Direct costs in patients hospitalised with community-acquired pneumonia after non-response to outpatient treatment with macrolide antibacterials in the US.

INTRODUCTION: Antibacterial cost-containment programmes emphasise the use of narrow-spectrum generic agents whenever possible. The use of these agents is driven by their lower purchase prices; the consequences of treatment failure are rarely considered. This study was conducted to identify the costs of treating patients hospitalised with community-acquired pneumonia (CAP) associated with Streptococcus pneumoniae following failure to respond to outpatient treatment with macrolide antibacterials. METHODS: A multicentre, retrospective, observational study was performed in patients with CAP due to S. pneumoniae who were admitted to 31 North American hospitals following a lack of response to >or=2 days of outpatient treatment with a macrolide antibacterial. Direct medical costs (year 2004 values) of infection-related hospital resources, including antibacterials (purchase, preparation, dispensing, administration and monitoring), diagnostic tests, therapeutic procedures, treatment of adverse events and therapeutic failures, and hospitalisation per diem (ward, critical care and ventilator days), were analysed. Total hospital costs were then compared with standard diagnosis-related group (DRG) reimbursement. RESULTS: A total of 122 patients were enrolled. Patients were frequently bacteraemic (52%) and infected with macrolide-resistant strains of S. pneumoniae (71%). Initial inpatient antibacterial treatment was not successful in 17 patients (14%) and seven patients (5.7%) died. The mean length of stay was 8.7 days (SD 7) including 1.3 days (SD 2.9) in a critical care unit and 1.4 days (SD 4.4) of mechanical ventilation. The mean cost of hospitalisation was US dollars 12,678 (SD 13 346) but standard DRG reimbursement averaged only US dollars 8,634. CONCLUSIONS: Patients who do not respond to outpatient treatment with a macrolide antibacterial and who are subsequently hospitalised with CAP caused by S. pneumoniae are likely to be infected with a non-susceptible strain, are frequently bacteraemic, are at an increased risk for mortality compared with previously published estimates in patients with CAP due to S. pneumoniae, and incur hospital costs that far exceed standard DRG reimbursement for CAP.

The safety profile of moxifloxacin and other fluoroquinolones in special patient populations.

BACKGROUND: Fluoroquinolones, including ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin, represent a major advance in the development of antimicrobial agents. They offer significant activity against Gram-negative pathogens, while more advanced generation fluoroquinolones including levofloxacin, gemifloxacin, and moxifloxacin are significantly active against Gram-positive (e.g., Streptococcus pneumoniae for some members of the class), typical, atypical, and anaerobic pathogens. Fluoroquinolones have a pharmacokinetic/pharmacodynamic profile that exhibits concentration-dependent killing and good oral absorption, allowing for once-daily dosing. OBJECTIVE: Review of data from fluoroquinolone studies, with an emphasis on the associated rare, but potentially clinically important, adverse events in specific patient populations. Review of clinical efficacy is included where relevant to the topic under discussion. METHODS: A literature search was conducted using terms including fluoroquinolones, moxifloxacin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, safety, adverse events, drug interactions, and pharmacokinetic parameters to identify literature providing information regarding the safety profile of specified fluoroquinolones in special patient populations (i.e., the elderly, patients with liver disease, kidney disease, glycemic disorder, those at risk for cardiovascular events). Although specific date criteria were not applied to the search, preference was given to more recent publications. Online databases searched include MEDLINE and EMBASE and relevant textbooks were utilized as well. FINDINGS: Fluoroquinolones, when used either as monotherapy or as combination therapy depending on their individual indications, attain adequate concentrations for treating infections in different target sites, including epithelial lining fluid, alveolar macrophages, skin, and gastrointestinal tissues. Overall, fluoroquinolones have predictable and mild-to-moderate adverse-event profiles and are generally well tolerated. Findings of this review are limited by the availability of publications and case reports. CONCLUSIONS: Fluoroquinolones, are associated with rare, but clinically important, adverse events in special patient populations (including the elderly; those with hepatic, renal, or glycemic disorders; and those at risk for cardiovascular events). Recognition of differences in the clinical efficacy and safety profiles of fluoroquinolones in special patient populations should lead to better antimicrobial agent selection.

Severity scoring in community-acquired pneumonia caused by Streptococcus pneumoniae: a 5-year experience.

Multiple severity scoring systems have been devised and evaluated in community-acquired pneumonia (CAP), but a simplified set of prognostic indicators has not yet been developed. Streptococcus pneumoniae is the most frequent aetiological agent of CAP. Our aim was to characterise the outcome in the light of different severity scoring systems and to compare the predictive values of different sets of clinical parameters, using available clinical data for pneumococcal CAP patients. This is a case series retrospective analysis that included consecutive adult pneumococcal CAP patients admitted to Danbury Hospital between 1 January 1996 and 31 December 2000. The aetiology was confirmed by positive sputum and/or blood cultures. The severity assessment included the Pneumonia Outcome Research Trial (PORT) and British Thoracic Society (BTS) scoring systems and other additional parameters. Primary end-points were in-hospital CAP-attributable deaths and length of hospitalisation. N = 151 patients with S. pneumoniae CAP were identified. The mean (+/- standard deviation) age at the time of diagnosis was 68 (+/-15) years. Thirty-three patients (22%) were admitted to the medical intensive care unit. The mean (median) hospitalisation duration was 7.5 (+/-5) days. Door-to-antibiotic mean (median) administration time was 3.7 (2) hours. Most frequent antibiotics used initially were cephalosporins plus/minus macrolides or fluoroquinolones. The mean (+/- standard deviation) PORT score was 105 (+/-37). The observed CAP-related mortality was 9/151 (5.9%, 95% confidence interval: 3-9%). The mortality rate in ICU was 18% (6/33). Sixty-nine patients (45%) had S. pneumoniae bacteraemia an admission. The bacteraemic and non-bacteraemic patients had similar PORT scores (107 vs. 104, P = 0.66), length of hospitalisation (8 vs. 7 days, P = 0.41) and mortality rates (9% vs. 4%, P = 0.30). In conclusion, patients admitted with pneumococcal CAP, although severe and with multiple co-morbidities had low in-hospital mortality rates and lengths of hospitalisation. Neither prior antimicrobial use (or failure) nor antimicrobial resistance contributed to an adverse outcome. S. pneumoniae bacteraemia failed to correlate with need for ICU, length of stay, higher morbidity index or fatal outcome. Low rates of empirical antibiotic use for non-bacterial infections in the local community, implementation of an emergency department protocol for CAP therapy, early recognition of higher risk patients and placement in ICU, use of broad spectrum antibiotics, infectious disease approval or critical pathway restriction for admission orders, could all have combined to effect a good outcome for these patients.

Prevention and management of antibacterial resistance for primary care patients with respiratory tract infections.

This review examines the problem of increasing antibacterial resistance among the pathogens commonly associated with community-acquired respiratory tract infections, particularly Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The increases in morbidity, mortality, and treatment cost associated with increased resistance to available antibiotics are challenging prescribers to find more effective therapeutic strategies. A MEDLINE search of the literature from 1966 to the present was performed to seek data relevant to the issue of resistance, especially the negative effects on patient outcomes and costs of therapy. Several observations and conclusions emerged. Data are lacking on local resistance patterns, broad-spectrum agents are overprescribed when narrower-spectrum choices would be more appropriate, a need exists for educational programs to encourage restricting drug use and changing prescribing habits, and there is a need for new antibiotic choices. The best antibiotic options are agents with a tailored spectrum of activity that are targeted at particular respiratory tract pathogens and have low potential to select for resistant organisms.

Emergence of fluoroquinolone resistance among Bacteroides species.

BACKGROUND: Several newer generation fluoroquinolones have demonstrated good in vitro activity against Bacteroides species; particularly when first introduced. However, resistance of Bacteroides to quinolones appears to be increasing. MATERIALS AND METHODS: From 1994 to 2001, consecutive non-duplicated Bacteroides isolates from clinical specimens in 12 US hospitals were sent to the Tufts anaerobe laboratory for identification and susceptibility testing. NCCLS recommended methodology for testing was employed. Breakpoints of 8 mg/l for trovafloxacin and 4 mg/l for moxifloxacin were used to examine susceptibility trends. RESULTS: In total, 4434 isolates were analysed. The geometric mean MIC increased significantly for clinafloxacin, trovafloxacin and moxifloxacin. Resistance to trovafloxacin (breakpoint of 8 mg/l) and moxifloxacin (breakpoint of 4 mg/l) increased from 8% to 25% and from 30% to 43%, respectively. Increased resistance was observed for all Bacteroides species, for all sites of isolation, and in 11 of 12 participating hospitals. Bacteroides vulgatus and isolates from decubitus ulcers were associated with increased resistance. During 2001, trovafloxacin and moxifloxacin resistance among blood isolates was 27% and 52%, respectively. The association between increased resistance and year of isolation remained significant after adjustment for hospital, species and site of isolation. CONCLUSIONS: Fluoroquinolone resistance among Bacteroides isolated in the US has markedly increased during the years 1994 to 2001. High rates of resistance among blood isolates are of particular concern.

Impact of initial antibiotic choice on clinical outcomes in community-acquired pneumonia: analysis of a hospital claims-made database.

BACKGROUND: Much controversy exists regarding the initial choice of antibiotics and selected outcomes for patients with community-acquired pneumonia (CAP). METHODS: The investigators analyzed a hospital claims-made database to assess the impact of initial antibiotic choice on 30-day mortality, total hospital costs, and hospital length of stay (LOS). Fine risk groups allowed for stratification for variations in the severity of illness. Patients were divided into five monotherapy groups (ie, ceftriaxone, "other" cephalosporins, fluoroquinolones, macrolides, or penicillins) and four groups that received dual therapy (ie, the agents listed above, except macrolides) plus macrolides. Patients also were stratified by age (ie, > 65 years of age and < 65 years of age). Severely ill patients were excluded. RESULTS: Overall, 44,814 persons met the criteria for inclusion. Among monotherapy patients, those who received macrolides had the least mortality but were the least ill. Patients who received dual therapy generally had shorter LOSs, lower total hospital charges, and decreased mortality compared with those who received monotherapy. Differences among dual-therapy regimens regarding outcomes studies were noted. Patients who were < 65 years of age had lower mortality rates, shorter LOSs, and lower hospital charges than did the more elderly patients. Within this group, those who received dual therapy had better outcomes than those who received monotherapy. CONCLUSIONS: We confirmed the value of dual therapy employing macrolides as a second agent in decreasing mortality from CAP, and we provided similar data regarding shorter LOSs and lower hospital charges. This appears to hold for a younger population. Differences among dual-therapy regimens (all employing macrolides) appear to exist and may be clinically relevant.

Moxifloxacin (Avelox): a novel fluoroquinolone with a broad spectrum of activity.

Moxifloxacin (Avelox) is a recently-developed fluoroquinolone that has a broad spectrum of antimicrobial activity, including typical respiratory pathogens, atypical and intracellular respiratory pathogens, Gram-negative pathogens and many anaerobes. This spectrum of activity makes moxifloxacin particularly suitable for the therapy of community-acquired respiratory tract infections. It also has enhanced activity against specific bacteria, such as Mycobacteria spp. and Legionella. Moxifloxacin has pharmacologic characteristics that support once-daily dosing regimens and dual routes of excretion that require little or no adjustment for renal or hepatic insufficiency. The drug has maintained an excellent safety profile based upon broad global usage, and no adverse events have occurred that were unanticipated. Streptococcus pneumoniae, which are resistant to earlier fluoroquinolones, are less likely to be resistant to moxifloxacin.

Gatifloxacin-associated corrected QT interval prolongation, torsades de pointes, and ventricular fibrillation in patients with known risk factors.

Drugs not commonly considered to be cardioactive agents have been reported to cause prolongation of the corrected QT interval with resultant torsades de pointes or ventricular fibrillation. We report 4 cases of gatifloxacin-associated cardiac toxicity in patients with known risk factors for this adverse event.

Cardiotoxicity of macrolides, ketolides and fluoroquinolones that prolong the QTc interval.

Macrolides, ketolides and fluoroquinolones as well as other classes of antimicrobial agents have been associated with prolongation of cardiac repolarisation. This effect is most notable with erythromycin, clarithromycin, gatifloxacin, moxifloxacin, levofloxacin and telithromycin. All of these agents produce a blockage of the HERG channel dependent potassium current in myocyte membranes resulting in a prolonged QTc interval which may give rise to polymorphic ventricular tachycardia, Torsades de Pointes or ventricular fibrillation. The risk of malignant arrhythmias is increased by concomitant usage with Type Ia or III anti-arrhythmic agents or with other drugs that prolong the QTc interval or have competitive metabolic routes. Electrolyte disturbances or underlying cardiac disease also increase the risk of ventricular arrhythmias. The best clinical outcome indicator is the incidence of the associated arrhythmias. The rough rank order of risk with these agents, albeit with limited and incomplete data, is in decreasing order; erythromycin, clarithromycin, gatifloxacin, levofloxacin and moxifloxacin. Telithromycin outcomes for associated arrhythmia are yet to be determined. The essential point is that the overall risk of ventricular arrhythmias is very small with these agents but can be reduced further by avoiding their usage for patients with other multiple risk factors for Torsades de Pointes.