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.

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.

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.

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.

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.

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.

Performance of the PIRO score for predicting mortality in patients with ventilator-associated pneumonia.

The ventilator-associated pneumonia (VAP) PIRO score is a new scoring system based on the PIRO concept. The aim of this study was to validate the PIRO score against the Acute Physiology and Chronic Health Evaluation (APACHE) II and VAP APACHE II in an independent group of VAP patients. Areas under the receiver operating characteristic curves were compared to determine the tests' abilities to predict intensive care unit and 28-day mortality. Variables associated with intensive care unit mortality were evaluated. One hundred and forty-eight intensive care unit patients who met radiographic and clinical criteria for VAP were included. The area under the receiver operating characteristic curves for predicting intensive care unit mortality with the PIRO, APACHE II and VAP APACHE II scores were 0.605 (P=0.03), 0.631 (P=0.01) and 0.724 (P <0.0001), respectively. Areas under the receiver operating characteristic curve for predicting 28-day mortality were 0.614 (P=0.01) for PIRO, 0.633 (P=0.01) for APACHE II and 0.697 (P=0.002) for VAP APACHE II. No differences in area under the receiver operating characteristic curve between scores were found at either endpoint. Variables independently associated with intensive care unit mortality were bacteraemia (adjusted odds ratio 7.16, 95% confidence interval 1.19 to 42.98, P=0.03) and APACHE II (1.06, 1.01 to 1.11, P=0.006). VAP PIRO score was not a good predictor of intensive care unit and 28-day mortality. The low sensitivity and specificity of VAP PIRO score preclude its use clinically.

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.

A pharmacodynamic simulation to assess tigecycline efficacy for hospital-acquired pneumonia compared with other common intravenous antibiotics.

A pharmacodynamic model was used to generate supportive data comparing tigecycline with other broad-spectrum agents against pathogens implicated in hospital-acquired pneumonia (HAP). A 5000 patient Monte Carlo simulation determined the probability of target attainment (PTA) of tigecycline (+/- ceftazidime) compared with imipenem, levofloxacin, and piperacillin/tazobactam (+/- vancomycin). PTA was calculated over MICs of current Gram-positive and Gram-negative bacteria collected from worldwide surveillance and weighted by the expected prevalence of these pathogens causing HAP. For monotherapy, the weighted PTA was imipenem (78.2%), piperacillin/tazobactam (73.3%), tigecycline (62.9%), and levofloxacin (62.5%). By pathogen PTA was greatest for tigecycline against Gram-positives, and ceftazidime or imipenem against Gram-negatives. Combination therapy increased PTA to 88.6%, 85.5%, 80.6%, and 69.8% for tigecycline, imipenem, piperacillin/tazobactam, and levofloxacin, respectively. Based on contemporary resistance data, tigecycline plus ceftazidime is predicted to achieve its pharmacodynamic targets similarly to combination therapy with imipenem plus vancomycin for the treatment of patients with HAP.

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.

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.

Intrapulmonary concentrations of telithromycin: clinical implications for respiratory tract infections due to Streptococcus pneumoniae.

BACKGROUND: Antimicrobial efficacy is dependent on the ability of the agent to reach the site of infection. To assess the bronchopulmonary drug disposition of a novel ketolide, telithromycin (TEL), the epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations were utilized as a surrogate marker for lung penetration. METHODS: Adult subjects scheduled for diagnostic bronchoscopy received oral TEL 800 mg once daily for 5 days. Plasma and bronchoalveolar lavage (BAL) samples were collected 2, 8, 12, or 24 h after the last TEL dose. TEL concentrations in the ELF and AM were determined using a validated HPLC assay. ELF drug concentrations were calculated using the urea dilution method. RESULTS: Seventeen subjects with a mean age 65 +/- 13 years and a mean weight of 81 +/- 25 kg completed this open-label study. The median (range) TEL concentrations in plasma and ELF, respectively, were 1.09 mg/l (1.00-4.81) and 3.91 mg/l (2.64-9.59) at 2 h (n = 6), 0.48 and 1.09 mg/l at 8 h (n = 1), 0.65 mg/l (0.18-1.55) and 1.81 mg/l (0.61-10.0) at 12 h (n = 5), and 0.11 mg/l (0.09-0.24) and 0.69 mg/l (0.15-1.58) at 24 h (n = 5). The median AM concentrations obtained from these subjects were 53.35 mg/l at 2 h, 32.55 mg/l at 8 h, 65.96 mg/l at 12 h, and 26.43 mg/l at 24 h. Overall TEL was well tolerated. No discontinuation was required due to an adverse event. CONCLUSIONS: TEL displayed high intrapulmonary penetration with ELF concentrations exceeding that of plasma at all time points. AM intracellular concentrations were multiple times higher than in the ELF and plasma. These data support the clinical efficacy of TEL against intracellular and extracellular pathogens, particularly with Streptococcus pneumoniae having an MIC(90 )well below achievable concentrations at the site of infection.

The integration of pharmacokinetics and pathogen susceptibility data in the design of rational dosing regimens.

The integration of pharmacokinetic and pathogen susceptibility data has had an increasing impact on the design of dosage regimens. Pathogen susceptibility is often described by the minimum inhibitory concentration (MIC). While the MIC is an indicator of drug potency, it does not predict pharmacologic response in vivo when drug concentrations are fluctuating. To this end, three pharmacokinetic/pharmacodynamic (PK/PD) parameters that result from indexing pharmacokinetics to MIC have proven quite useful. A number of experimental models of infection have determined the magnitude of each parameter, AUC/MIC, Cmax/MIC and %T>MIC, required for the optimal treatment of specific pathogens. These measurements have proven to be predictive of clinical outcomes as well. As a result, PK/PD breakpoints have been determined based on the likelihood that the pharmacokinetic profile of a given dose will achieve a target PK/PD parameter value. These breakpoints correlate well with treatment success or failure, particularly evident in infections conducive to microbiologic sampling such as otitis media. Therefore, PK/PD assessments have fostered a much more targeted approach to the treatment of patients with infectious diseases, and have proven useful in the selection of antimicrobial therapy and the development of novel dosing strategies.

Beneficial pharmacokinetic interaction between cyclosporine and itraconazole in renal transplant recipients.

BACKGROUND: Itraconazole is often given for fungal prophylaxis to renal transplant recipients, who require concomitant cyclosporine in the immediate posttransplant period. We determined the extent of the pharmacokinetic interaction between cyclosporine and itraconazole oral solution in renal transplant recipients and the effect on daily drug costs. METHOD: This was a single-center, open-label, nonrandomized study. Posttransplantation, renal transplant recipients received itraconazole solution 200 mg twice daily and cyclosporine, dosed to achieve target concentrations. Once at steady state, blood samples were collected over 12 hours for pharmacokinetic evaluation of cyclosporine, itraconazole, and hydroxy-itraconazole. Itraconazole was discontinued after approximately a 3-month prophylaxis regimen. Cyclosporine doses were titrated to achieve target concentrations and cyclosporine concentrations were once again determined when steady state was achieved. A noncompartmental analysis was used to analyze cyclosporine pharmacokinetic parameters. The pharmacoeconomic impact was measured based on the percent change in dose of cyclosporine when administered with and without itraconazole. Drug costs were calculated using the average wholesale price. The cost per patient, as well as the average cost, was calculated for the cyclosporine/itraconazole combination, as well as the cyclosporine regimen alone. RESULTS: Eight renal transplant recipients completed the study. All were included for itraconazole analyses and seven for cyclosporine analyses. Mean peak and trough itraconazole levels were 1.64 +/- 0.82 and 1.23 +/- 0.90 microg/mL respectively. Mean peak and trough hydroxy-itraconazole levels were 2.37 +/- 1.55 and 2.20 +/- 1.48 microg/mL, respectively. While on itraconazole, a 48% reduction in the mean total daily dose of cyclosporine was necessary to maintain target concentrations (171 +/- 63.6 versus 329 +/- 103.5 mg, P =.003). This reduction in cyclosporine dose resulted in a discounted itraconazole daily drug cost of approximately 29.5%. CONCLUSION: Administering itraconazole with cyclosporine allows for a decrease in the cyclosporine dose, thus lowering daily drug costs and providing adequate antifungal coverage with itraconazole and hydroxy-itraconazole trough concentrations above the MIC(90) of Candida and Aspergillus spp.