Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7 to 15 days to intravenous imipenem/cilastatin (500 to 1000 mg every 6 to 8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7 to 15 days. Levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1 to 16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1 to 19 days).
Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was empirically initiated at study entry in 56 of 93 (60.2%) patients in the levofloxacin arm and 53 of 94 (56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the levofloxacin arm and 7 days in the comparator. In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa infection, 15 of 17 (88.2%) received ceftazidime (N = 11) or piperacillin/tazobactam (N = 4) in the levofloxacin arm and 16 of 17 (94.1%) received an aminoglycoside in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was added to the treatment regimen of 37 of 93 (39.8%) patients in the levofloxacin arm and 28 of 94 (29.8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection.
Clinical success rates in clinically and microbiologically evaluable patients at the posttherapy visit (primary study endpoint assessed on day 3 to 15 after completing therapy) were 58.1% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-17.2, 12]. The microbiological eradication rates at the posttherapy visit were 66.7% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of eradication rates (levofloxacin minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication rates by pathogen are detailed in Table 9.
|* Methicillin-susceptible S. aureus † See above text for use of combination therapy‡ The observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study|
|Pathogen||N||Levofloxacin No. (%) of Patients Microbiologic/ Clinical Outcomes||N||Imipenem/Cilastatin No. (%) of Patients Microbiologic/ Clinical Outcomes|
|MSSA*||21||14 (66.7)/13 (61.9)||19||13 (68.4)/15 (78.9)|
|P. aeruginosa†||17||10 (58.8)/11 (64.7)||17||5 (29.4)/7 (41.2)|
|S. marcescens||11||9 (81.8)/7 (63.6)||7||2 (28.6)/3 (42.9)|
|E. coli||12||10 (83.3)/7 (58.3)||11||7 (63.6)/8 (72.7)|
|K. pneumoniae‡||11||9 (81.8)/5 (45.5)||7||6 (85.7)/3 (42.9)|
|H. influenzae||16||13 (81.3)/10 (62.5)||15||14 (93.3)/11 (73.3)|
|S. pneumoniae||4||3 (75)/3 (75)||7||5 (71.4)/4 (57.1)|
Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae , and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies are presented in Table 10.
|Pathogen||No. Pathogens||Bacteriological Eradication Rate (%)|
Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae
Levofloxacin was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/ sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in Table 11.
|* One patient had a respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and TMP/SMX and intermediate to penicillin and a blood isolate that was intermediate to penicillin and cefuroxime and resistant to the other classes. The patient is included in the database based on respiratory isolate.† n = the number of microbiologically evaluable patients who were clinical successes; N = number of microbiologically evaluable patients in the designated resistance group.‡ n = the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients; N = number of MDRSP isolates in a designated resistance group.|
|Screening Susceptibility||Clinical Success||Bacteriological Success*|
|n/N †||%||n/N ‡||%|
|2nd generation Cephalosporin resistant||31/32||96.9||31/32||96.9|
|Trimethoprim/ Sulfamethoxazole resistant||17/19||89.5||17/19||89.5|
Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 12.
|Type of Resistance||Clinical Success||Bacteriologic Eradication|
|Resistant to 2 antibacterials||17/18 (94.4%)||17/18 (94.4%)|
|Resistant to 3 antibacterials||14/15 (93.3%)||14/15 (93.3%)|
|Resistant to 4 antibacterials||7/7 (100%)||7/7 (100%)|
|Resistant to 5 antibacterials||0||0|
|Bacteremia with MDRSP||8/9 (89%)||8/9 (89%)|
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