First, an independent international panel of infectious diseases experts, whose goal was to identify ways to improve prescription of antibiotics for lower respiratory tract infections, stressed that an important purpose of therapy is to reduce bacterial load and, in fact, treat to bacteriologic cure.19 Antibiotic therapy that allows some bacteria to survive increases the risk of early recurrence or relapse and encourages resistance selection. Such therapy is, therefore, inappropriate. The panel concurred with the WHO and others that the likelihood of bacterial persistence increases when antibiotics are prescribed in low doses, especially if given over long periods.18,39-41 Prolonged low-dose antibiotic therapy, which has been common practice for many infections, is contrary to the WHO Global Strategy for Containment of Antimicrobial Resistance, which notes that single-agent therapy for a short duration is 1 of several actions that can be taken to minimize bacterial resistance.42 Shorter courses of antibiotic therapy also are consistent with SHEA/IDSA recommendations.10
The clinical appropriateness of this recommendation is reinforced by the changes that have occurred during the past decade in the management of selected urinary tract infections (UTIs). Some UTIs that previously had been treated with low-dose antibiotics for 10 to 14 days now are treated with only 1 or a few high doses of a single agent. Other infections for which clinical data support shorter courses of antibiotic therapy include uncomplicated cellulitis,43 ventilator-associated pneumonia,44 and meningococcal disease.45
Shorter-course antibacterial therapy for CARTIs increasingly has been the focus of clinical trials. The focus is not unreasonable. Many of the antibiotics used for CARTIs are very potent against the pathogens commonly encountered, penetrate infected tissues well, are available in oral formulations, and are generally well tolerated. However, to optimize an antibiotic’s bactericidal potential, it is necessary to base the dosing regimen on its pharmacodynamics. From a pharmacodynamic perspective, there are 2 groups of antibiotics, those with concentration-dependent killing and those with time-dependent killing. For agents with concentration-dependent killing, such as fluoroquinolones, ketolides, and aminoglycosides, the goal is to select a dose that achieves a higher peak concentration and/or a larger area under the plasma concentration curve, with acceptable tolerability. In contrast, antibiotics that rely on time-dependent killing, such as β-lactams, macrolides, azalides, tetracyclines, and some others, require extended durations of concentrations above the MIC90 of the bacterial pathogen(s). Consequently, multiple daily dosing may be preferable.46
Dose. A few studies have compared high-dose, short-course therapy with therapy using standard doses and durations (TABLE 4). To assess the impact of highdose, short-course therapy on post-treatment resistant pneumococcal carriage, Schrag compared amoxicillin given either as 90 mg/kg/day for 5 days (high-dose, short-course) or 40 mg/kg/day for 10 days (standard) in 797 children with a respiratory tract infection.47 At day 28, nasal carriage of penicillin-resistant S pneumoniae was detected in 24% of the high-dose, shortcourse group and in 32% of the standard group (relative risk, 0.77; P=0.03). Among the pneumococcal carriers, the risk of penicillin-resistant S pneumoniae was significantly lower in the high-dose, short-course group than in the standard therapy group (relative risk, 0.78; P=0.01)
Another study investigated high-dose, short-course therapy with levofloxacin in patients with mild to severe community-acquired pneumonia. Patients received levofloxacin 750 mg/d for 5 days or 500 mg/d for 10 days.48 The clinical success rates were 92.4% and 91.1%, respectively, while the bacteriologic eradication rates at 7 to 14 days post-therapy were 93.2% and 92.4%, respectively, thereby demonstrating that high-dose, shortcourse levofloxacin therapy is at least as effective as standard levofloxacin therapy.
Duration. Short-course therapy using standard doses of azithromycin, gemifloxacin, levofloxacin, moxifloxacin, and telithromycin has been investigated in clinical trials of CARTIs (FIGURE). In patients with community-acquired pneumonia, 5 days of therapy with telithromycin was shown to be equivalent to a 7-day course (both using a single daily dose of 800 mg), as well as to clarithromycin 500 mg bid for 10 days.49
In studies of acute exacerbations of chronic bronchitis, a 3-day course of azithromycin was equivalent to clarithromycin for 10 days50 and gemifloxacin for 5 days was equivalent to a sequential combination of ceftriaxone and cefuroxime axetil for up to 10 days.51 Levofloxacin for 3 days and azithromycin for 5 days provided equivalent outcomes,52 as did levofloxacin for 5 days and amoxicillin/clavulanate for 10 days.52 Moxifloxacin for 5 days provided results equivalent to those of 7 days of amoxicillin, clarithromycin, or cefuroxime axetil.53 Five days of telithromycin was shown to be equivalent to 10 days of amoxicillin/clavu-lanate54 or cefuroxime axetil.55
Studies of acute bacterial rhinosinusitis have demonstrated equivalent results with azithromycin for 3 days and amoxicillin/clavulanate for 10 days.50 Similarly, telithromycin for 5 days was equivalent to 10 days of telithromycin, amoxicillin/clavulanate, or cefuroxime axetil.56
