Efficacy of Telavancin in Comparison to Linezolid in a Porcine Model of Severe Methicillin-Resistant Staphylococcus aureus Pneumonia.

Current guidelines recommend vancomycin and linezolid as first-line agents against methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Telavancin is a potential new therapeutic alternative, specifically in monomicrobial MRSA pneumonia. This study compared the efficacies of telavancin versus linezolid in a porcine model of severe MRSA pneumonia. In 18 mechanically ventilated pigs (32.11 ± 1.18 kg), 75 ml of 106 CFU/ml of MRSA was administered into each pulmonary lobe. After the onset of pneumonia, pigs were randomized into three groups: a control group, a group receiving 22.5 mg/kg of body weight every 24 h (q24h) of telavancin, and a group receiving 10 mg/kg q12h of linezolid intravenously. Tracheal aspirate and bronchoalveolar lavage (BAL) fluids were cultured every 24 h. After 48 h of treatment, tissue samples were collected from the ventral and dorsal sections of each lobe. Microbiological and histopathological analyses were performed. Lung tissue concentrations differed among the groups (P = 0.019), with the lowest MRSA lung burden in the telavancin group (P < 0.05 versus the control). MRSA was detected in 46.7%, 40.0%, and 21.7% of the lung tissue samples from the control, linezolid, and telavancin groups, respectively (P < 0.001). MRSA concentrations differed among the groups in tracheal aspirate fluid (P = 0.011) but not in BAL fluid. Furthermore, there was no increased risk of kidney injury during telavancin use. Thus, telavancin has higher bactericidal efficacy than linezolid during the first 48 h of treatment in a porcine model of severe MRSA pneumonia. However, studies are needed to confirm the benefits of telavancin in treating MRSA nosocomial pneumonia.

In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-ß-Lactam-Susceptible Klebsiella pneumoniae Strains.

Recent findings have identified Klebsiella pneumoniae strains that are pan-ß-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro We assessed the efficacy of a humanized exposure of piperacillin-tazobactam (TZP) against 12 TZP-R/PBL-S K. pneumoniae isolates in an immunocompromised murine lung infection model. Discordance between the in vitro resistance profile and the in vivo efficacy of human-simulated TZP exposures against this phenotypic profile was observed. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.

In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-ß-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model.

The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed.

In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-ß-Lactam-Susceptible Escherichia coli.

Recent findings have identified Escherichia coli strains that are pan-ß-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro We assessed the in vivo significance of this resistance profile in a neutropenic murine pneumonia model using humanized exposures of TZP with 18 clinical E. coli isolates, 8 TZP-S/PBL-S and 10 genotypically confirmed TZP-R/PBL-S. Despite phenotypically and genotypically defined resistance, TZP displayed efficacy against these isolates. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.

Comparative efficacies of human simulated exposures of tedizolid and linezolid against Staphylococcus aureus in the murine thigh infection model.

Tedizolid (formally torezolid) is an expanded-spectrum oxazolidinone with enhanced in vitro potency against Gram-positive pathogens, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The efficacies of human simulated exposures of tedizolid and linezolid against S. aureus in an immunocompetent mouse thigh model over 3 days were compared. Four strains of MRSA and one of MSSA with tedizolid and linezolid MICs ranging from 0.25 to 0.5 and from 2 to 4 µg/ml, respectively, were utilized. Tedizolid or linezolid was administered in a regimen simulating a human steady-state 24-h area under the free concentration-time curve of 200 mg every 24 h (Q24) or 600 mg Q12, respectively. Thighs were harvested after 4, 8, 12, 24, 36, 48, and 72 h, and efficacy was determined by the change in bacterial density. The mean bacterial density in control mice increased over the 3-day period. After 24 h of treatment, a reduction in bacterial density of ≥1 log CFU was observed for both the tedizolid and linezolid treatments. Antibacterial activity was enhanced for both agents with a reduction of ≥2.6 log CFU after 72 h of treatment. Any statistically significant differences (P ≤ 0.05) in efficacy between the agents were transient and did not persist throughout the 72-h treatment period. The tedizolid and linezolid regimens demonstrated similar in vivo efficacies against the S. aureus isolates tested. Both agents were bacteriostatic at 24 h and bactericidal on the third day of treatment. These data support the clinical utility of tedizolid for skin and skin structure infections caused by S. aureus, as well as the bactericidal activity of the oxazolidinones after 3 days of treatment.

Intrapulmonary pharmacokinetics of high doses of tigecycline in patients with ventilator-associated pneumonia.

Tigecycline is commonly used for infections by multidrug-resistant bacteria. However, it is not approved for ventilator-associated pneumonia (VAP) as increased mortality has been reported in VAP patients treated with conventional doses. The purpose of this study was to prospectively evaluate the intrapulmonary pharmacokinetics of off-label high-dose tigecycline in patients with VAP. Nine mechanically ventilated patients received tigecycline intravenously (loading dose 200 mg followed by 100 mg every 12 h). After ≥5 doses, two bronchoscopies were performed in each patient on consecutive days and eight blood samples were collected. Tigecycline concentrations in plasma and bronchoalveolar lavage fluid were determined by liquid chromatography. The urea dilution method was used to calculate epithelial lining fluid (ELF) concentrations. A two-compartmental pharmacokinetic (PK) model with linear elimination was used to estimate PK parameters. Mean patient age was 69 ± 11.86 years and mean APACHE II score was 21. The estimated population mean PK parameters (relative standard error) were: clearance, 11.64 L/h (54%); volume of distribution in central compartment, 79.01 L (37%); volume of distribution in peripheral compartment, 92.95 L (17%); intercompartmental clearance, 62.81 L/h (34%); and ELF penetration ratio, 2.41 (40%). Cmax, Cmin, plasma AUC0-12, plasma fAUC0-12 and ELF AUC0-12 were 1.99 ± 1.82 µg/mL, 0.81 ± 1.27 µg/mL, 12.89 ± 17.25 µg•h/mL, 3.24 ± 3.09 µg•h/mL and 7.13 ± 2.61 µg•h/mL, respectively. The increased plasma and ELF AUC0-12 achieved with a 200 mg daily tigecycline dose, combined with high ELF penetration, support the effectiveness of off-label high-dose tigecycline in VAP.

Anti-anaerobic activity of serum from patients treated with tigecycline for skin/soft tissue infections.

To gain additional data concerning the anti-anaerobic activity of tigecycline in serum, we analyzed blood samples from six patients with a complicated skin/soft tissue infection who were receiving IV tigecycline 50 mg every 12 h. Venous blood samples were obtained after multiple doses of tigecycline at 1, 6 and 12 h after the initiation of a 1 h IV infusion. Sera from these samples were tested to determine serum inhibitory and bactericidal activity over time against 4 anaerobic bacteria (Bacteroides fragilis, Peptoniphilus asaccharolyticus, Prevotella bivia and Finegoldia magna). An analysis of serum titers found that tigecycline exhibited early (1 h) and prolonged (12 h) inhibitory activity against each study isolate. Moreover, it provided bactericidal activity for 12 h against these strains with the exception of F. magna. Tigecycline was found to exhibit antibacterial activity at serum concentrations below the MICs of the anaerobic bacteria tested. This finding further supports that the antimicrobial activity of tigecycline can be greater than that suggested by the free fraction of drug and that serum appears to enhance this antibacterial activity.

Pharmacodynamic comparison of linezolid, teicoplanin and vancomycin against clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci collected from hospitals in Brazil.

Pharmacodynamic exposures, measured as the ratio of steady-state total drug area under the curve to MIC (AUC/MIC), were modelled using a 5000-patient Monte-Carlo simulation against 119 non-duplicate clinical isolates of Staphylococcus aureus and 82 coagulase-negative staphylococci (CNS) collected from hospitals in Brazil between 2003 and 2005. Pharmacodynamic targets included an AUC/MIC >82.9 for linezolid and >345 for teicoplanin and vancomycin, as well as a free drug AUC/MIC >180 for vancomycin. The cumulative fractions of response (CFRs) against all S. aureus isolates were 96.0%, 30.1%, 71.6%, 48.0% and 65.1% for linezolid 600 mg every 12 h, teicoplanin 400 mg every 24 h and 800 mg every 24 h, and vancomycin 1000 mg every 12 h and every 8 h, respectively. Using a free drug target for vancomycin improved the CFR to 94.6% for the high-dose regimen, but did not substantially alter results for the lower dose. CFRs against all CNS isolates were 97.8%, 13.4%, 34.6%, 10.9% and 31.3%, respectively, for the same antibiotic regimens. The CFR was reduced for all compounds among the methicillin-resistant isolates, except for linezolid against methicillin-resistant CNS. Sensitivity analyses did not alter the final order of pharmacodynamic potency against these isolates. Although higher doses of vancomycin and teicoplanin increased the CFR, the likelihood of achieving bactericidal targets was still lower than with linezolid. The results for the high-dose vancomycin regimen were highly dependent on the pharmacodynamic target utilised. These data suggest that linezolid has a greater probability of attaining its requisite pharmacodynamic target than teicoplanin and vancomycin against these staphylococci.

Optimizing skin and skin structure infection outcomes: considerations of cost of care.

INTRODUCTION: Skin and skin structure infections (SSSIs) refer to a collection of clinical infectious syndromes involving layers of skin and associated soft tissues. Although associated with less morbidity and mortality than other common skin infections, SSSIs represent a significant increasing source of healthcare expense, with a prevalence of 500 episodes per 10,000 patient-years in the United States resulting in burdening health care systems, of approximately $6 billion annually. AREAS COVERED: Opportunities to reduce costs of care associated with SSSI are highlighted, including transitions of care and avoiding unnecessary hospital admissions. Moreover, we reviewed new antibiotics (e.g. single dose glycopeptides), and the impact of consulting specialists in the emergency department on SSSI treatment outcomes. EXPERT COMMENTARY: New healthcare models and payment strategies combined with new therapeutics are challenging norms of care. Newer drugs to treat skin infections can move a substantive percent of patients previously admitted to hospital care to the outpatient setting. Additionally, patients can be managed with oral or one time intravenous regimens, improving the likelihood of patient adherence and satisfaction. These variables need to be weighed against added acquisition costs and the development of thoughtful algorithms is needed to direct care and optimize treatment, cost, and patient satisfaction.

Management of KPC-producing Klebsiella pneumoniae infections.

BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) has become one of the most important contemporary pathogens, especially in endemic areas. AIMS: To provide practical suggestion for physicians dealing with the management of KPC-KP infections in critically ill patients, based on expert opinions. SOURCES: PubMed search for relevant publications related to the management of KPC-KP infections. CONTENTS: A panel of experts developed a list of 12 questions to be addressed. In view of the current lack of high-level evidence, they were asked to provide answers on the bases of their knowledge and experience in the field. The panel identified several key aspects to be addressed when dealing with KPC-KP in critically ill patients (preventing colonization in the patient, preventing infection in the colonized patient and colonization of his or her contacts, reducing mortality in the infected patient by rapidly diagnosing the causative agent and promptly adopting the best therapeutic strategy) and provided related suggestions that were based on the available observational literature and the experience of panel members. IMPLICATIONS: Diagnostic technologies could speed up the diagnosis of KPC-KP infections. Combination treatment should be preferred to monotherapy in cases of severe infections. For non-critically ill patients without severe infections, results from randomized clinical trials are needed for ultimately weighing benefits and costs of using combinations rather than monotherapy. Multifaceted infection control interventions are needed to decrease the rates of colonization and cross-transmission of KPC-KP.

Addressing resistance evolution in Pseudomonas aeruginosa using pharmacodynamic modelling: application to meropenem dosage and combination therapy.

Isolates of Pseudomonas aeruginosa (n = 208) were collected from an 810-bed hospital in Connecticut, USA. A model employing the pharmacokinetic properties of meropenem, susceptibility results and Monte Carlo simulation was used to analyse four different dosing regimens of meropenem at pharmacodynamic endpoints. Cumulative fraction of response (CFR) was assessed at bacteriostatic and bactericidal endpoints for the entire population of isolates, as well as for isolates from principal anatomical sites. CFR was also evaluated at endpoints shown to suppress emergence of resistance in 'susceptible'P. aeruginosa with either monotherapy or combination therapy. The bacteriostatic/bactericidal CFR of meropenem 1 g every 8 h (q8h), 2 g q8h, 1 g q8h infused over 3 h (3-h INF), and 2 g q8h 3-h INF were 76%/73%, 80%/76%, 77%/75% and 79%/78%, respectively. At the monotherapeutic suppressive endpoint, CFRs against susceptible isolates were 21%, 35%, 32% and 50%, respectively. When combination therapy with an aminoglycoside was simulated, the CFRs for the same regimens were 50%, 64%, 65% and 79%, respectively. Bactericidal CFRs for all regimens against wound isolates were significantly higher (p <0.03 for each regimen) than CFRs for the entire population. Meropenem 2 g q8h with a 3-h infusion in combination with an aminoglycoside provides the greatest likelihood of P. aeruginosa coverage, and may help to prevent development of resistance, although local MIC data are essential to inform therapeutic decisions.

Association of healthcare exposure with acquisition of different Clostridium difficile strain types in patients with recurrent infection or colonization after clinical resolution of initial infection.

BACKGROUND: Following the resolution of an episode of Clostridium difficile infection (CDI), the factors associated with acquisition of different C. difficile strain types in patients with recurrent infection or persistent colonization have not been evaluated. AIM: To explore factors with potential correlation with acquisition of different C. difficile strain types in patients clinically cured of CDI through long-term follow-up across the continuum of care. METHODS: Polymerase chain reaction ribotyping was performed on C. difficile isolates recovered at baseline and follow-up (days 19-38) from stool samples of patients successfully treated for CDI, and those who had recurrence and/or colonization following symptom resolution. Chart review was conducted to determine factors associated with acquisition of a different C. difficile ribotype. FINDINGS: Of 25 patients initially cured of CDI, five had a recurrence and eight were colonized at follow-up. Patients did not differ with regard to age, sex, and whether the initial infection was with the BI/NAP1/027 strain. Ribotyping revealed that two out of five patients had recurrence attributed to a different strain type. Three of the colonized patients demonstrated strain switching compared with five patients who carried the same baseline strain. All patients (both infected and colonized) with different C. difficile ribotypes were exposed to the healthcare system. Exposure to antibiotics and proton pump inhibitors were not related to strain switching. CONCLUSION: Exposure to healthcare, but not to antibiotics or proton pump inhibitors, was consistently associated with recurrence or colonization with a different C. difficile ribotype.

Pharmacodynamic profiling of levofloxacin and gatifloxacin using Monte Carlo simulation for community-acquired isolates of Streptococcus pneumoniae.

In vitro and in vivo models of infection suggest that the area under the concentration-time curve (AUC): minimum inhibitory concentration (MIC) ratio is the pharmacodynamic parameter that is most predictive of bactericidal activity for the fluoroquinolones. Additionally, this parameter has also been correlated with clinical outcomes in humans with respiratory tract infection. Despite these defined relationships, broad-scale application of these principles in the section of optimal therapy in the clinical arena has been restricted by the imprecise estimates of drug exposures (ie, AUC:MIC ratio) in the infected population. In an effort to best describe the known variability in the pharmacokinetic and susceptibility profile of agents of interest, Monte Carlo simulation has been employed to assess the probability of attaining the desired AUC:MIC ratio. In this report Monte Carlo simulation was used to estimate the probability of attaining various target AUC:MIC ratios using AUC values from patients treated with either gatifloxacin or levofloxacin and the in vitro potency of the compounds as assessed in 881 clinical isolates of Streptococcus pneumoniae isolated from outpatients. Using a simulated patient population of 5,000, the median AUC:MIC ratios were 144 and 50 for gatifloxacin and levofloxacin, respectively. The probability of attaining AUC:MIC ratios of 30, 40, 65, 100, and 125 for gatifloxacin were 99%, 95%, 85%, 68%, and 60%, respectively. For levofloxacin, similar dynamic hit rates were 82%, 61%, 35%, 17%, and 12% over the range of target values. Regardless of the optimal ratio selected, gatifloxacin had a higher probability of achieving the AUC:MIC target than did levofloxacin. Simulations of this type can assist in the decision process surrounding the choice of optimal therapies based on our current understanding of antimicrobial pharmacodynamic principles.

Lomefloxacin clinical pharmacokinetics.

Lomefloxacin is a quinolone antibiotic with chemical and microbiological properties similar to most commercially available agents of this class. There are differences, however, between lomefloxacin and other quinolones in activity against specific micro-organisms, a situation that is typical of most antibiotic classes. The pharmacokinetics of lomefloxacin support once- or twice-daily dosage, depending on the pathogen or site of infection. This is a result of its relatively high serum concentrations and long half-life. The outstanding pharmacokinetic features of lomefloxacin are its high degree of tissue distribution, lack of significant metabolism (and, therefore, no competitive drug interactions with other metabolised drugs showing a common metabolic pathway), and good oral absorption. Like most fluoroquinolones, lomefloxacin can chelate with heavy metals. However, this interaction can be eliminated by administering lomefloxacin 2h before the cation-containing products. Dosage adjustments are required in patients with renal dysfunction. However, patients with liver disease do not require alterations in lomefloxacin dosage regimens. The safety profile, lack of significant drug interactions and convenience of administration make lomefloxacin a useful agent in specific clinical settings.

Population pharmacokinetics of continuous infusion ceftazidime.

OBJECTIVE: The purpose of this study was to develop and validate a model that predicts clearance and steady-state ceftazidime concentrations during continuous infusion. DESIGN: This was a prospective clinical observational trial. Two models describing drug clearance during the continuous infusion of ceftazidime to infected patients were developed. The first model included inter- and intraindividual variability (IIV) while the second extended the first model by including interoccasional variability (IOV). SETTING: This was a study of patients in a US hospital between January and June 1996. PATIENTS AND PARTICIPANTS: The analysis included 39 patients aged > 18 years with infections at various sites. INTERVENTIONS: Patients received ceftazidime as either a 1000 or 2000mg loading dose followed by a continuous infusion of 1000 to 4000 mg/day. Serum samples were collected under approximate steady-state conditions and ceftazidime concentrations were analysed using high performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. RESULTS: 75 serum concentration measurements were included in the analysis. The routinely available clinical variables bodyweight, age, gender and serum creatinine were found to be statistically independent predictors of ceftazidime clearance. The IIV model was cross validated yielding a mean prediction error (with a 95% confidence interval) of -0.51 mg/L (-2.5 to 1.4 mg/L) and a mean absolute prediction error of 6.5 mg/L (5.3 to 7.8 mg/L). CONCLUSION: We have developed and validated a model to estimate ceftazidime concentrations during continuous infusion using commonly available clinical information. Additional work is needed to compare outcomes of patients receiving continuous and intermittently administered ceftazidime, and to define the optimal target steady-state ceftazidime concentrations during continuous infusion.

Clinical pharmacokinetics of newer cephalosporins.

Several new cephalosporins have been developed in recent years. These agents include several oral and parenteral agents with extended activity against Gram-negative pathogens. The pharmacokinetic literature for these agents is quite extensive; therefore, we have summarised this information and presented it in tabular form for critical comparison. With a few exceptions, the newer cephalosporins share similar pharmacokinetic properties. Cefixime, cefetamet pivoxil and ceftibuten differ from the others in that they exhibit nonlinear pharmacokinetic properties. The nonlinear nature of these agents is reflected by decreasing maximal concentrations with escalating doses of cefixime and cefetamet pivoxil, decreasing area under the serum concentration-time curve with increasing doses for cefixime, and a reduced bioavailability with large doses of ceftibuten. Attention to such characteristics aid the clinician in selecting appropriate dosage regimens that will optimise drug absorption. The majority of agents are primarily renally eliminated; however, renal elimination accounts for only 20% of cefixime elimination. The pharmacokinetic parameters noted for the newer cephalosporins are not influenced by multiple-dose administration, suggesting lack of drug accumulation over time. The pharmacodynamics of antimicrobials should be considered when extrapolating pharmacokinetic information into the clinical arena. In the case of the beta-lactams, the time which drug concentrations remain above some critical threshold, such as the minimal inhibitory concentration, appears to have the greatest influence on bactericidal activity. Therefore, it is important to select dosage regimens that will optimise the time serum concentrations remain above this threshold. We present an evaluation of these agents with respect to their activity against a variety of pathogens in an effort to demonstrate a pharmacokinetically-based process of antimicrobial selection.

Chylous transport of amiodarone.

A patient receiving amiodarone for longstanding ventricular dysrhythmias presented with idiopathic chylothorax. During drainage of chylothorax for pleurodesis, serial plasma amiodarone concentrations declined while pleural fluid concentrations remained stable. Chylous transport of amiodarone and other lipid-bound drugs should be recognized to avert complications during chylothorax drainage.

Amiodarone-cyclosporine interaction in a heart transplant patient.

We report the case of a heart transplant patient whose cyclosporine clearance decreased by more than 50% after the institution of amiodarone therapy. This interaction necessitated a significant dosage reduction to maintain cyclosporine concentrations within the therapeutic range. To investigate the mechanism of the interaction, a cyclosporine-lipoprotein-binding determination was performed. The results suggest that drug displacement from competitive lipoprotein-binding sites is not responsible for the alterations in cyclosporine pharmacokinetics. Clearance data suggests, however, that the primary mechanism for the interaction is the inhibition cyclosporine metabolism by the cytochrome P-450 system. This report emphasizes the importance of reevaluating therapeutic drug regimens when new agents are added to prevent complications caused by drug interactions. If amiodarone and cyclosporine must be used concomitantly, cyclosporine levels must be monitored frequently, in anticipation of this interaction.