Past, Present, and Future of Antibacterial Economics: Increasing Bacterial Resistance, Limited Antibiotic Pipeline, and Societal Implications.

Growing antimicrobial resistance and a dwindling antibiotic pipeline have resulted in an emerging postantibiotic era, as patients are now dying from bacterial infections that were once treatable. The fast-paced "Golden Age" of antibiotic development that started in the 1940s has lost momentum; from the 1980s to the early 2000s, there was a 90% decline in the approval of new antibiotics as well as the discovery of few new novel classes. Many companies have shifted away from development due to scientific, regulatory, and economic hurdles that proved antibiotic development to be less attractive compared with more lucrative therapeutic areas. National and global efforts are focusing attention toward potential solutions for reinvigorating the antibiotic pipeline and include "push" incentives such as public-private partnerships and "pull" incentives such as reimbursement reform and market exclusivity. Hybrid models of incentives, global coordination among stakeholders, and the appropriate balance of antibiotic pricing, volume of drug used, and proper antimicrobial stewardship are key to maximizing efforts toward drug development to ensure access to patients in need of these therapies.

Community-based outpatient parenteral antimicrobial therapy (CoPAT) for Staphylococcus aureus bacteraemia with or without infective endocarditis: analysis of the randomized trial comparing daptomycin with standard therapy.

OBJECTIVES: Administering outpatient parenteral antimicrobial therapy in the community setting (CoPAT) is becoming more common with the increasing emphasis on controlling costs. However, few controlled trials have evaluated this treatment modality. METHODS: Using data from a recent randomized trial comparing daptomycin with standard therapy (semi-synthetic penicillin or vancomycin, each with initial low-dose gentamicin) for Staphylococcus aureus bacteraemia and infective endocarditis (SAB/IE), patient characteristics and outcomes were evaluated. Patients receiving their full course of therapy in the hospital setting were compared with those who received some portion outside of the hospital (CoPAT). RESULTS: Among the 200 patients, 51.5% received CoPAT. These patients were generally younger (median age 50 versus 54 years, P = 0.028). In the CoPAT group, there tended to be fewer patients with endocardial involvement (8.7% versus 18.6%, P = 0.061) and pre-existing valvular heart disease (7.8% versus 15.5%, P = 0.120). CoPAT patients received longer therapy courses (mean 25.4 versus 13.5 days, P < 0.001) and had higher rates of therapy completion (90.3% versus 45.4%, P < 0.001) and clinical success (86.4% versus 55.7%, P < 0.001). Persisting or relapsing S. aureus was less frequent in the CoPAT group (3.9% versus 15.5%, P = 0.007) and there were fewer deaths (3.9% versus 18.6%, P = 0.001) 6 weeks after the end of therapy. Hospital readmission occurred for 18 of the 103 (17.5%) CoPAT patients. Clinical success rates were similar for CoPAT patients receiving daptomycin (90.0%) or standard therapy (83.0%). CONCLUSIONS: With proper monitoring, stable patients can complete treatment for SAB/IE as outpatients in the community setting. Daptomycin is an appropriate option for this setting.

Daptomycin in the treatment of bacteremia.

The aim of this study was to describe the clinical experience with daptomycin in the treatment of bacteremia. Patients with a diagnosis of catheter-related or non-catheter-related bacteremia and no other concurrent infection were identified from the Cubicin Outcomes Registry and Experience (CORE) 2004. Treatment success was determined by investigators using protocol criteria and defined as cure or improvement. Of 168 patients with bacteremia, 126 were clinically evaluable. Of those, 52 (41%) patients were aged > or =66 years, 54 (43%) received daptomycin in an intensive care unit, and 25 (20%) had chronic renal failure. The most common pathogens isolated were methicillin-resistant Staphylococcus aureus (33%), vancomycin-resistant enterococci (30%), and coagulase-negative staphylococci (30%). Of 126 patients, 86% received daptomycin after previous antibiotic therapy and most (69%) received concomitant antibiotics with daptomycin. Daptomycin therapy was started at a median dose of 4.0 mg/kg (range, 2.5 to 9.2 mg/kg). Daptomycin therapy had an overall clinical success rate of 89%. Clinical success was independent of baseline renal function, daptomycin dose, pathogen, first-line use, or concomitant antibiotic therapy. These results support the findings of a recent study in which daptomycin was demonstrated to be an effective option in the treatment of S aureus bacteremia. Data in the current study provide insight into the clinical experience using daptomycin to treat bacteremia caused by other gram-positive pathogens. Given the limitations of retrospective studies and lack of follow-up data, additional studies are needed to make definitive evaluations with these pathogens.

Clinical experience with daptomycin for the treatment of patients with osteomyelitis.

Data from a registry were analyzed to describe the clinical experience with daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) for the treatment of patients with osteomyelitis. The Cubicin Outcomes Registry and Experience (CORE) 2004 database was used to identify patients treated for osteomyelitis. Posttherapy follow-up outcome assessments were collected for a subset of these patients. A total of 67 patients with osteomyelitis were clinically evaluable for outcome at the end of daptomycin therapy and had outcome assessed at a posttherapy visit. The median follow-up interval after the last dose of daptomycin was 76 days (range, 1 to 547 days). The median initial dose was 5.6 mg/kg (range, 3.2 to 7.5 mg/kg), and the median duration of therapy was 35 days (range, 3 to 546 days). Daptomycin was given concurrently with other antibiotics in 48% of cases. Methicillin-resistant Staphylococcus aureus was the most common pathogen (45%). Clinical outcomes at follow-up were cure, 42 (63%); improved, 13 (19%); failure, 7 (10%); and nonevaluable, 5 (7%). A total of 82% of patients with an orthopedic device (n = 17) were successfully treated, as were 88% of patients with concurrent bacteremia (n = 16). Failures were more likely if surgical debridement was not performed (24% vs. 5%; P = 0.045). The clinical success rate for patients treated with an initial daptomycin dose >4 mg/kg was significantly higher than for patients treated with an initial dose < or =4 mg/kg (88% vs. 65%; P = 0.013, chi2 test). Daptomycin had a 94% success rate when used alone with no follow-up antibiotics. The results indicate that daptomycin is being used in clinical practice to treat patients with osteomyelitis caused by gram-positive pathogens including MRSA. Prospective, controlled clinical trials of daptomycin are warranted that include rigorous data collection and long-term follow-up analysis.

Postmarketing clinical experience in patients with skin and skin-structure infections treated with daptomycin.

A registry describing daptomycin's clinical use was analyzed to describe treatment of skin and skin-structure infections (SSSIs). The Cubicin Outcomes Registry and Experience (CORE) 2004 retrospectively collected demographic, microbiologic, and clinical outcome information of patients treated with daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA). The database was accessed to identify patients with a diagnosis of an SSSI with an outcome determined. Of 577 patients identified with a SSSI, 522 (90%) were evaluable. Diabetes mellitus and peripheral vascular disease were present in 27% and 10% of the population, respectively. Pathogens were identified for 65% of all patients-Staphylococcus aureus (75%; 85% methicillin-resistant) and Enterococcus species (19%; 44% vancomycin-resistant) most commonly. Concomitant use of other antibiotics was common (42%). Of 522 patients studied, 334 (64%) had complicated infections (cSSSIs), and 188 (36%) had uncomplicated infections (uSSSIs). Overall cure, improved, and failure rates were 53%, 43%, and 4%, respectively, for cSSSI and 66%, 32%, and 2%, respectively, for uSSSI. The median dose administered was 4.0 mg/kg for cSSSI (mean, 4.5+/-1.0 mg/kg; range, 2.3 to 12 mg/kg) and 4.0 mg/kg for uSSSI (mean, 4.2+/-0.8 mg/kg; range, 2.1 to 9 mg/kg); the dose was significantly higher in cSSSI (P <0.001, median test). Median daptomycin treatment duration was 12 days (range, 1 to 148 days) and was longer for cSSSI than for uSSSI (14 vs. 10 days, P = 0.002). The results of this study support previously published reports and suggest that daptomycin is effective for the treatment of skin infections due to gram-positive pathogens.

Population pharmacokinetics and pharmacodynamics of garenoxacin in patients with community-acquired respiratory tract infections.

Garenoxacin (T-3811ME, BMS-284756) is a novel, broad-spectrum des-F(6) quinolone currently under study for the treatment of community-acquired respiratory tract infections. This analysis assessed garenoxacin population pharmacokinetics and exposure-response relationships for safety (adverse effects [AE]) and antimicrobial activity (clinical cure and bacteriologic eradication of Streptococcus pneumoniae and the grouping of Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis). Data were obtained from three phase II clinical trials of garenoxacin administered orally as 400 mg once daily for 5 to 10 days for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, and sinusitis. Samples were taken from each patient before drug administration, 2 h following administration of the first dose, and on the day 3 to 5 visit. Individual Bayesian estimates of the fu (fraction unbound), the Cmax, and the fu for the area under the concentration-time curve from 0 to 24 h (fu AUC(0-24)) were calculated as measurements of drug exposure by using an ex vivo assessment of average protein binding. Regression analysis was performed to examine the following relationships: treatment-emergent AE incidence and AUC(0-24), Cmax, or patient factors; clinical response or bacterial eradication and drug exposure (fu Cmax/MIC, fu AUC(0-24)/MIC, and other exposure covariates); or disease and patient factors. Garenoxacin pharmacokinetics were described by a one-compartment model with first-order absorption and elimination. Clearance was dependent on creatinine clearance, ideal body weight, age, obesity, and concomitant use of pseudoephedrine. The volume of distribution was dependent on weight and gender. Patients with mild or moderate renal dysfunction had, on average, approximately a 16 or 26% decrease in clearance, respectively, compared to patients of the same gender and obesity classification with normal renal function. AE occurrence was not related to garenoxacin exposure. Overall, clinical cure and bacterial eradication rates were 91 and 90%, respectively, for S. pneumoniae and 93 and 92%, respectively, for the grouping of H. influenzae, H. parainfluenzae, and M. catarrhalis. The fu AUC(0-24)/MIC ratios were high (>90% were >200), and none of the pharmacokinetic-pharmacodynamic exposure measurements indexed to the MIC or other factors were significant predictors of clinical or bacteriologic response. Garenoxacin clearance was primarily related to creatinine clearance and ideal body weight. Although garenoxacin exposure was approximately 25% higher for patients with moderate renal dysfunction, this increase does not appear to be clinically significant as exposures in this patient population were not significant predictors of AE occurrence. Garenoxacin exposures were at the upper end of the exposure-response curves for measurements of antimicrobial activity, suggesting that 400 mg of garenoxacin once daily is a safe and adequate dose for the treatment of the specified community-acquired respiratory tract infections.

Characterization of the penetration of garenoxacin into the breast milk of lactating women.

The primary objective of this study was to characterize the extent of excretion of garenoxacin, a novel des-F(6)-quinolone antimicrobial, into the breast milk of lactating women. A secondary objective was to determine the time after dose administration that garenoxacin was no longer detected in breast milk so as to define when a mother may resume breastfeeding if it was interrupted for garenoxacin administration. Six healthy, lactating women (age [mean +/- SD]: 32 +/- 6 years; weight: 68.3 +/- 19.8 kg; body mass index: 26 +/- 5 kg/m(2)) who had completed weaning their infants were administered a single 600-mg oral dose of garenoxacin. Plasma samples were collected predose and repeatedly up to 72 hours postdose. Breast milk was collected predose and for 6- to 12-hour intervals repeatedly up to 120 hours postdose. Breast milk/plasma concentration ratios for garenoxacin ranged from 0.35 to 0.44 up to 24 hours postdose, and the mean peak breast milk concentration was 3.0 microg/mL (0- to 6-h collection interval). Overall, garenoxacin exposure in breast milk was minimal, with a mean of 0.07% of the administered dose recovered within 120 hours. Indeed, garenoxacin was undetectable in the breast milk of a majority of subjects within 84 hours of dosing. As such, an infant nursing from a mother who had received a single 600-mg oral dose of garenoxacin could theoretically be exposed to 0.42 mg of garenoxacin (0.105 mg/kg/day for a 4-kg infant over the period of 5 days of nursing). If extrapolated to a 14-day course of garenoxacin 600 mg once daily, total exposure would be approximately 5.88 mg. These findings indicate that, like other quinolone antimicrobials, garenoxacin is secreted in breast milk.

Efficacy and tolerability of gatifloxacin in community treatment of acute exacerbations of chronic bronchitis.

BACKGROUND: Recognizing acute exacerbations of chronic bronchitis (AECB) and selecting appropriate antibiotic treatment for patients who would benefit most is a challenge for community-based physicians. OBJECTIVE: The Tequin Clinical Experience Study, an open-label, noncomparative, postmarketing trial, assessed the efficacy and tolerability of gatifloxacin, an 8-methoxy fluoroquinolone, in the treatment of AECB in the community-practice setting. METHODS: Consecutive patients with respiratory tract infections in community-based settings were eligible for participation. Treated patients (N = 2512) included 1107 men (44.1%) and 1405 women (55.9%) aged > or =18 years with a clinical diagnosis of chronic bronchitis. All participants received oral gatifloxacin 400 mg once daily for 7 to 10 days. Clinical response was determined via telephone contact conducted by the investigator or study coordinator using case-report forms or during an office visit after the last dose. The investigator or coordinator collected expectorated or induced sputum specimens that were then smeared on a microscope slide, stored in a tube, and transported to a central reference laboratory for Gram-staining and culture. Of 1388 pretreatment sputum specimens submitted, pathogens were isolated from 424. RESULTS: The most frequently detected pathogens were Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. All H. influenzae and 99% of S. pneumoniae isolates tested were susceptible to gatifloxacin. Of the 2267 patients with a determinable clinical response, 2084 (91.9% [95% CI, 90.8%-93.0%]) were cured (all acute symptoms improved or returned to baseline level, no new symptoms present, no additional antibiotic required). The 95.8% cure rate in 166 patients with H. influenzae included 100% of those with beta-lactamase-positive strains. Overall, 89.2% of 111 patients with M. catarrhalis were cured; rates were similar regardless of beta-lactamase production. The clinical cure rate in 74 patients with S. pneumoniae was 98.6% and was independent of the degree of penicillin resistance (minimum inhibitory concentration > or =2.0 microg/ mL). All 6 patients infected with S. pneumoniae fully resistant to penicillin were cured. Gatifloxacin was generally well tolerated, and the majority of adverse events were mild to moderate; only 11 drug-related adverse events in 10 patients (0.4%) were serious. Drug-related nausea (3.0%), dizziness (1.5%), diarrhea (1.2%), and vomiting (0.9%) were the most common adverse events. CONCLUSIONS: The high clinical cure rate and favorable tolerability support gatifloxacin as a rational choice for the treatment of AECB in patients such as those in this community-based study.