Treatment of CAP with Levofloxacin: What Dose? What Duration?

Abstract & Commentary

Synopsis: Treatment of CAP with 750 mg of levofloxacin daily for 5 days was as effective as a 10-day course of 500 mg daily.

Source: Dunbar LM, et al. High-dose, short-course levofloxacin for community-acquired pneumonia: A new treatment paradigm. Clin Infect Dis. 2003;37:752-760.

Dunbar and colleagues at 70 us sites randomized, after stratification by severity, 530 adults with community-acquired pneumonia (CAP) to receive 1 of 2 regimens of levofloxacin—750 mg daily for 5 days or 500 mg daily for 10 days. A total of 122 patients had relatively mild disease, with pneumonia severity index (PSI) scores < 70. All but 3 of the remaining patients had PSI scores of 71-130. The most frequently encountered among the 158 infectious etiologies identified was Mycoplasma pneumoniae, which accounted for 79 (50%), followed by Streptococcus pneumoniae (27%) and Chlamydia pneumoniae (24%). There were 11 Legionella pneumophila infections in the 5-day group and only 3 in the 10-day group.

The clinical success rates among the 390 evaluable patients were similar in the 2 treatment groups at 92.4% and 91.1%, respectively. Defervescence occurred significantly more rapidly in the 750 mg group. The frequency of subsequent clinical relapse did not differ significantly between those receiving 5 days of treatment (4.3%) and 10 days (1.2%). Microbiological efficacy also did not differ between the 2 treatment arms and was > 90% in each arm for each identified pathogen. Seven cases of pneumococcal bacteremia were detected in each arm, with all but (possibly) 1 being cured.

There were no significant differences in the frequencies of drug related adverse events.

Comment by Stan Deresinski, MD, FACP

This study demonstrates that a 5-day course of 750 mg levofloxacin daily is not inferior to a 10-day course of 500 mg daily. The rationale for the shorter course with a higher dose has sound bases. The antibacterial activity of fluoroquinolones is concentration-dependent, and outcome of infection appears to be most closely linked to the achieved Cmax/MIC and AUC/MIC, both of which are optimized at higher doses. In addition, the blood levels achieved with the 500 mg daily dose of levofloxacin may be becoming marginally effective in some areas as the MIC of S pneumoniae creeps upward. Such marginally effective concentrations may also increase the likelihood of selection of resistant mutants. A CDC study has demonstrated a reduced risk of selection of resistant pneumococci in nasopharyngeal cultures of children given higher-dose, shorter-course amoxicillin than the reverse.1 This analogy is not perfect, however, since beta-lactams exhibit time-dependent, rather than concentration-dependent, activity. Also, however, in terms of gross tonnage, the shorter course levofloxacin regimen exposes the bacterial ecology to a total of 25% less antibiotic.

Some caveats are warranted. It is reported that 140 of the 530 (26%) randomized patients were not clinically evaluable. With the exception of 3 patients, those with the most severe pneumonia (PSI >130) were not included in this study. In addition, an etiologic agent was apparently identified in only a minority of cases and one-half of these were believed to be due to M pneumoniae. The identification of this etiology, as well as C pneumoniae, relied on serological testing. However, Dunbar et al neglect to indicate the methodology, whether a central laboratory was used, and what the criteria for diagnosis were. Thus, one could question these diagnoses.

The 750 mg dose appeared to be well tolerated. This is not surprising since this dose has received US FDA approval in both skin/skin structure infection and nosocomial pneumonia.

Dr. Derenski is Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.

Reference

1. Schrag SJ, et al. Effect of short-course, high-dose amoxicillin therapy on resistant pneumococcal carriage: A randomized trial. JAMA. 2001;286:49-56.