromised murine pneumonia model, this study evaluated in vivo efficacy of human simulated exposures of clarithromycin for 62 isolates of Streptococcus pneumoniae considered resistant by current methods of breakpoint determinations. Changes in bacterial density were compared between treated animals and untreated controls. Inhibition of bacterial growth was consistently observed for the majority of isolates tested with mean (S.D.) reductions in logCFU per lung of -0.88 (0.69), -1.02 (0.87), -0.47 (0.79), -0.84 (0.66), -0.25 (0.26), -0.80 (0.72) and -0.58 (0.47) for MICs of 1, 2, 4, 8, 16, 32 and 64 mg/l, respectively. A beneficial treatment effect was clearly noted for isolates with clarithromycin MICs <==8 mg/l. However, the sample size of isolates tested beyond the MIC of 8 mg/l was diminished due to mortality in both treated and untreated animals. Consistent suppression of bacterial growth observed in this neutropenic model provides support for the in vivo efficacy of clarithromycin with low-level macrolide-resistant S. pneumoniae.

Bactericidal effect of cethromycin (ABT-773) in an immunocompetent murine pneumococcal pneumonia model.

The efficacy of cethromycin was assessed against isolates of Streptococcus pneumoniae in the presence of neutrophils. Comparison with data from our previous neutropenic model revealed that the presence of neutrophils enhanced the bacteriostatic and bactericidal effect of cethromycin by an average of two- to four-times, respectively.

Pharmacokinetic and pharmacodynamic evaluation of two dosing regimens for piperacillin-tazobactam.

STUDY OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic profiles of two dosing regimens for piperacillin-tazobactam against commonly encountered pathogens. The regimens compared were piperacillin 4.0 g-tazobactam 0.5 g administered every 8 hours, and piperacillin 3.0 g-tazobactam 0.375 g administered every 6 hours. DESIGN: Multiple-dose, open-label, randomized, crossover study. SETTING: Clinical research center at Hartford Hospital. SUBJECTS: Twelve healthy volunteers. INTERVENTION: The two dosing regimens for piperacillin-tazobactam were administered intravenously in crossover design. Blood was sampled after the third dose. MEASUREMENTS AND MAIN RESULTS: Drug concentrations were determined by a validated high-performance liquid chromatography assay. The percentage of time above minimum inhibitory concentration (%T>MIC) for piperacillin was calculated for a range of MIC values. The maximum concentration (Cmax), area under the concentration-time curve (AUC0-tau), and total clearance of piperacillin differed significantly between the two study regimens, as did the Cmax, AUC0-tau, volume of distribution, and total clearance of tazobactam (p<0.05). The piperacillin 4.0 g-tazobactam 0.5 g regimen provided 40-50% T>MIC for MIC values 8-16 microg/ml; a similar value for the piperacillin 3.0 g-tazobactam 0.375 g regimen was 16-32 microg/ml. CONCLUSION: Although statistically significant differences in the pharmacodynamic profile were noted for the regimens, both provide adequate T>MIC against commonly encountered pathogens considered susceptible to piperacillin-tazobactam. However, for treatment of Pseudomonas aeruginosa infection, combination therapy or higher-dosage regimens (e.g., piperacillin 3.0 g-tazobactam 0.375 g every 4 hours, piperacillin 4.0 g-tazobactam 0.5 g every 6 hours, or continuous-infusion piperacillin 12 g-tazobactam 1.5 g/day) may be a prudent option when full MIC data are unavailable.

Meropenem administered as a prolonged infusion to treat serious gram-negative central nervous system infections.

The treatment of gram-negative infection of the central nervous system (CNS) presents a clinical challenge due to antibiotic resistance and difficulties with penetration into the cerebrospinal fluid (CSF). Two patients with gram-negative CNS infections were treated successfully with high-dose, prolonged infusions of meropenem. The CSF meropenem concentrations exceeded the minimum inhibitory concentration of the pathogen for virtually the entire dosing interval in both cases. Our experience demonstrates that dosage modification to maximize pharmacodynamic targets and bactericidal activity may be practically applied to optimize antibiotic treatment for difficult-to-treat CNS infections.

Cost-effective approaches to the treatment of community-acquired pneumonia in the era of resistance.

Community-acquired pneumonia (CAP) infects upwards of four million people in the US each year, of which 20% require subsequent hospitalisation. Consequently, it is a large contributor to excessive healthcare resource consumption and cost. Since the aetiology of CAP is not identified in a majority of patients, treatment is often empiric, aimed at the most common causes, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and the atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila). A variety of pharmaceutical agents exist for the treatment of CAP, most notably the cephalosporin and penicillin derivatives, the macrolide/azalide antibacterials, the newer tetracyclines, and most recently the respiratory fluoroquinolones. Choosing an agent is usually related to issues such as patient compliance, adverse event profiles, and the presence of resistance. Of these, resistance seems to be the main factor today. S. pneumoniae, the most common cause of CAP, is steadily acquiring resistance to a majority of the currently available antibacterials, thus further increasing costs due to prolonged hospitalisation, treatment of relapses and the use of more expensive antibacterials. Understanding and maximising the pharmacodynamic properties of the available antibacterials will not only prevent the emergence of resistance, thus prolonging their clinical utility, but also reduce the costs associated with treating the infection through rapid symptom improvement and earlier patient discharge. Numerous methods for reducing costs in patients with bacterial infections are documented in the literature and can be applied to CAP. Choosing monotherapy instead of combination therapy can reduce costs associated with the administration of the antibacterial. Agents with longer half-lives allow for once-daily administration, which in turn, leads to improved compliance, successful outcomes, and decreased costs. Administering antibacterials to maximise their pharmacodynamics, such as with continuous infusion of beta-lactams, reduces the amount of drug needed in addition to savings associated with administration and supplies. Finally, transitioning patients to oral therapy as soon as they are clinically stable can significantly reduce the length of hospital stay, which is the major contributing factor of healthcare costs. The use of a clinical pathway in an institution is the most effective way to apply these cost-saving approaches in the treatment of CAP. These pathways should be specific to each institution, thus considering the resistance rates in the area and encouraging the use of the most active, cost-effective agents to produce rapid, positive clinical outcomes.

Pharmacoeconomic analysis of amphotericin B lipid complex versus liposomal amphotericin B in the treatment of fungal infections.

BACKGROUND: Potential differences in toxicity, potency and acquisition price among the liposomal amphotericin B formulations makes it unclear which agent is less costly when total resource consumption and treatment-associated costs are considered. DESIGN: A retrospective cost-minimisation analysis in 51 patients was performed to compare the cost of amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB) from the hospital perspective. Costs ($US, 2001 values) were divided into level I (acquisition price only), level II (costs of all associated treatment, i.e. adverse events, failures, etc.) and level III (total fungal-related hospitalisation) costs. RESULTS: No significant differences in patient demographics or length of therapy were apparent among those receiving ABLC or L-AMB. The clinical success rate in this population was similar between ABLC and L-AMB (53% vs 60%, p = 0.68), thus justifying the use of a cost-minimisation analysis. Among patients with baseline elevations in serum creatinine, 47% receiving ABLC and 10% receiving L-AMB experienced further increases in serum creatinine (p = 0.025). No differences in total treatment costs (level I, II, or III) were evident between patients receiving ABLC or L-AMB. When adjusted for duration of therapy, however, costs were significantly lower for ABLC than for L-AMB (level I: ABLC $US340 versus L-AMB $US435, p = 0.002; level II: ABLC $US361 versus L-AMB $US454, p = 0.027). The costs attributable to the prevention or treatment of adverse events were not different between the two treatments, and the economic outcome in this analysis was highly sensitive to the acquisition price and dosage of the lipid antifungal formulation. Two-way sensitivity analysis revealed that as long as the milligram price of L-AMB was greater than 135% of the milligram price of ABLC, ABLC remained the less costly formulation. CONCLUSION: In this patient population, total hospitalisation costs were not different between lipid antifungal formulations. However, after controlling for duration of therapy, ABLC was less costly than L-AMB, when considering acquisition costs of the lipid antifungal agent and costs associated with concomitant antifungal therapy and the treatment of adverse events or lipid failures, indicating that the acquisition price of these agents should be predictive of their cost differences.

Impact of patient characteristics and infection type on clinical outcomes of patients who received linezolid or vancomycin for complicated skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus: a pooled data analysis.

Phase III randomized, clinical trials are primarily designed to evaluate overall treatment-outcome comparisons. Although valuable data are gained from such comparisons, it is difficult to draw meaningful inferences about potential outcomes differences in specific patient groups and infection types. It is well established that clinical outcomes are dependent on host, treatment- and pathogen-related factors and understanding which groups benefit from one treatment relative to another is of great importance. This study sought to determine if clinical success in the treatment of complicated skin and skin structure infections (cSSSI) caused by methicillin resistant Staphylocccus aureus (MRSA) with linezolid or vancomycin varied across subpopulations and infection type. Data from 3 prospective, randomized trials evaluating linezolid and vancomycin for the treatment of MRSA cSSSI were pooled. Treatment related differences in outcomes were found, on both the absolute and relative scales, for most subpopulations and infection types. Identifying treatment differences in outcome by patient subpopulation can enhance clinical decision making.

The impact of linezolid versus vancomycin on surgical interventions for complicated skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus.

BACKGROUND: We conducted a study with the primary objective of assessing whether a difference existed in the frequency and type of surgical interventions (SIs) implemented in patients treated with linezolid versus vancomycin for the management of complicated skin and skin structure infections (cSSSIs) caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: We analyzed data from a phase IV clinical trial evaluating the safety and efficacy of linezolid and vancomycin, given for 7-14 d, to treat cSSSIs other than cellulitis that were caused by MRSA. The study included patients who received ≥1 dose of drug, had a cSSSI caused by culture-proved MRSA, and underwent ≥1 SI after commencement of the study. The types and frequencies of SIs were assessed on a per-patient basis during the following three time periods: (1) study days 0-3: the estimated time to reach steady-state serum drug concentrations; (2) study days 4-14: the drug-treatment period (days 4-14) during which steady state drug concentrations are likely reached; and (3) study days 15-28: the post-treatment period through end of the study (EOS). Independent predictors of ≥2 SIs during the drug-treatment period were identified by logistic regression. Clinical and microbiologic outcomes were assessed at the end of treatment (EOT), and at EOS for the SI population. RESULTS: The data analysis included 323 patients (linezolid, n=167; vancomycin, n=156). The majority of patients (81% in the linezolid group and 83% in the vancomycin group) underwent an initial SI or source control procedure within 72 h of study initiation. The most common cSSSIs among patients having SIs were abscesses (59%) and infected ulcers (20%). Independent predictors of ≥2 SIs during study days 4-14 included treatment with vancomycin (OR 5.97; 95% CI 1.97-18.03), polymicrobial infection (OR 2.84; 95% CI 1.13-7.12), and degree of wound induration (OR 1.06; 95% CI 1.02-1.10). Clinical success rates in the SI population were 88% in the linezolid group and 80% in the vancomycin group (p=0.14) at EOT and 80% in the linezolid group and 68% in the vancomycin group (p=0.04) at EOS. Microbiologic success rates were 83% in the linezolid group and 68% in the vancomycin group (p=0.004) at EOT and 71% in the linezolid group and 60% in the vancomycin group (p=0.05) at EOS. CONCLUSION: Patients who received linezolid had a lower probability of undergoing ≥2 SIs during drug treatment. Type of antibiotic received was the only modifiable predictor of a greater rate of SI during the drug-treatment period. In the patient population of the study, with cSSSIs other than cellulitis that were caused by MRSA, and in which at least one SI per patient was done within 72 h of the commencement of drug treatment, linezolid was associated with a higher rate of clinical success at EOS than was vancomycin, as well as with a higher rate of microbiologic success at both EOT and EOS.

Population pharmacokinetic evaluation with external validation and Bayesian estimator of voriconazole in liver transplant recipients.

OBJECTIVES: The objectives of this study were to evaluate the pharmacokinetics of voriconazole in liver transplant patients, probe covariate effects on voriconazole pharmacokinetics, externally validate the model and explore limited sampling strategies (LSSs) using Bayesian approaches. METHODS: Full pharmacokinetic profiles were collected within one oral dosing interval from 13 liver transplant patients. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM software. The final model was internally evaluated using bootstrapping and visual predictive check (VPC), and externally validated by predicting additional samples from different patients that were not used for model building. Maximum a posteriori Bayesian estimators were developed to predict the area under the plasma concentration-time curve (AUC) using the validated final model as the a priori model, actual dosing record and covariate values as the input, and a few concentrations (limited sampling) as feedback information (LSS). Mean prediction error (MPE) and mean absolute prediction error (MAPE) were calculated for external validation and LSS. RESULTS: A one-compartment model with an absorption lag time (t(lag)) adequately described the data. Population estimates of total clearance after oral administration (CL/F) and volume of distribution after oral administration (V(d)/F) were 7.92 L/h and 248 L, respectively. Values of CL/F, V(d)/F and t(lag) decreased with post-operative time and converged to stable levels in about 7 post-operative days. CL/F significantly decreased with increased international normalized ratio. Co-administration of pantoprazole, race and alanine aminotransferase were also significantly associated with pharmacokinetic parameters but ultimately excluded in the final model. VPC showed that most of the data fell within the 90% prediction interval and were symmetrically distributed around the median. Additional 52 samples from 19 patients were collected for external validation. MPE was 0.206 µg/mL (not significantly different from zero) and MAPE was 0.99 µg/mL. Compared with trough levels, LSS using two samples or one sample at a different time provided better MPE, MAPE and correlation (R2) between the observed and LSS-predicted AUC. CONCLUSIONS: The population model that was developed showed significant association of voriconazole pharmacokinetics with post-operative time and liver function, and was able to predict an independent external dataset. Our observations suggested a need for intravenous administration of voriconazole in the immediate post-operative period before an oral dose can be administrated. LSS using one sample appeared to be sufficient for reasonable AUC estimation.

Intrapulmonary disposition of amphotericin B after aerosolized delivery of amphotericin B lipid complex (Abelcet; ABLC) in lung transplant recipients.

BACKGROUND: Inhaled amphotericin preparations have been used for prophylaxis against invasive aspergillosis in lung transplant recipients. However, no published data exist regarding the pharmacokinetic profile of amphotericin B lipid complex in lung transplant recipients. METHODS: We prospectively determined the concentrations of amphotericin B in the epithelial lining fluid (ELF) and plasma after aerosolized nebulization (AeroEclipse), of amphotericin B lipid complex at 1 mg/kg every 24 hr for 4 days in 35 lung transplant recipients. One brochoalveolar lavage sample and a simultaneous blood sample were collected at various time points after the fourth dose from each subject. High-performance liquid chromatography and high-performance liquid chromatography-MS-MS were used to measure amphotericin B. RESULTS: Concentrations of amphotericin B in ELF (median, 25-75 IQR) were at 4 hr (n=5) 7.20 µg/mL (1.3-17.6), 24 hr (n=6) 8.26 µg/mL (3.9-82.7), 48 hr (n=5) 2.15 µg/mL (1.4-5.5), 72 hr (n=4) 1.25 µg/mL (0.75-5.5), 96 hr (n=6) 0.86 µg/mL (0.55-1.4), 120 hr (n=4) 1.04 µg/mL (0.44-1.6), 144 hr (n=1), 4.25 µg/mL, 168 hr (n=3) 1.14 µg/mL, and 192 hr (n=1) 1 µg/mL. The plasma concentration of the drug remained below 0.08 µg/mL at all time points. During the study, the side effects noted included wheezing, coughing, and 12% decline in forced expiratory volume in 1 sec. CONCLUSIONS: We conclude that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphotericin B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated.

Acquisition of rectal colonization by vancomycin-resistant Enterococcus among intensive care unit patients treated with piperacillin-tazobactam versus those receiving cefepime-containing antibiotic regimens.

In contrast to expanded-spectrum cephalosporins, beta-lactam-beta-lactamase inhibitor combinations such as piperacillin-tazobactam have rarely been associated with vancomycin-resistant Enterococcus (VRE) colonization and infection. In mice, piperacillin-tazobactam has sufficient antienterococcal activity to inhibit the establishment of colonization during treatment, but this effect has not been confirmed in human patients. We prospectively evaluated the acquisition of rectal colonization by VRE among intensive care unit patients receiving antibiotic regimens containing piperacillin-tazobactam versus those receiving cefepime, an expanded-spectrum cephalosporin with minimal antienterococcal activity. Rectal swabs were obtained weekly and were cultured for VRE. For 146 patients with a negative rectal swab for VRE prior to therapy, there was no significant difference in the frequency of VRE acquisition between patients receiving piperacillin-tazobactam- and cefepime-containing regimens (19/72 [26.4%] and 23/74 [31.1%], respectively; P = 0.28). Of the 19 patients who acquired VRE in association with piperacillin-tazobactam, 10 (53%) developed the new detection of VRE during therapy. Patients initiated on treatment with cefepime-containing regimens were significantly more likely than those initiated on treatment with piperacillin-tazobactam-containing regimens to have received antibiotic therapy in the prior 30 days (55/74 [74.3%] and 22/72 [30.6%], respectively; P < 0.001). These findings suggest that piperacillin-tazobactam- and cefepime-containing antibiotic regimens may be associated with the frequent acquisition of VRE in real-world intensive care unit settings. Although piperacillin-tazobactam inhibits the establishment of VRE colonization in mice when exposure occurs during treatment, our data suggest that this agent may not prevent the acquisition of VRE in patients.