High-Dose, Short-Course Levofloxacin for Community-Acquired ...

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MAJOR ARTICLE

High-Dose, Short-Course Levofloxacin for Community-Acquired Pneumonia: A New Treatment Paradigm Lala M. Dunbar,1 Richard G. Wunderink,2 Michael P. Habib,3 Leon G. Smith,4 Alan M. Tennenberg,5 Mohammed M. Khashab,5 Barbara A. Wiesinger,5 Jim X. Xiang,5 Neringa Zadeikis,5 and James B. Kahn5 1

Louisiana State University Medical Center, New Orleans, Louisiana; 2Methodist University Hospital, Memphis, Tennessee; Southern Arizona VA Health Care System, University of Arizona Department of Medicine, Tucson, Arizona; 4Saint Michael’s Medical Center, Newark, and 5Ortho-McNeil Pharmaceutical, Raritan, New Jersey

3

(See the editorial commentary by Mandell and File on pages 761–3)

Levofloxacin demonstrates concentration-dependent bactericidal activity most closely related to the pharmacodynamic parameters of the ratio of area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) and the ratio of peak plasma concentration (Cmax) to MIC. Increasing the dose of levofloxacin to 750 mg exploits these parameters by increasing peak drug concentrations, allowing for a shorter course of treatment without diminishing therapeutic benefit. This was demonstrated in a multicenter, randomized, double-blind investigation that compared levofloxacin dosages of 750 mg per day for 5 days with 500 mg per day for 10 days for the treatment of mild to severe community-acquired pneumonia (CAP). In the clinically evaluable population, the clinical success rates were 92.4% (183 of 198 persons) for the 750-mg group and 91.1% (175 of 192 persons) for the 500-mg group (95% confidence interval, ⫺7.0 to 4.4). Microbiologic eradication rates were 93.2% and 92.4% in the 750-mg and 500-mg groups, respectively. These data demonstrate that 750 mg of levofloxacin per day for 5 days is at least as effective as 500 mg per day for 10 days for treatment of mild-to-severe CAP. Strategies for the empirical treatment of communityacquired pneumonia (CAP) are complicated by shifting etiologies and the emergence of drug-resistant pathogens. Streptococcus pneumoniae has long been identified as the most important pathogen among adults with CAP, followed by Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus [1–4]. However, recent studies have documented an increased incidence of pneumonia due to “atypical” (e.g., Legionella pneumophila, Myco-

Received 25 February 2003; accepted 2 May 2003; electronically published 28 August 2003. Financial support: Ortho-McNeil Pharmaceutical. Reprints or correspondence: Dr. Alan Tennenberg, Ortho-McNeil Pharmaceutical, 1000 Rt. 202 S, Raritan, NJ 08869-0602 ([email protected]). Clinical Infectious Diseases 2003; 37:752–60  2003 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2003/3706-0002$15.00

plasma pneumoniae, and Chlamydia pneumoniae) and gram-negative pathogens [3–5]. Of additional concern is the increasing incidence of resistance to previously effective antimicrobial agents [1, 4, 6]. The 2001–2002 Tracking Resistance in the United States Today (TRUST) study revealed that 18.4% of S. pneumoniae isolates were penicillin resistant [7]. The incidence of S. pneumoniae that are multidrug-resistant (MDR; i.e., resistant to ⭓3 antimicrobial classes) has also increased, from 6.2% of isolates in 1997–1998 to 14.5% of isolates in 2001–2002 [7]. The most common MDR phenotype identified in the 2001–2002 TRUST surveillance exhibited resistance to penicillin, azithromycin, and trimethoprim-sulfamethoxazole and accounted for 92.1% of the MDR isolates recovered. If a key contributor to the emergence of drugresistant pathogens is antimicrobial overuse, then

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Table 1. Main criteria for participation in a study of highdose, short-course levofloxacin treatment for communityacquired pneumonia.

PATIENTS, MATERIALS, AND METHODS

Inclusion criteria Presence of ⭓1 of the following characteristics: fever (oral temperature, ⭓38C), hypothermia (oral temperature, ⭐35C), leukocytosis (WBC count, 110,000 cells/mm3), or 110% bands Exclusion criteria Infection(s) due to organisms known to be resistant to levofloxacin Previous allergic or serious reaction to any quinolone Previously treatment failure with any quinolone Life expectancy of !72 h Pneumonia acquired in a hospital At high risk for infection with Pseudomonas aeruginosa Neutropenia (⭐500 polymorphonuclear leukocytes/mm3) Empyema or presence of pleural fluid requiring a chest tube Pneumonia known to be due to aspiration of gastric contents Documented HIV infection with a CD4 cell count of ⭐200 cells/mm3 Known or suspected meningitis Pregnancy Nursing

strategies to counter this phenomenon should be evaluated. Such approaches include restricting antibacterial use to true bacterial infections and reducing the duration of therapy to the threshold needed for effective treatment, thereby reducing the amount of drug to which bacteria are unnecessarily exposed. Abbreviating treatment duration may be facilitated by optimizing antibacterial regimens on the basis of pharmacodynamic principles. Levofloxacin is a concentration-dependent antimicrobial agent, with therapeutic outcome most closely linked to the ratio of the area under the concentration-time curve (AUC) to the MIC for the organism, rather than time of concentration greater than the MIC. Also, a high ratio of peak plasma concentration (Cmax) to MIC has been associated with prevention of the emergence of resistance [8–11]. If these pharmacodynamic parameters are exploited by increasing the dose, thereby increasing the Cmax and the AUC, it should be possible to shorten the duration of treatment without compromising efficacy. Reducing the total amount of drug to which bacteria are unnecessarily exposed may limit the development of resistance. This “highdose, short-course” paradigm for fluoroquinolone dosing was tested in this study of levofloxacin at a dosage of 750 mg per day for 5 days for the treatment of mild to severe CAP.

Study population. Adult men and women (age, ⭓18 years) with a diagnosis of mild-to-severe CAP based on clinical signs and symptoms of a lower respiratory tract infection and radiographic evidence of acute pneumonia were eligible for enrollment. The main criteria for study entry are shown in table 1. To avoid the requirement of levofloxacin dosage adjustment and to help maintain treatment blinding, patients with a calculated creatinine clearance of !50 mL/min were excluded from participation. Study design. This was a randomized, double-blind, active treatment–controlled, noninferiority study conducted in the United States, with 70 sites enrolling patients. The protocol was approved by the participating institutions’ institutional review boards, and written informed consent was obtained before initiation of study procedures. Randomization included stratification of patients by study center and by Pneumonia Severity Index (PSI) score [12] to maintain a balance of disease severity between treatment groups. Patients with a PSI score of ⭐70 (stratum II) could be treated as inpatients or outpatients, whereas those with a PSI score of 170 but ⭐130 (stratum I) were to be treated as inpatients for ⭓24 h. Study drug was administered either intravenously or orally, at the investigator’s discretion, for a total of 10 days. Patients randomized to the 750-mg dose group received levofloxacin once per day for the first 5 days and placebo once per day for an additional 5 days. Patients ranTable 2. Classifications and definitions of clinical and microbiologic responses after levofloxacin therapy. Clinical response definitions Cure: resolution of pretreatment abnormal clinical signs and symptoms, with no further antimicrobial therapy required for CAP Improvement: clinical findings subsided significantly but with incomplete resolution of clinical evidence of infection in a patient who required no further antimicrobial therapy for CAP Failure: no apparent response to therapy or an incomplete response requiring additional antimicrobial therapy for CAP Unable to evaluate: clinical judgment of cure, improvement, or failure could not be made because patient was lost to follow-up Microbiologic responsea Eradicated: all pathogens isolated from sputum and blood samples at study entry were eradicated or presumed to have been eradicated Persisted: persistence or presumed persistence of ⭓1 pathogen isolated at study entry and found in the previous culture Unknown: ⭓1 pathogen had a posttherapy microbiologic response of “unknown,” with no persisting pathogens NOTE. a

CAP, community-acquired pneumonia.

Determined from culture of a respiratory or blood specimen.

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Figure 1.

Disposition of patients in a study of high-dose, short-course levofloxacin for treatment of community-acquired pneumonia. ITT, intent-to-treat.

domized to the 500-mg dose group received levofloxacin once per day for 10 days. Collection of clinical and microbiologic data. At study entry, clinical signs and symptoms of CAP were evaluated and disease severity was determined using the PSI classification. Within 24 h after study entry, respiratory secretion specimens were obtained for routine culture, Gram staining, and L. pneumophila testing. Acceptable specimens included deep expectorated or suctioned sputum samples; transtracheal aspirates; bronchial brushings, washings, or biopsy specimens; and pleural fluid. Samples were required to contain ⭓25 polymorphonuclear leukocytes and ⭐10 squamous epithelial cells per low-powered field [13]. Acute- and convalescent-phase blood specimens were obtained for serologic testing for “atypical” organisms, and a urine sample was tested for L. pneumophila antigen. Blood cultures were also done for identification of bacteremic patients.

Because of different durations of active therapy, each group was evaluated at 2 posttherapy visits (1 of which was timed to occur 7–14 days after receipt of the last dose of active drug for each group). Clinical signs and symptoms were reassessed for each group during an on-therapy visit (study day 3), each of the 2 posttherapy visits, and a poststudy visit (conducted between days 31 and 38). Clinical and microbiologic efficacy analyses. Clinical response after therapy was classified as “cure,” “improvement,” “failure,” or “unable to evaluate” (table 2). Microbiologic outcomes were determined for patients who had a respiratory or blood pathogen identified at study admission. After therapy, microbiologic response of the patient’s infection was classified as “eradicated,” “persisted,” or “unknown.” In the absence of a posttherapy visit culture and for atypical pathogens identified by serologic testing or urine antigen a response of “presumed eradicated” was used to classify the microbiologic outcome for

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Table 3. Evaluability of clinical and microbiologic efficacy of levofloxacin regimens in the intent-to-treat population. No. (%) of patients 750-mg groupa (n p 256)

500-mg groupb (n p 272)

198 (77.3)

192 (70.6)

Inappropriate posttherapy visit date

22 (8.6)

24 (8.8)

Deviation from protocol dosing regimen

14 (5.5)

26 (9.6)

Class of efficacy, evaluability status Clinical efficacy Evaluable Not evaluable, by reason

Other protocol violation

9 (3.5)

9 (3.3)

Unconfirmed clinical diagnosis

8 (3.1)

12 (4.4)

Lost to follow-upc

3 (1.2)

5 (1.8)

Effective concomitant therapy

2 (0.8)

4 (1.5)

103 (40.2)

92 (33.8)

123 (48.1)

139 (51.1)

8 (3.1)

12 (4.4)

Microbiologic efficacy Evaluable Not evaluable, by reason Infection not bacteriologically proven Unconfirmed clinical diagnosis

a b c

Deviation from protocol dosing regimen

8 (3.1)

10 (3.7)

Inappropriate bacteriologic culture

6 (2.3)

11 (4.0)

Other protocol violation

6 (2.3)

6 (2.2)

Lost to follow-upc

2 (0.8)

1 (0.4)

Receipt of effective concomitant therapy

0 (0.0)

1 (0.4)

Levofloxacin, 750 mg q.d. iv or po for 5 days. Levofloxacin, 500 mg q.d. iv or po for 10 days. Patient did not return for posttherapy visits for reason other than clinical failure.

patients deemed clinical successes, and the term “presumed persisted” was used to classify the microbiologic outcome for patients deemed to have had clinical failure (table 2). Safety evaluation. All patients who received ⭓1 dose of study medication were evaluated for adverse events. Safety assessments included evaluation of changes in vital signs, clinical laboratory results, and physical examination findings. Statistical analyses. The prospectively defined primary efficacy end point in this study was clinical success rate (proportion of patients who were cured or whose condition improved) at the posttherapy visit scheduled to occur 7–14 days after receipt of the last dose of active drug for each group. Patients with an unconfirmed diagnosis of CAP, who were lost to follow-up, who received therapy that was insufficient (!80% of scheduled doses) or excessive (1120% of scheduled doses), or who received effective concomitant antimicrobial therapy during the study period were excluded from the primary efficacy analysis. Secondary response variables included posttherapy microbiologic response for each patient, posttherapy microbiologic response of each pathogen identified at study entry, changes in signs and symptoms from study entry to the posttherapy period, changes in radiography findings from study

entry to the posttherapy and poststudy periods, and poststudy clinical and microbiologic response of patients who were cured or improved at the posttherapy visits and who returned for the poststudy visit. Noninferiority was determined by calculating the 2-sided 95% CI for the difference in clinical success rates between treatments (rate for 10-day levofloxacin regimen minus rate for the 5-day levofloxacin regimen) in clinically evaluable patients. To conclude that the 5-day regimen of 750 mg of levofloxacin per day was at least as efficacious as (i.e., noninferior to) the 10-day regimen of 500 mg of levofloxacin per day, the upper limit of the 2-sided 95% CI had to be !15% if the clinical success rates were 80%–90% in both groups, and !10% if one or both clinical success rates were ⭓90%. RESULTS Study population. The disposition of patients participating in this study is outlined in figure 1. A total of 530 patients were randomized. One patient in each group received no study medication and, therefore, was not included in the intent-to-treat (ITT) population. The most common reason for premature

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Table 4. Demographic and baseline characteristics for the intent-to-treat (ITT) and clinically evaluable populations. a

b

500-mg group

750-mg group ITT population (n p 256)

Clinically evaluable population (n p 198)

ITT population (n p 272)

Clinically evaluable population (n p 192)

Male

148 (57.8)

114 (57.6)

162 (59.6)

113 (58.9)

Female

108 (42.2)

84 (42.4)

110 (40.4)

79 (41.1)

Characteristic Sex

Age, mean years  SD

53.1  17.5

52.7  17.8

55.3  18.2

55.4  17.7

Weight, mean kg  SD

79.48  19.53

80.20  18.95

76.66  21.06

81.05  20.97

White

179 (69.9)

139 (70.2)

183 (67.3)

135 (70.3)

Black

51 (19.9)

41 (20.7)

64 (23.5)

38 (19.8)

Asian

4 ( 1.6)

2 ( 1.0)

3 ( 1.1)

3 ( 1.6)

19 ( 7.4)

14 ( 7.1)

21 ( 7.7)

16 ( 8.3)

3 ( 1.2)

2 ( 1.0)

1 ( 0.4)

0 ( 0.0)

I/IIc

155 (60.5)

122 (61.6)

149 (54.8)

106 (55.2)

III/IVd

101 (39.5)

76 (38.4)

123 (45.2)

86 (44.8)

Race

Hispanic Other PSI class

NOTE. a b d c

Data are no. (%) of patients, unless otherwise indicated. PSI, Pneumonia Severity Index.

Levofloxacin, 750 mg q.d. iv or po for 5 days. Levofloxacin 500 mg q.d. iv or po for 10 days. PSI score, ⭐70. PSI score, 170 but ⭐130. Five patients with a PSI score of 1130 are included in this stratum.

discontinuation of levofloxacin was occurrence of adverse events, which led to premature withdrawal of 16 (6.3%) of 256 patients in the 750-mg group and 21 (7.7%) of 272 patients in the 500-mg group. One hundred ninety-eight patients (77.3%) in the 750-mg group and 192 patients (70.6%) in the 500-mg group were evaluable for clinical efficacy. The microbiologically evaluable population consisted of 103 patients (40.2%) and 92 patients (33.8%) in the 750-mg and 500-mg groups, respectively (table 3). The 2 groups were demographically similar for both the ITT and clinically evaluable populations (table 4). The proportion of patients in the ITT population categorized as PSI class III/ IV (stratum I) was 45.2% in the 500-mg treatment arm and 39.5% in the 750-mg treatment arm (P p .19, by 2-sided Fisher’s exact test). Clinical efficacy. At the posttherapy assessment, the clinical success rates in the clinically evaluable population were 92.4% (183 of 198 patients) for the 750-mg group and 91.1% (175 of 192 patients) for the 500-mg group (95% CI, ⫺7.0 to 4.4). Within the 2 severity strata, clinical success rates were comparable for both groups (table 5). Clinical response rates are summarized by pathogen for both groups in table 6. Patients who were cured or improved at the posttherapy visits were scheduled to return for a poststudy visit 31–38 days after receipt of the first dose of study medication. At this poststudy visit, 7 (4.3%) of 164 patients in the 750-mg group and 2 (1.2%)

of 166 patients in the 500-mg group were initially thought to have experienced clinical relapses (P p .10 , by 2-sided Fisher’s exact test). Upon detailed examination, 5 patients were conTable 5. Clinical success rates for the clinically evaluable population at the 7–14-day posttherapy visit, according to the Pneumonia Severity Index (PSI) score. n/N (%) b

Patient category

750-mg group (n p 198)

a

500-mg groupc (n p 192)

95% CId

Evaluable patients 183/198 (92.4) 175/192 (91.1) ⫺7.0 to 4.4 Stratum Ie Total

69/76 (90.8)

73/86 (84.9)

⫺16.5 to 4.7

PSI class IIIf

44/49 (89.8)

44/51 (86.3)

⫺17.2 to 10.2

PSI class IVg

25/27 (92.6)

27/32 (84.4)

0/0 (0.0)

2/3 (66.7)

h

PSI class V i

Stratum II

⫺26.1 to 9.6 Not applicable

114/122 (93.4) 102/106 (96.2) ⫺3.4 to 9.0

a

No. of patients in the category with clinically successful treatment/no. of patients in the category (%). b Levofloxacin, 750 mg q.d. iv or po for 5 days. c Levofloxacin, 500 mg q.d. iv or po for 10 days. d Two-sided 95% CI around the difference (10-day levofloxacin regimen minus 5-day levofloxacin regimen). e PSI classes III, IV, and V combined. f PSI score, 71–90. g PSI score, 91–130 h PSI score, 1130. i PSI classes I and II combined.

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Table 6. Clinical success rates, by pathogen of primary interest, identified in ⭓5 clinically evaluable patients at the 7–14-day posttherapy visit. n/N (%)a 750-mg groupb

500-mg groupc

Haemophilus influenzae

12/13 (92.3)

13/14 (92.9)

Haemophilus parainfluenzae

12/12 (100.0)

9/10 (90.0)

Streptococcus pneumoniae

20/22 (90.9)

18/20 (90.0)

Chlamydia pneumoniae

20/22 (90.9)

16/16 (100.0)

Legionella pneumophila

11/11 (100.0)

3/3 (100.0)

Mycoplasma pneumoniae

41/43 (95.3)

34/36 (94.4)

Pathogen class, species Typical pathogen

d

Atypical pathogen

e

a

No. of patients infected with the pathogen who had a clinical response of “cure” or “improvement”/no. of patients infected with the pathogen (%). b Levofloxacin, 750 mg q.d. iv or po for 5 days. c Levofloxacin, 500 mg q.d. iv or po for 10 days. d Identified from respiratory-specimen cultures. e Identified using serologic tests.

sidered to have new infections rather than relapses (2 patients from the 500-mg group had microbiologically confirmed new infections, and 3 patients from the 750-mg group had clinically confirmed new infections). The remaining 4 patients, all of whom were in the 750-mg group, were classified as having relapses solely on the basis of clinical and radiographic criteria. Microbiologic efficacy. Of the 158 pathogens isolated at study entry for which susceptibility data were available, 157 (99.4%) were fully susceptible to levofloxacin. The levofloxacin MIC90 values for H. influenzae (0.03 mg/mL), H. parainfluenzae (0.125 mg/mL), and S. pneumoniae (1.0 mg/mL) were less than the susceptibility breakpoint of 2.0 mg/mL. One pathogen (Pseudomonas aeruginosa recovered from a respiratory-secretion culture) had intermediate susceptibility (MIC, 4.0 mg/mL). Microbiologic eradication rates for pathogens commonly isolated at study entry are presented in table 7. At the posttherapy visits, eradication rates for these common respiratory pathogens were similar for both groups. Of the 6 S. pneumoniae isolates recovered from sputum samples (3 in each study arm) that were characterized as not eradicated after therapy, 2 (1 in each arm) were confirmed to have “persisted,” whereas the remaining 4 were classified as “presumed persisted.” Both patients with persistent pathogens were classified as having clinical cures, and neither pathogen acquired resistance during therapy. S. pneumoniae bacteremia was identified in 14 patients (ITT population). In the 750-mg group, 7 cases of pneumococcal bacteremia were identified, none of which were confirmed to have persisted after treatment. In the 500-mg group, 7 cases of pneumococcal bacteremia were also identified. One case was labeled as “persisted.” The MIC of the causative organism remained unchanged (1 mg/mL). Symptom resolution. Improvement of CAP-related symp-

toms (fever, chills, shortness of breath, cough, pleuritic chest pain, and purulent sputum) at day 3 of therapy was compared for the 2 groups. By day 3 of therapy, 67.4% of patients in the 750-mg group reported subjective resolution of fever, compared with 54.6% of patients in the 500-mg group (P p .006, by 2sample McNemar’s test). This statistically significant difference existed for objectively measured temperatures as well. By day 3 of therapy, 49.1% of patients in the 750-mg group had defervescence, compared with 38.5% of patients in the 500-mg group (P p .027). Shortness of breath and purulent sputum also trended toward more-rapid resolution with the 750-mg dose than with the 500-mg dose, but not to a statistically significant degree. No differences between the 2 groups were found with regard to the presence of chills, cough, or pleuritic chest pain at day 3. Safety. Safety data were available for 256 patients who received at least one 750-mg dose of levofloxacin and for 265 patients who received at least one 500-mg dose of levofloxacin (table 8). The incidence of treatment-emergent adverse events, regardless of relationship to the study drug, was similar for the 2 groups (95% CI, ⫺6.8 to 10.5). The most common adverse events in the 750-mg group were headache (8.6% of patients), nausea (8.6%), insomnia (7.0%), constipation (5.1%), and vomiting (5.1%). In the 500-mg group, the most common adverse events reported were insomnia (10.6% of patients), diarrhea (6.0%), headache (5.7%), and nausea (5.7%). The most common drug-related adverse events in the 750-mg group were nausea, rash, and aggravation of CAP symptoms, whereas rash, insomnia, and diarrhea were most common in the 500mg group. The most frequently reported serious adverse event in both the 750-mg group (3.5% of patients) and 500-mg group (3.4% of patients) was worsening CAP. None of the deaths reported in this study were considered to be related to study drug treatment.

DISCUSSION In this study, we demonstrated that treatment with 750 mg of levofloxacin per day for 5 days is at least as effective and well tolerated as treatment with 500 mg of levofloxacin per day for 10 days for the treatment of mild to severe CAP. The clinical success rate for the 750-mg group (92.4%) was comparable to the clinical success rate for the 500-mg group (91.1%; 95% CI, ⫺7.0 to 4.4). These rates are similar to those observed in previous controlled trials evaluating levofloxacin for CAP [14–16]. Of note, patients in the 750-mg group were more likely to have defervescence by day 3 of therapy than were patients in the 500-mg group (P p .006). It is important to acknowledge some limitations of this study. First, there were fewer enrolled patients in PSI stratum I than

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Table 7. Microbiologic eradication rates at the 7–14-day posttherapy visit in the microbiologically evaluable population. n/N (%) Pathogen

750-mg groupb (n p 103)

a

500-mg groupc (n p 92)

95% CId

Aerobic Gram-positive

24/29 (82.8)

29/34 (85.3)

⫺17.4 to 22.4

Gram-negative

51/53 (96.2)

39/43 (90.7)

⫺16.8 to 5.7

Other pathogens Total by pathogen Total by patiente

61/65 (93.8)

50/52 (96.2)

⫺6.5 to 11.1

136/147 (92.5)

118/129 (91.5)

⫺7.9 to 5.8

96/103 (93.2)

85/92 (92.4)

⫺8.6 to 7.0

Typicalf Haemophilus influenzae

12/13 (92.3)

12/14 (85.7)

⫺33.8 to 20.6

Haemophilus parainfluenzae

12/12 (100.0)

9/10 (90.0)

⫺33.6 to 13.6

Streptococcus pneumoniae

19/22 (86.4)

17/20 (85.0)

⫺25.1 to 22.4

Atypicalg ⫺6.0 to 24.2

Chlamydia pneumoniae

20/22 (90.9)

16/16 (100.0)

Legionella pneumophila

11/11 (100.0)

3/3 (100.0)

Not applicable

Mycoplasma pneumoniae

41/43 (95.3)

34/36 (94.4)

⫺12.1 to 10.3

a

No. of patients infected with the pathogen who had a microbiologic response of “eradication” or “presumed eradication”/no. of patients infected with the pathogen (%). b Levofloxacin, 750 mg q.d. iv or po for 5 days. c Levofloxacin, 500 mg q.d. iv or po for 10 days. a Two-sided 95% CI around the difference (10-day levofloxacin regimen minus 5-day levofloxacin regimen) in microbiologic eradication rates for pathogens identified in ⭓10 patients in each group. b Eradication of all pathogens identified at study entry. f Identified from respiratory-specimen cultures. g Identified using serologic tests.

in stratum II (tables 4 and 5). Although patients with a PSI score of 1130 were excluded from the study, patients with PSI scores of 170 but ⭐130 were enrolled and not limited. Also of note is the relatively large number of CAP cases attributed to M. pneumoniae (tables 6 and 7), which is generally understood to have a less severe presentation. These observations may limit the ability to generalize the study results to all patients with CAP. Despite these observations, clinical response rates, microbiological eradication rates, poststudy relapse rates, and adverse event rates were similar for both groups for all pathogens isolated and for all severity classes. Of the 14 cases of bacteremia due to S. pneumoniae identified in this study, a single case (in the 500-mg group) was labeled as microbiologically “persisted.” This determination was made by culture of a blood sample that was obtained when the patient, who was PSI class IV at study entry, was deemed to have had treatment failure and was withdrawn from the study by the investigator after receiving study medication for !48 h. The MIC of the isolated organism was 1.0 mg/mL on both determinations. In a recent review of 98 cases of CAP-associated pneumococcal bacteremia from phase III and IV clinical trials, including 8 cases of bacteremia due to penicillin-resistant S. pneumoniae, there were no cases of persistent pneumococcal

bacteremia after treatment with 500 mg of levofloxacin for 7– 14 days [17]. The majority (199%) of pathogens identified at study entry were fully susceptible to levofloxacin in vitro. Broad-based, national surveillance studies have demonstrated that clinical isolates of S. pneumoniae, H. influenzae, and M. catarrhalis in the United States continue to be highly susceptible to levofloxacin (⭓99% of isolates) [18–20]. In addition, the MIC90 of levofloxacin against S. pneumoniae (1.0 mg/mL) has remained stable for the past 5 years (1998–2002) [7]. Resistance to antimicrobial agents is often the result of suboptimal dosing. To identify optimal dosage regimens, the pharmacokinetics and pharmacodynamics of a drug should be considered. Levofloxacin is a concentration-dependent bactericidal agent; therefore, therapeutic success is linked to AUC/MIC and Cmax /MIC rather than to time of concentration greater than the MIC. A high Cmax /MIC has also been associated with the prevention of the emergence of resistance. In an in vitro pharmacodynamic model, it was demonstrated that, in fact, 750 mg of levofloxacin exhibited more rapid and complete killing of ciprofloxacin-resistant strains of S. pneumoniae with elevated MICs than did the 500-mg dose [21]. The 750-mg dose of levofloxacin increases the AUC /MIC and Cmax/MIC by in-

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Table 8. Overall safety results in a study of 2 levofloxacin regimens for treatment of community-acquired pneumonia. No. (%) of patients Outcome

750-mg groupa (n p 256)

500-mg groupb (n p 265)

95% CIc

148 (57.8)

158 (59.6)

⫺6.8 to 10.5

18 (7.0)

15 (5.7)



25 (9.8)

37 (14.0)



18 (7.0)

22 (8.3)



5 (1.9)

9 (3.4)



d

⭓1 treatment-emergent adverse event ⭓1 drug-related adverse event ⭓1 serious adverse event

e

f g

Discontinuation due to adverse event Deathh a

Levofloxacin, 750 mg q.d. iv or po for 5 days. Levofloxacin, 500 mg q.d. iv or po for 10 days. c Two-sided 95% CI around the difference (10-day regimen minus 5-day regimen). d Any adverse event that was new in onset after study initiation or any adverse event that increased in intensity or frequency during the study period. e Any treatment-emergent adverse event assessed by the investigator as probably or very likely related to study drug. f Any treatment-emergent adverse event that was fatal, immediately life-threatening, required or prolonged inpatient hospitalization, caused permanent or significant disability, was a congenital anomaly, or was deemed medically important. g This included 3 patients for whom treatment with the drug was stopped because of an adverse event but who were indicated as discontinuing study because of “clinical failure” or “other” reason, as determined by the investigator. h Any death that occurred from study entry to the post study visit is included. b

creasing peak concentrations. This may optimize therapeutic outcomes by hastening bacterial demise and reducing the risk for selection of resistant organisms. Peak levofloxacin concentrations with the 750-mg dose are increased in the plasma and in intrapulmonary compartments. The mean maximum steady-state levofloxacin concentration (4 h postdose) in epithelial lining fluid was 9.9 mg/mL with 500mg dosing, compared with 22.1 mg/mL with 750-mg dosing. In alveolar macrophages, mean maximum concentrations of 97.9 mg/mL and 105.1 mg/mL were noted for 500-mg and 750mg doses, respectively [22]. These higher concentrations with the 750-mg dose maximize AUC/MIC and Cmax/MIC at key sites of microbial killing of both extracellular (S. pneumoniae) and intracellular (L. pneumophila and C. pneumoniae) pathogens in pulmonary infections [22]. With few exceptions, the duration of therapy for infectious processes has been empirical. Several factors argue in favor of reducing therapy to the shortest duration that is effective; these include cost, patient compliance, and the potential to reduce the occurrence of adverse events. A fourth reason, however, is at least as important. Any treatment strategy that decreases the amount of antibacterials used could theoretically decrease resistance selection. In this study, despite the increase in daily levofloxacin dose to 750 mg, total drug exposure during the 5-day CAP treatment course was reduced to 3750 mg—a 25% reduction, compared with the 10-day regimen of 500 mg per day. The 750-mg daily dose coupled with a shorter duration of therapy could optimize therapy by capitalizing on levoflox-

acin’s concentration-dependent properties while at the same time decreasing total drug exposure. Use of 750 mg of levofloxacin is possible because of its wide therapeutic index [23–26]. To date, ∼800 patients have received 750 mg of levofloxacin intravenously or orally in ongoing or completed phase III clinical trials. In addition, the 750-mg dose has been approved for complicated skin and skin structure infections and nosocomial pneumonia. No significant difference in safety from the 500-mg dose has been reported [27, 28]. In our study of patients with mild-to-severe CAP, 750 mg of levofloxacin per day for 5 days was as safe and well tolerated as 500 mg per day for 10 days. The rates of all treatmentemergent adverse events, drug-related adverse events, and serious adverse events, regardless of relationship to study drug, were comparable for both groups. The types and rates of treatment-emergent adverse events observed in both groups were consistent with the well-characterized safety profile of levofloxacin. In summary, the short-course (5 days), high-dose (750 mg q.d.) regimen of levofloxacin was at least as effective and well tolerated for the treatment of mild to severe CAP as 500 mg of levofloxacin per day for 10 days. It is possible to increase peak concentrations of levofloxacin by increasing the daily dose to take advantage of its pharmacodynamic properties, while at the same time shortening the duration of drug exposure and total dose exposure, without compromising efficacy or safety in the management of CAP.

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Acknowledgments

We would like to thank the Short-Course CommunityAcquired Pneumonia Study investigators for their contribution to this work. We also thank Nicola Dahl, Angela Gagliano, and Susan Singer for their assistance in the preparation of this manuscript. Statistical and other analyses were performed by OrthoMcNeil Pharmaceutical.

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E R R AT U M

An error appeared in the 15 September 2003 issue of the journal (Dunbar LM, Wunderink RG, Habib MP, Smith LG, Tenneberg AM, Khashab MM, Wiesinger BA, Xiang JX, Zadeikis N, Kahn JB. High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin

Infect Dis 2003; 37:752–60.) In table 4, the letters for footnotes c and d were reversed. Footnote c should read “PSI score, ⭐70,” and footnote d should read “PSI score, 170 but ⭐130. Five patients with a PSI score of 1130 are included in this stratum.” The journal regrets this error.

Clinical Infectious Diseases 2003; 37:1147  2003 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2003/3709-0028$15.00

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