Identifying exposure targets for treatment of staphylococcal pneumonia with ceftobiprole.

Ceftobiprole is a cephalosporin with potent activity against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). In order to treat patients with severe staphylococcal pneumonia, it is important to understand the drug exposure required to mediate the killing of multiple log(10) cells in a preclinical-infection model. We measured drug exposure in terms of the percentage of penetration of the drug into epithelial lining fluid (ELF) and in terms of the time for which the drug concentration was above the MIC (time>MIC) in plasma and ELF. In a murine model of staphylococcal pneumonia, we demonstrated that ceftobiprole penetrated into ELF from the plasma at a median level of nearly 69% (25th to 75th percentile range, 25 to 187%), as indexed to the ratio of values for the area under the concentration-time curve in ELF and plasma. The total-drug times>MIC in ELF that were required to kill 1 log(10) and 2 log(10) CFU/g of lung tissue were 15% and 25% of the dosing interval. We also examined the penetration of ELF by ceftobiprole in volunteers, demonstrating mean and median penetration percentages of 25.5% and 15.3%, respectively (25th to 75th percentile range, 8 to 30%). Attainment rates were calculated for kill targets of 1 log(10) and 2 log(10) CFU/g, taken from the murine model, but using the volunteer ceftobiprole ELF penetration data. The standard dose for ceftobiprole is 0.5 g every 8 h as a 2-h infusion. The attainment rates remained above 90% for 1-log(10) and 2-log(10) CFU/g kill targets at MICs of 1 and 0.5 mg/liter, respectively. Taking the expectation over the distribution of ceftobiprole MICs for 4,958 MRSA isolates showed an overall target attainment of 85.6% for a 1-log(10) CFU/g kill and 79.7% for a 2-log(10) CFU/g kill. It is important to derive exposure targets in preclinical-infection models of the infection site so that these targets can be explored in clinical trials in order to optimize the probability of a good clinical outcome.

Pharmacodynamic characterization of ceftobiprole in experimental pneumonia caused by phenotypically diverse Staphylococcus aureus strains.

Ceftobiprole (BPR) is an investigational cephalosporin with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains. The pharmacodynamic (PD) profile of BPR against S. aureus strains with a variety of susceptibility phenotypes in an immunocompromised murine pneumonia model was characterized. The BPR MICs of the test isolates ranged from 0.25 to 2 mug/ml. Pharmacokinetic (PK) studies were conducted with infected neutropenic BALB/c mice; and the BPR concentrations were measured in plasma, epithelial lining fluid (ELF), and lung tissue. PD studies with these mice were undertaken with eight S. aureus isolates (two methicillin-susceptible S. aureus strains, three hospital-acquired MRSA strains, and three community-acquired MRSA strains). Subcutaneous BPR doses of 2 to 125 mg/kg of body weight/day were administered, and the change in the number of log(10) CFU/ml in lungs was evaluated after 24 h of therapy. The PD profile was characterized by using the free drug exposures (f) determined from the following parameters: the percentage of time that the concentration was greater than the MIC (T > MIC), the maximum concentration in serum/MIC, and the area under the concentration-time curve/MIC. The BPR PK parameters were linear over the dose range studied in plasma, and the ELF concentrations ranged from 60 to 94% of the free plasma concentration. fT > MIC was the parameter that best correlated with efficacy against a diverse array of S. aureus isolates in this murine pneumonia model. The 80% effective dose (ED(80)), ED(50), and stasis exposures appeared to be similar among the isolates studied. BPR exerted maximal antibacterial effects when fT > MIC ranged from 6 to 22%, regardless of the phenotypic profile of resistance to beta-lactam, fluoroquinolone, erythromycin, clindamycin, or tetracycline antibiotics.

Cost-effectiveness of telavancin versus vancomycin for treatment of complicated skin and skin structure infections.

STUDY OBJECTIVE: To determine the cost-effectiveness of telavancin versus vancomycin for the treatment of complicated skin and skin structure infections (cSSSIs). DESIGN: Pharmacoeconomic analysis conducted from the hospital's perspective using data from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections (ATLAS) phase III clinical trial. SETTING: One hundred twenty-nine hospitals in the United States and internationally. PATIENTS: A total of 1044 clinically evaluable patients who were hospitalized with a cSSSI during the ATLAS trial and who received at least one dose of telavancin or vancomycin in the hospital. MEASUREMENTS AND MAIN RESULTS: Diagnosis-related group-specific hospital bed costs, antibiotic acquisition prices, and cost of vancomycin monitoring were applied to the resource utilization data collected during the ATLAS trial. Infection-related length of stay (LOS(ir)) and hospitalization costs (COST(ir)) were compared between the telavancin (514 patients) and vancomycin (530 patients) groups. Incremental cost-effectiveness ratios (ICERs) were calculated for the total population and a subset of patients infected with methicillin-resistant Staphylococcus aureus (MRSA) by using a 25,000-sample bootstrap analysis. During sensitivity analyses, the daily acquisition price for telavancin was increased from the equivalent to vancomycin ($13.44) to $50, $100, $150, or $200, and the rate of MRSA acquisition was varied between 30% and 75%. The median (interquartile range) LOS(ir) was 8 days (6-12 days) for both telavancin and vancomycin (p=0.742), and median (interquartile range) COST(ir) was $8118 ($6291-11,758) and $8185 ($6474-11,405), respectively (p=0.560). Similar findings were observed for the MRSA subset. Telavancin cost-effectiveness was greater for the MRSA population versus the total population. During bootstrap analyses of the MRSA population, the ICER for telavancin ranged from dominant (-$9560) to $27,889 as acquisition price was increased. CONCLUSIONS: Telavancin LOS(ir) and total COST(ir) were similar to those of vancomycin for the treatment of cSSSIs. Particularly in those infected with MRSA, telavancin may be more cost-effective than vancomycin over the range of acquisition prices tested.

Surgical site infections: does inadequate antibiotic therapy affect patient outcomes?

BACKGROUND: Complicated skin/skin structure infections involve deeper soft tissues and include surgical site infections (SSIs). Inadequate antibiotic therapy (IAT) has been associated with adverse outcomes in respiratory and blood stream infections, but is seldom evaluated in SSIs. This study assessed the impact of IAT on primary outcomes of length of stay (LOS) and costs in complicated SSIs; identifying risk factors associated with receiving IAT was a secondary objective. METHODS: This retrospective cohort study of discharges from our 810-bed urban teaching hospital from Quarter 4/2004-Quarter 1/2006 identified 130 patients with complicated SSI among 298 patients with postoperative infections. Superficial infections and infections not involving the skin/skin structures were excluded. Patient characteristics, culture data, and antibiotic history were collected from charts. Inadequate antibiotic therapy was said to have occurred when a drug active against the organism cultured was not given within 24 h of culture. Multiple regression identified variables associated with LOS and increase hospital accounting costs. RESULTS: A total of 39 subjects (30%) received IAT; patient characteristics did not differ from those receiving adequate therapy, except that prior antibiotic use was more likely in IAT subjects (p = 0.053). Staphylococcus aureus (45% methicillin-resistant) was the most common pathogen (39%). More than one-half (60%) of the subjects received empiric vancomycin. The IAT patients experienced longer post-infection LOS and higher costs (median [25%, 75%]): 10 [6, 21] days vs. 7 [4, 11] days; p = 0.007 and $11,746 [$6,652, $28,442] vs. $7,116 [$5,210, $16,443]; p = 0.04). Longer LOS was associated significantly with Acute Physiology and Chronic Health Evaluation score, IAT, Pseudomonas infection, and sternal incisions, as were higher costs, excepting Pseudomonas infection. Inadequate antibiotic therapy was more likely in polymicrobial infections (p < 0.001), pseudomonal (p < 0.001) or enterococcal (p = 0.002) infections, and infected abdominal incisions (p < 0.001). Methicillin-resistant S. aureus was not associated with adverse outcomes, possibly because empiric therapy frequently included vancomycin. CONCLUSIONS: Inadequate antibiotic therapy is associated with longer LOS and higher costs in complicated SSIs. Risk factors for IAT include prior antibiotic therapy, polymicrobial infection, infection with P. aeruginosa or Enterococcus spp., and abdominal incisions.

Expression of the MexXY-OprM efflux system in Pseudomonas aeruginosa with discordant cefepime/ceftazidime susceptibility profiles.

While MIC distributions and percent susceptibility for cefepime and ceftazidime are generally similar among Pseudomonas aeruginosa, we noted an increasing discordance in susceptibility favoring ceftazidime at our hospital. Quantitative reverse transcriptase-polymerase chain reaction was utilized to explore overexpression of the MexXY-OprM efflux as the mechanism for this phenotype profile. Thirteen of 15 (87%) randomly selected isolates had mexY gene expression levels of 5.8-40.8-fold relative to the wild-type reference strain. While mexY overexpression was noted in the majority of isolates, other resistance mechanisms appear to contribute to the observed phenotypic profile of the Pseudomonas aeruginosa studied. Clinicians must understand not only the magnitude of difference in the MIC profiles between agents, but also the mechanism(s) responsible for these observations if strategies (ie, pharmacodynamic dosing) are to be designed to optimize patient care outcomes in the face of increasing resistance.

Telavancin: a novel lipoglycopeptide for serious gram-positive infections.

Telavancin, a once-daily dosing lipoglycopeptide derived from vancomycin, has a broad-spectrum microbiologic activity against gram-positive bacteria, including vancomycin-resistant staphylococci. Telavancin displays a dual mode of action and a rapid bactericidal killing. The in vitro activity of telavancin is superior to vancomycin and comparable with, or greater than, linezolid, daptomycin and other novel lipoglycopeptides. Telavancin is effective against gram-positive pathogens in animal models of soft tissue infections and deep-seated infections including endocarditis, pneumonia and bacteremia. Clinical experience with telavancin in Phase II and III studies for complicated skin and skin structure infections have demonstrated similar efficacy and tolerability compared with standard anti-staphylococcal beta-lactams and vancomycin. Telavancin is in Phase III studies for nosocomial pneumonia. Telavancin seems to be promising as a novel agent for empiric therapy or as an alternative agent in serious infections caused by clinically important resistant gram-positive pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin intermediate-susceptible S. aureus, vancomycin-resistant S. aureus and vancomycin-resistant enterococci.