Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study

CLINICALTHERAPEUTICSVVOL.19, NO. 5, 1997

Sparfloxacin Versus Cefaclor in the Weatment of Patients with Community-Acquired Pneumonia: A Randomized, Double-Masked, Comparative, Multicenter Study Gerald R. Donowitz, iWD,l Milan L. Brandon, MD,2 John I? Salisbury, MD,3 Colleen I? Harmun RN,’ Dime M. lXpping, MS,4 Ann E. Urick, RN,dand George H. Talbot, iW@ ‘Division of Infectious Diseases, University of Wrginia, Charlottesville, Mrginia, 2Califomia Research Foundation, San Diego, California, 3Eatontown Medical Association, Eatontown, New Jersey, and 4RhGne-Poulenc Rorer Pharmaceuticals, Inc., Collegeville, Pennsylvania

ABSTRACT Community-acquired pneumonia remains an important infectious disease problem, with more than 4 million cases occurring in the United States annually. Although Streptococcus pneumoniae remains the most commonly identified organism, a variety of bacterial and nonbacterial pathogens may be involved. Hospitalization is unnecessary in most cases, and oral antibiotic therapy is common. In the majority of cases, the etiology of pneumonia is unknown at the time of presentation, necessitating the use of empiric therapy. Quinolones have not been utilized in this setting in the past because of their inconsistent coverage of S pneumoniae. Sparfloxacin (RP 64206) is a broad-spectrum fluoroquinolone with excellent activity in vitro against the majority of bacteria involved in community-acquired pneumonia, including pneurnococcus. We therefore studied the efficacy and safety of sparfloxacin compared with the sec936

ond-generation cephalosporin cefaclor as empiric therapy for patients with community-acquired pneumonia in a doublemasked, double-dummy, multicenter trial. Three hundred thirty patients aged 18 years or older with community-acquired pneumonia suspected of being bacterial in etiology were enrolled at 74 centers in the United States from June 1, 1992, to March 4, 1995. Patients meeting the inclusion criteria were randomized to receive 10 days of either sparfloxacin 400 mg orally once followed by sparfloxacin 200 mg orally daily (n = 168), or cefaclor 500 mg orally every 8 hours (n = 162). There were no significant differences between groups with regard to baseline characteristics. Patients were followed up serially at 4 f 1 days, 20 -c 3 days, and 38 f 7 days after the beginning of therapy. Patients were evaluated for clinical response, clinical recurrence of infection, and eradication of baseline pathogens. The primary efficacy variable was the clinical response (cured or improved) in the subgroup of patients 0149-2918/97/$3.50

G.R. DGNOWllZ ET AL.

meeting the definition of clinically assessable. Responses were also evaluated in the intent-to-treat population. In the intent-to-treat population, 35.7% of patients receiving sparfloxacin were clinically cured, compared with 32.1% of patients receiving cefaclor. Clinical successes (patients clinically cured plus improved) were also comparable (72.6% of patients in the sparfloxacin group and 71 .O% of patients in the cefaclor group). Similar clinical success rates were noted using only the clinically assessable population (primary efficacy variable). Forty-four percent of patients receiving sparfloxacin and 39.1% of patients receiving cefaclor were clinically cured. In the sparfloxacin group, 86.6% of patients were clinical successes, compared with 84.4% of patients in the cefaclor group. Microbiologic cures were comparable in both groups. There was no difference in the incidence of recurrence of infection or superinfection. Adverse events thought to be due to study drug occurred equally in both groups (14.3% in the sparfloxacin group vs 14.8% in the cefaclor group). Results show that sparfloxacin is ‘a safe and effective empiric therapy for patients with community-acquired pneumonia and is comparable to cefaclor. Key wurtfs: bacterial pneumonia, anti-infective agents, fluoroquinolone, sparfloxacin. INTRODUCTION Community-acquired pneumonia remains a common infectious disease. An estimated 4 million cases occur annually, accounting for more than 500,000 hospitalizations.’ Pneumonia is the sixth most common cause of death in the United States and the most common infectious cause of death2 In the preantibiotic era, 80% of cases of pneu-

monia were caused by Streptococcus pneunwniae. Although pneumococcus remains the single most common bacterium isolated in patients with community-acquired pneumonia, many other pathogens have been identified as etiologic agents, including Haemophilw injluenzae, Moraxella catarrhulis, and Legionella pneunwphila.” Staphylococcus aureus remains an important pathogen in episodes of pneumonia occurring after influenza infections.6 In addition, “atypical” agents such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Chlamydia psittaci, as well as

respiratory viruses, have been shown to account for almost 50% of episodes of ambulatory community-acquired pneumonia.7 Because the etiology of pneumonia is rarely defined at the time of presentation, empiric therapy is the rule. Selecting appropriate antibiotics is a clinical challenge because of the number of possible etiologic agents and because the distinction between typical bacterial and “atypical” etiologies is not evident in clinical presentation or in laboratory and radiographic findings at the time of diagnosis.8*g A variety of treatment strategies have been developed to make logical choices for empiric therapy. The American Thoracic Society has stratified patients according to age, presence of comorbid disease, and likelihood that a bacterial pathogen rather than an atypical agent is present.‘O The use of therapeutic models has been complicated by the increasing incidence of penicillin-resistant S pneumoniae.11*12 Because the majority of patients with community-acquired pneumonia do not require hospitalization, oral cephalosporins or beta-la&am-beta-lactamase inhibitor combinations have been used commonly in association with macrolide-azalide compounds if atypical agents cannot be 937

CLINICALTHEFUF’EUTICS~

excluded. Until recently, quinolone use has not been popular because of inconsistent coverage of even penicillin-susceptible strains of S pneunwniae. Sparfloxacin (RP 64206) is a broadspectrum fluoroquinolone that has excellent in vitro activity against most of the important agents associated with community-acquired pneumonia. 13,14Ninety percent minimum inhibitory concentrations (MIC,,s) of 0.25 to 0.5 pg/mL against S pneumoniae have been noted, including strains resistant to penicillin. MIC,,s of 0.008 to 0.03 l&nL have been observed for beta-lactamase-producing strains of H injluenzae and M catarrhalis. MICs of 0.06 pg/mL have been noted for Lcgionella micdadei. Against atypical pathogens, MICs of 0.06 to 0.25 pg/mL for C pneumoniae and 0.1 l&nL for M pneumoniae have been reported. These data, as well as the demonstration that sparfloxacin diffuses into respiratory tract secretions and is concentrated in alveolar macrophages, have made it an attractive agent for use in patients with communityacquired pneumonia.15 Results from animal models of pneumonia and initial human evaluations confirm sparfloxacin’s efficacy as therapy for pneumonia.‘“19 The present study was designed to study the efficacy and safety of sparfloxacin as empiric therapy for patients with presumed bacterial community-acquired pneumonia compared with the secondgeneration cephalosporin cefaclor. PATIENTS AND METHODS This was a double-masked, doubledummy, randomized, comparative trial conducted at 74 centers in the United States during the period from June 1, 1992, to March 4, 1995. 938

Inclusion/Exclusion

Criteria

The study population consisted of patients 18 years of age or older with community-acquired pneumonia suspected to be bacterial in origin because of acute onset of cough and purulent or mucopurulent sputum production. Study participants were required to have the following: (1) a Gram’s stain of sputum showing >25 neutrophils and
G.R. DONOWITZ ET AL.

tients with a history of convulsive disorders, gastrointestinal disorders, severe hepatic disease with cholestasis, creatinine clearance <30 mL/min, or conditions causing immune suppression, as well as patients receiving concomitant medications that would interfere with absorption of oral medication. Two additional exclusion criteria require special comment. Initially, patients with a baseline corrected QT interval (QT,) YMO ms were excluded from participation because Phase I studies and preclinical data showed that sparfloxacin produces a small (approximately 3%) increase in QT, interval.20 In October 1993 the protocol was amended to exclude only those patients with a baseline QT, >500 ms. In addition, this amendment relaxed the level at which patients with an elevated QT, during therapy would be discontinued from the study, from 2500 ms or an increase of 15% above baseline to 2550 ms. In November 1994 these exclusion criteria were eliminated completely. Patients with congenital prolonged QT syndrome or conditions that could be proarrhythmic and patients taking concomitant drugs known to cause QT prolongation were excluded throughout the study period. The process for evaluation of sparfloxacin’s QT, effect has been published elsewhere.20 The protocol was also amended in October 1993 to exclude patients from the study who had a history of photosensitivity with quinolones or who could not minimize their exposure to sunlight while taking the therapy. In addition, all enrolled patients were advised to avoid even indirect sun exposure, to use sunblock lotions if sun exposure was unavoidable, and to discontinue study drug therapy at the first sign of photosensitivity.

Patients meeting the inclusion criteria were randomized to receive 10 days of either sparfloxacin 400 mg orally once and then 200 mg orally daily, or cefaclor 500 mg orally every 8 hours. Study medications were packaged in masked “dose packs,” with a specifically numbered dose pack assigned at randomization. Each dose pack contained the assigned active drug and placebo tablets that were identical in appearance to the study drug not assigned. A baseline evaluation was performed on all patients before randomization. Sputum was obtained for Gram’s staining. An unstained slide of the sputum and a portion of the sputum specimen were sent to a central laboratory (SciCor Inc., Indianapolis, Indiana) for Gram’s staining and culture. In addition, a blood sample for chemistry and hematology testing and a throat swab for Chkzmydiu culture were sent to the central laboratory. A chest radiograph (posteroanterior and lateral views) and a 12lead electrocardiogram (ECG) were obtained. A blood culture was obtained in patients with an oral temperature >38.6 “C or when clinically indicated, in the investigator’s judgment. A pregnancy test was performed when applicable. Patients were then randomized and given the first 5 days of their study medication in a dose pack. Patients were given an appointment to return to the clinic for three subsequent visits (figure). Patients were seen on day 4 f 1 of therapy (visit 2) for evaluation of compliance, interim response to therapy, and interim development of adverse events. On day 20 f 3 (posttreatment day 10 f 3, visit 3), patients were evaluated for clinical response to therapy. On day 38 f 7 (visit 4), patients were evaluated for recurrence or re939

CLINICALTHERAF’EUTICS’

Visit 1 (Day 1)

Baseline evaluation Medication dispensed for days l-5

-1 -1 Visit 2 (Day4f 1) “1 d d Study drug discontinued Failure to respond Adverse events Diagnosis not confirmed

d

1

Evaluation for: Compliance interim response Development of adverse events Medication dispensed for days 8-l 0

-1 1 1 1 .J Visit 3 (Day 20 f 3)

Evaluation of clinical response

.L 4 Visit 4 (Day 38 f 7)

Evaluation for recurrence

Figure. Flow chart of study procedures. lapse. A clinical examination was performed at each visit, and sputum was collected, if possible, for Gram’s staining and culture. A chest radiograph was repeated at visit 3 and, if it had not returned to premorbid condition, again at visit 4. A 12lead ECG and laboratory tests were repeated at visits 2 and 3 and again at visit 4 if clinically indicated. Study drug was discontinued at visit 2 if any of the following conditions were met: (1) QT, elevated to 2500 ms or an increase of 15% above baseline or, from October 1993 to November 1994, QT, elevated to 2550 ms; (2) formal interpretation of the baseline chest radiograph did not confii the diagnosis of pneumonia; (3) results of Gram’s staining performed by the central laboratory did not meet in940

clusion criteria; (4) the patient was not improving with therapy; (5) the isolated etiologic pathogen was found to be resistant to either of the study drugs, and the clinical signs of pneumonia had not improved; or (6) treatment-limiting adverse events were experienced. Patients who met the inclusion criteria but whose sputum culture failed to grow a pathogen were allowed to remain in the study. Sputum samples were sent to the central laboratory for Gram’s staining and culture. MIC determinations were performed for any bacterial pathogens. In addition to sputum cultures, the following diagnostic procedures were used to identify atypical etiologic agents: (1) Legionella infection was defined by a positive sputum culture, a positive urine

G.R. DONOWlTZ ET AL.

antigen test or a positive DNA probe of sputum, a fourfold rise in serum immunoglobulin G (IgG) titer to 21:128, or a progressive fourfold decrease in IgG titer in the absence of a pathogen identified by culture. (2) A4pneumoniae was defined by a positive sputum culture, a single serum immunoglobulin M (IgM) titer of 21: 16, a fourfold increase in serum IgG, or a progressive fourfold decrease in IgG titer in the absence of a pathogen identified by culture. (3) C pneumoniae and Cpsittaci were defined by a positive throat swab culture, a single serum IgM titer of 21:20, a single Cpneumoniae IgG titer of 21:512, or a fourfold increase in serum IgG. A progressive fourfold decrease in IgG titer was accepted in the absence of a pathogen identified by culture. Response to therapy was determined at visit 3 or at the time the patient was dropped from the study before visit 3. Clinical response to therapy was classified as cure, improvement, failure, or indeterminate. Cure was defined as resolution of all signs and symptoms of pneumonia, with no new signs or symptoms associated with the original infection, and stabilization, improvement, or resolution at visit 3 (or at dropout before visit 3) of the abnormalities noted on the visit 1 chest radiograph. Improvement was defined as resolution or reduction of the majority of signs and symptoms of pneumonia, with no new or worsened signs or symptoms associated with the original infection, and stabilization, improvement, or resolution at visit 3 (or at dropout before visit 3) of the abnormalities noted on the visit 1 chest radiograph. Failure was defined as no resolution and no reduction in a majority of signs and symptoms of pneumonia, or worsening of one or more signs or symptoms, or new signs or symp-

toms associated with the original infection or a new infection, or worsened findings on chest radiograph compared with visit 1, or addition of antimicrobial therapy for this infection before or at visit 3. A classification of indeterminate was used whenever response to therapy could not be assessed. Superinfection was defined as emergence of an organism not present at baseline, accompanied by signs and symptoms of pneumonia. A second efficacy evaluation was done at visit 4 to assess sustained response to therapy. Patients were evaluated for recurrence or relapse. Recurrence was defined as new or worsened signs and symptoms of pneumonia and a stabilized or worsened chest radiograph in a patient who was cured or improved at visit 3. Relapse was defined as reappearance of a baseline pathogen that had been previously eradicated, accompanied by signs and symptoms of infection. The primary efftcacy variable was the clinical response rate at visit 3 (or dropout before visit 3). This analysis was performed for both the clinically assessable and the intent-to-treat populations. Additional efficacy variables included the clinical recurrence rate in both the clinically assessable and the intent-to-treat populations and the by-pathogen eradication rate. Statistical Analysis

Sample size calculations were based on a two-sided 95% confidence interval (CI,,) method of establishing equivalence of two proportions, with an assumed clinical response success rate (cured plus improved) of 90% in the cefaclor group. It was determined that 190 clinically assessable patients per treatment group would be required to have an 80% prob941

CLINICAL THER4F'EUTlCS'

ability of showing that sparfloxacin did not differ from cefaclor by more than 10% in either direction. Given an expected attrition rate of approximately 10% and a clinical assessability rate of 90%, total study enrollment was estimated a priori at 470 patients. During the course of the study, it was determined that based on the observed masked clinical response for both treatment arms combined, the final rates would be less than 90%. Therefore, enrollment was discontinued when an estimated 300 clinically assessable patients had been enrolled. The two-sided CI,, on the treatment difference was used to establish equivalence between sparfloxacin and cefaclor for the efficacy analyses. The primary efficacy variable was the clinical response (cured or improved), using an analysis of the subgroup of patients meeting the definition of clinically assessable. Clinical response was also analyzed using the intent-to-treat population. Treatment groups were assessed for comparability of demographic variables and baseline characteristics using twoway analysis of variance (ANOVA) for continuous variables and the Cochran-MantelHaenszel test for categoric variables. ECGs were analyzed using a two-way ANOVA model. Overall adverse events incidences and response rates by pathogen were analyzed using Fisher’s exact test. RESULTS

Three hundred thirty patients were enrolled and randomized, 168 in the sparfloxacin group and 162 in the cefaclor group. All patients receiving study medication were considered eligible for an intent-to-treat analysis. There were no significant differences between the groups 942

with regard to age, sex, body weight, or race distribution. A summary of patient demographic characteristics is presented in Table I. There were no significant differences between groups with respect to baseline characteristics, including smoking status and number of pack-years smoked, alcohol use and gram-per-day intake, and underlying disease (including chronic obstructive pulmonary disease, diabetes mellitus, coronary artery disease, congestive heart failure, and other lung diseases). Signs and symptoms of pulmonary infection were similar in both groups (Table II). A statistically significant difference was observed between the two groups with respect to fever (2101 “F orally) documented at the time of enrollment, with fewer patients in the sparfloxacin group having fever at study entry (11.9%) when compared with the cefaclor group (19.8%) (P = 0.032). Response to lheatment Response to therapy was equivalent for the treatment groups, in both the intent-totreat population and the population meeting the definition of clinically assessable. Sixty (35.7%) of the 168 patients in the intent-to-treat population who received sparfloxacin were clinically cured, compared with 52 (32.1%) of 162 patients who received cefaclor (CI,,, -6.6 to 13.8). Sixty-two patients (36.9%) receiving sparfloxacin and 63 patients (38.9%) receiving cefaclor were clinically improved (CIss, -12.4 to 8.5). The clinical success rate (cured plus improved) was also comparable: 72.6% (122 of 168) for the sparfloxacin group versus 71.0% (115 of 162) for the cefaclor group (CIs5, -8.1 to 11.3). Twenty-two patients in each

G.R. DONOWlTZET AL.

Table I. Demographic characteristics. Characteristic

Sparfloxacin (n = 168)

Cefaclor (n = 162)

48.0 18-89

50.9 18-103

93 (55.4) 75 (44.6)

101 (62.3) 61 (37.7)

136 (81.0) 28 (16.7) 0 (0.0) 4 (2.4) 64 (38.1)

128 (79.0) 26 (16.0) 2 (1.2) 6 (3.7) 53 (32.7)

59 (35.1) 47 (28.0) 62 (36.9) 57 (33.9)

56 (34.6) 34 (21.0) 72 (44.4) 43 (26.5)

Treatment Croup Comparison

0.224’

Age (~1

Mean Range Sex, n (%) Male Female Race, n (%) white Black Oriental Hispanic Underlying diseaset Cigarette use Current Past Never Alcohol use

P

0.239+

0.509+

‘Two-way analysis of variance on ranks. ~Generalized Co&au-Mantel-Haenszel test. *Including chronic obstructive pulmonary disease, coronary artery disease, congestive mellitus, and other lung disease.

group-13.1% of patients receiving sparfloxacin and 13.6% of patients receiving cefaclor-were failures (C&,s,-7.8 to 6.8) (Table III). Twenty-four patients receiving sparfloxacin (14.3%) and 25 patients receiving cefaclor (15.4%) had a clinical response of indeterminate, in which the clinical outcome could not be determined. When these patients were eliminated from the efficacy analysis, the clinical success rate was similar in both groups: 84.7% (122 of 144) in the sparfloxacin group and 83.9% (115 of 137) in the cefaclor group (C&, -7.7 to 9.3). Two hundred sixty-two patients (134 receiving sparfloxacin and 128 receiving

0.255+ 0.260+

0.078+

heart failure, diabetes

cefaclor) met the criteria for being clinically assessable. Reasons for excluding patients from the clinically assessable analysis included inaccurate diagnosis of pneumonia (negative baseline chest radiograph or a baseline sputum Gram’s stain that did not meet the inclusion criteria) or failure to complete all visit 3 or dropout procedures for assessment of clinical response within 4 to 26 days after the last dose. In addition, patients were excluded who received less than 2 full days of study drug or who missed more than 20% of active doses of study drug. Also excluded were patients who received nonstudy systemic antimicrobial therapy within the 3 943

CLINICAL

Table II. Clinical signs and symptoms

of pulmonary

infection

THERAPEUTICS”

at baseline.

No. (%) of Patients

Sign/Symptom Present

Sparfloxacin

Cefaclor

No. of patients Fever Rigor Pulmonary consolidation Cough Shortness of breath Sputum production Pleuritic chest pain

168 20 (11.9) 66 (39.3) 90 (53.6) 168 (100) 140 (83.3) 168 (100) 110 (65.5)

162 32 (19.8)’ 51 (31.5) 92 (56.8) 162 (100) 126 (77.8) 162 (100) 107 (66.0)

‘P = 0.032, cefaclor versus spartloxacin.

Table III. Results at test-of-cure

assessment

(intent-to-treat

Response

Sparfloxacin (n = 168)

Cefaclor (n = 162)

Clinical cure Improved Cure + improved Failure Indeterminate

60 (35.7%) 62 (36.9%) 122 (72.6%) 22 (13.1%) 24 (14.3%)

52 (32.1%) 63 (38.9%) 115 (71.0%) 22 (13.6%) 25 (15.4%)

days before starting the study drug or at any time during the study period before completing visit 3. Patients were excluded who were found to have any condition that would interfere with the evaluation of clinical response (eg, lung cancer or other pulmonary disease). Patients with a clinical response of failure were included in the clinically assessable group even if they failed to meet the criteria for clinical assessability. Results of analysis of clinical response in the clinically assessable population were consistent with the results obtained

944

population). 95% Confidence Interval -6.6 -12.4 -8.1 -7.8 -8.8

to to to to to

13.8 8.5 11.3 6.8 6.6

in the intent-to-treat analysis. Fifty-nine (44.0%) of the 134 clinically assessable patients who received sparfloxacin were clinically cured, compared with 50 (39.1%) of 128 assessable patients who received cefaclor (CI,,, -7.0 to 16.9). One hundred sixteen patients (86.6%) receiving sparfloxacin had a clinical response of cured or improved, compared with 108 patients (84.4%) in the cefaclor group (C&, -6.3 to 10.7). A clinical response of failure was observed in 18 patients ( 13.4%) receiving sparfloxacin and 20 patients (15.6%) receiving cefaclor.

G.R. DGNOWI’IZET AL. Eradication of Pathogens

Two hundred ninety-six patients in the intent-to-treat population-15 1 in the sparlloxacin group (89.9%) and 145 in the cefaclor group (89.5%)-had at least one pathogen isolated from baseline sputum cultures. Treatment groups were equivalent with regard to eradication of pathogens. One hundred fifteen sparlloxacin patients (76.2%) and 100 cefaclor patients (69.0%) had documented or presumed eradication of baseline pathogens (CJ,s, -2.9 to 17.3). Eradication was presumed when there was no material available for culture at a postbaseline visit, with a corresponding clinical response of cured or improved. Seventeen sparfloxacin patients and 13 cefaclor patients had documented eradication of the baseline pathogen, and 98 sparfloxacin patients (64.9%) and 87 cefaclor patients (60.0%) had presumed eradication. There were 219 pathogens isolated at baseline in the sparfloxacin group, and 192 baseline pathogens isolated in the cefaclor group. Haemophilus parainfluenzae was the most frequently isolated organism in both groups. This organism was present in 64 cultures (42.4% of patients with a baseline pathogen receiving sparlloxacin) and 52 cultures (35.9% of patients with a baseline pathogen receiving cefaclor). H in&enzae, M pneumoniae, and S pneumoniae were the next most frequently isolated organisms in both groups. Baseline pathogens and the percent eradication are shown in Table IV. In patients receiving sparfloxacin, 88.6% of the pathogens isolated at baseline were eradicated or presumed eradicated compared with 81.8% in the cefaclor group (P = 0.068). Spneumoniae was isolated from 5 1 cultures at baseline. All isolates were susceptible to sparfloxacin by MIC testing.

The majority of the isolates were also susceptible to cefaclor, with two isolates moderately susceptible and two isolates resistant to cefaclor. Blood cultures were obtained in 23 patients (9 sparfloxacin and 14 cefaclor patients), but no organisms were isolated. Recurrence of Symptoms, Relapse, and Super-infection

In the intent-to-treat population, no difference between groups was noted in the incidence of recurrence of symptoms of infection or in the incidence of relapse documented by culture. Of the 122 patients in the sparfloxacin group and 115 patients in the cefaclor group who had responded to therapy at visit 3, 101 patients in the sparfloxacin group and 104 patients in the cefaclor group were assessable at visit 4. Development of new pulmonary processes, antibiotic use for nonpulmonary infection, and loss to follow-up accounted for the difference in assessable patients between visits 3 and 4. Three (3.0%) of 101 patients in the sparfloxacin group and 2 (1.9%) of 104 patients in the cefaclor group who were cured or improved at visit 3 (“test of cure” visit) had a recurrence of signs and symptoms of infection at a later visit. (Data pertaining to recurrence of infection were unavailable in 21 patients in the sparfloxacin group and 11 patients in the cefaclor group who were lost to follow-up or had conditions that precluded evaluation.) Relapse was noted in a single patient. The patient had received cefaclor and demonstrated eradication of the baseline pathogen, Neisseria meningitidis, at visit 3. Subsequently, the organism reappeared, accompanied by signs and symptoms of 945

CLINICAL THERAPEUTICS’

Table lV. Bacteriologic response at test-of-cure assessment (intent-to-treat population). No. of Eradicated or Presumed Eradicated/No. Isolated (%) Pathogen

All baseline pathogens Haemophilus parainjluenz_ae Haemophilus injluenzae Mycoplasma pneunwniae* Streptococcus pneumoniaetS Penicillin-sensitive

Sparfloxacin

Cefaclor

P

194/219 (88.6)

157/192 (81.8)

0.068

58164 (90.6) 25130 (83.3) 27/30 (90.0) 28/30 (93.3)

40152 (76.9) 29137 (78.4) 23127 (85.2) 19/21 (90.5)

0.069 0.759 0.697 AI.99

22/23 (95.7)

17/19 (89.5)

Intermediate penicillin resistance

4/5 (80.0)

Penicillin-resistant

l/l (100)

l/l (100) l/l (100)

Chlamydia pneumoniae’ Chlamydia sp Staphylococcus aureus Streptococcus sp (other than S pneumoniae)

1 l/14 (78.6) 313 (100)

6/7 (85.7) 919 (loo)

313 (loo) 415 (80.0) 313 (100)

Gram-negative aerobes

24129 (82.8)

29137 (78.4)

0.761

313 (loo)

o/o

NAS

Legionella pneumophila group”

7/7 (100)

0.521 NAO NAO NAO

NA = not available.

*Resultsobtained by serology. +No isolate was available for susceptibility testing for one patient. *Sensitive: minimum inhibitory concentration (MIC) I 0.06 &I& sistant: MIC 2 2 p,g/mL. *Numbers too small for analysis. ‘identified by urinary antigen (1 patient) or culture (2 patients).

pneumonia. (Incidence of relapse could not be determined in 57 sparfloxacin patients and 55 cefaclor patients.) Five patients (two sparfloxacin and three cefaclor) had superinfections. The superinfecting organisms included two isolates of H infuenzae and one isolate each of H parainfuenzae, Streptococcus pyogenes, and S aureus. In 11 patients (1 sparfloxacin and 10 cefaclor), organisms not present at baseline were isolated from a later culture but without accompanying signs or symptoms of pneumonia. 946

intermediate: MIC = 0.01-l

p,g/mL; re-

Safety Adverse events occurring during the study period that were determined by the investigators to be possibly or probably related to study drug are shown in Table V. Adverse events considered by the investigator to be related to study medication occurred in 14.3% of the sparfloxacin group and 14.8% of the cefaclor group (P >0.99). Overall, the most commonly reported event was diarrhea, which was reported in 1.8% of the sparfloxacin group and 4.3% of the cefaclor group. No single

G.R. DGNOWll-2 ET AL.

Table V. Safety summary. No. (%) of Patients

Adverse Event No. of patients with an adverse event* Photosensitivity reaction Preamendment Postamendment Digestive system Nausea Diarrhea Nervous system Cardiovascular system QT interval prolonged Adverse events leading to discontinuation* Adverse laboratory events Most common Elevated ALT Elevated APT Blood glucose (increased/decreased)

Sparfloxacin (n = 168) 24 (14.3) 4 (2.4) 2l58 (3.4) 2/110 (1.8) 10 (6.0) 3 (1.8) 3 (1.8) 5 (3.0) 3 (1.8) 2 (1.2) 3 (1.8) 18 (10.7) 9 (5.4) 8 (4.8) 4 (2.4)

Cefaclor (n = 162) 24 (14.8) 1 (0.6) 0155 (0) l/107 (0.9) 11 (6.8) 4 (2.5) 7 (4.3) 5 (3.1) 1 (0.6) 1 (0.6) 2 (1.2) 14 (8.6) 6 (3.7) 5 (3.1) 1 (0.6)

ALT = alanine transaminase;APT = aspartatetraasaminase. *Possibleor probable relationship to therapy as assessed by the investigator.

adverse event was reported at an incidence of 25% in either treatment group. The low incidence of specific adverse events occurring in each group precludes any meaningful comparison between groups. Nineteen patients, 11 in the sparfloxacin group (6.5%) and 8 in the cefaclor group (4.9%), experienced adverse events that led to study discontinuation. Of these, only three patients receiving sparfloxacin and two patients receiving cefaclor had adverse events that were considered by the investigator to be possibly or probably related to study drug therapy. Photosensitivity reactions were observed in four patients in the sparfloxacin group (2.4%) and one patient in the cefaclor group (0.6%) (P = 0.177). All five pa-

tients were white. For patients enrolled in this study before October 1993 (when the protocol was amended regarding risk of photosensitivity), the percentage of patients who experienced a photosensitivity reaction was 3.4% (2 of 58) in the sparfloxacin group versus 0% in the cefaclor group. The reactions in the sparfloxacin group were classified as mild (one patient) and severe (one patient) by the investigators. The frequency of photosensitivity reaction in sparfloxacin patients enrolled on or after October 25,1993, was 1.8%. After the amendment, one severe reaction and one mild reaction were noted in patients receiving sparfloxacin. One moderate photosensitivity reaction was noted in a patient receiving cefaclor.

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Prolonged QT interval occurred in 3 patients, 2 (1.2%) in the sparfloxacin group and 1 (0.6%) in the cefaclor group. The mean change from baseline to maximum on treatment value for QT, was 0.006 f 0.003 seconds in the sparfloxacin group and 0.001 f 0.003 seconds in the cefaclor group (P = 0.142). Four patients died during the study period, three patients in the sparfloxacin group and one patient in the cefaclor group. None of the deaths were attributed to study drug by the investigator. DISCUSSION Therapy for patients with communityacquired pneumonia remains a significant clinical challenge because of the large number of potential etiologic agents and the fact that both bacterial and nonbacterial pathogens may be involved. The increasing number of penicillin- and macrolide-resistant strains of S pneumoniue has further complicated the problem. This double-masked, double-dummy, multicenter study was designed to examine the efficacy and safety of sparfloxacin against bacterial etiologies of communityacquired pneumonia versus an accepted standard therapy. Several points concerning the design of the present study are important to note. First, because of the difficulty of identifying pneumonia caused by nonbacterial pathogens using clinical and radiographic data available at the time of enrollment, small numbers of atypical pneumonias were included in both groups. This reflects the reality of therapy for patients with community-acquired pneumonia in which both bacterial and nonbacterial etiologies may play a role. Cases were evaluated for both bacterial and atypical 948

pathogens, although the emphasis of the study was on bacterial pathogens. Second, definition of microbial etiology depended on the identification of a predominant pathogen from sputum. Although more rigid definitions have been used in previous studies (eg, isolation of etiologic agents from blood or pleural effusions, bronchoscopy or bronchial alveolar lavage with quantitative cultures of bronchoscopic samples, or transtracheal aspiration), Gram’s stain examination and culture of expectorated sputum remains the usual method for initial assessment of patients with pneumonia.4y21y22Third, as noted previously, 74 centers were involved in patient accrual. To minimize bias in postrandomization evaluation of patients, an intent-to-treat analysis was performed in addition to the analysis of patients meeting the criteria for clinical assessability. No difference between groups was noted in either analysis. Finally, the study was powered to meaningfully assess equivalence of the primary efftcacy variable, clinical response to tberapy in the clinically assessable population. Other variables such as toxicity were examined, but the number of patients accrued was generally too small to identify significant differences between groups for any single adverse reaction. Sparfloxacin was shown to be as effective as cefaclor in producing clinical cure or improvement (72.6% vs 71.0%, respectively) in patients with communityacquired pneumonia. The overall response rate for sparfloxacin in this study was somewhat lower than that reported in earlier European studies, in which success rates of 82% to 91% were reported.‘&t9 Although study design and patient selection were similar, only 35% to 55% of episodes in the previous series were mi-

G.R. DONOWITZ ET AL.

crobiologically documented, making interpretation of the differing success rates difficult. It is probably important to note that in both previous series as well as in the present study, success rates with sparfloxacin were comparable to those observed with control regimens. Quinolones have not been widely used to treat respiratory infections in which S pneumoniae was thought to have a role. The MICs of ciprofloxacin for S pneumoniue are borderline at 1 to 2 &mL. Although clinical success rates of more than 90% have been reported for ciprofloxacin against pneumococcal infections in some series,23v24others have reported success rates of only 35%. 25 Furthermore, persistence rates of 42% have been observed when ciprofloxacin has been used to treat pneumococcal infections. Ofloxacin has lower MICs against pneumococcus, but clinical data remain scant.26 Sparfloxacin, in contrast, is effective in treating patients with community-acquired pneumonia caused by S pneumoniae, with an overall eradication rate of 93% in this study and success rates of 78% to 86% in treating patients with pneumococcal pneumonia in previously published studies.16-19 Based on in vitro data and animal models, sparfloxacin would be expected to be effective in treating infection caused by S pneumoniae that shows intermediate or complete resistance to penicillin. Although eradication rates of 80% to 100% were observed in our study, the number of isolates was too small to address this issue meaningfully. A variety of series have examined the in vitro and in vivo activity of sparfloxacin against agents causing the atypical pneumonia syndrome, including Chlamydia species and M pneumoniae. In vitro, sparfloxacin has demonstrated activity

against C psittaci, Chlamydia trachomatis, and C pneumoniae, with MICs of 0.063 p,g/mL. 27,28In a mouse model,28 survival rates with sparfloxacin therapy were comparable to those with minocycline therapy and superior to those with clarithromycin and other quinolones. MICs of 0.063 pg/mL for sparfloxacin against M pneumoniae have been demonstrated, compared with 0.016 pg/mL for erythromycin and 0.5 &mL for minocycline.29 In animal models sparlloxacin appeared at least as effective as erythromycin.29These data suggest that sparlloxacin should be an excellent drug for treatment of patients with atypical pneumonia. This study was designed to study pneumonias of bacterial etiology, but it was inevitable that pneumonia due to atypical agents would be included. Sparfloxacin eliminated 87% of the agents of atypical pneumonia in this study. This success rate is comparable to that noted in previous studies, in which 93.5% of atypical agents were eradicated.1G19,30In the present series, similar rates of elimination were noted with cefaclor, an agent that has no proven efficacy against either Mycoplasma or Chlamydia species. Interestingly, similar results have been noted in other series using comparator agents that have no clear efficacy against agents causing atypical pneumonia.17J8 Spontaneous resolution of disease may be playing a role, making it difficult to interpret sparfloxacin’s efficacy in this setting. However, sparfloxacin’s efftcacy in treating atypical pneumonia is comparable to that of erythromycin and other macrolides, which are accepted treatments.19*30 Both sparfloxacin and cefaclor appeared to be equally well tolerated, with possibly or probably drug-related adverse events noted in only approximately 949

CLINICAL THERAPEUTICS@

14% of patients. Gastrointestinal disturbances, the most common side effect, were noted in approximately 6% of patients in both groups. Neither prolongation of QT, interval nor photosensitivity reactions emerged as important complications of therapy in this trial. Enrollment was interrupted temporarily in October 1993 because of data from other sparfloxacin studies indicating an unacceptably high rate of photosensitivity reactions. Interim analysis of ongoing North American trials showed approximately a 7% incidence of sparfloxacin-associated photosensitivity. Rates at sites at high altitudes approximated 20%.31 In European Phase III trial~,~l primarily conducted in inpatients, sparfloxacin was associated with photosensitivity in 1.9% of patients. Moderate-to-severe phototoxic reactions were reported in patients exposed to direct or indirect sunlight, including shaded light and exposure through glass. The incidence of photosensitivity reactions in patients receiving sparfloxacin in this study was 3.4% before the amendment of the protocol and 1.8% after the protocol was amended to decrease the risk of photosensitivity reactions. More rigid screening of patients with histories of photosensitivity and increased protection from sun exposure may account for these findings, which implies that proper instructions can minimize the incidence of this adverse event. CONCLUSIONS Overall, sparfloxacin is a well-tolerated and effective oral therapy for patients with community-acquired pneumonia. Its demonstrated efficacy against the common bacterial agents involved, including S pneumoniae, should allow its use as empiric monotherapy in patients with com950

munity-acquired pneumonia when bacterial pathogens are suspected. Although data from this study alone do not prove that sparfloxacin provides adequate coverage for atypical agents, the aggregate experience in other series suggests that sparfloxacin is effective monotherapy for patients with community-acquired pneumonia in which bacterial and atypical pathogens cannot be differentiated. ACKNOWLEDGMENTS This study was funded by Rh6ne-Poulenc Rorer Pharmaceuticals, Inc., Collegeville, Pennsylvania. Data from the study were presented in part at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 15-18, 1996, New Orleans, Louisiana. The authors would also like to thank Mary Beth Dorr and Kim Granito at RhBne-Poulenc Rorer for their help with the preparation of this manuscript. The efforts of the study group and their study coordinators are gratefully acknowledged. Study investigators included the following: Lawrence K. Alwine, DO; Mohamed Al-Ibrahim, MD; Sadri Avsar, MD; George Bensch, MD; Wayne Beuford, MD; M.G. Kim Bloom, MD; Fred K. Branditz, MD; Milan L. Brandon, MD; Jerry W. Bush, MD; Sammy C. Campbell, MD; Dana Cemea, MD; Alan M. Chausow, MD; Selwyn A. Cohen, MD; Frank Cole, MD; David Collins, MD; Gregory Collins, MD; Daniel David, MD; Steven J. D’Amico, MD; Gerald R. Donowitz, MD; Mack Temple Douglas, MD; J.E. Erlandson, MD; John Ervin, MD; Neal Fellers, MD; Bruce Fleegler, MD; Roan L. Flenniken, MD; Frank Garamy, MD; David Ginsberg, DO; Nelson Greene, MD; Dan Henry, MD; William J. Henry

G.R. DGNOWDZ ET AL.

III, MD; Matthew Hilmi, MD; Robert Holloway, MD; Raymond J. Hu, MD; Monroe S. Karetzky, MD; Dean L. Kirby, MD; Judith Kirstein, MD; Steven J. Kulback, MD; John Lalonde, MD; John Matlock, MD; David McColhun, MD; Robert D. McInroy, MD; Nazir A. Memon, MD; Venita Morell, MD; Duaine Murphree, MD; Thomas Nolen, MD; Greg Pape, MD; Stanley C. Parman, MD; Gerald Pierone, Jr, MD; Leslie Riley-&nacho, MD; Jeffrey Rosen, MD; Robert Rosen, MD; Gary E. Ruoff, MD; Jon Salisbury, MD; Silverio M. Santiago, MD; Craig Schultz, DO; Cary Scott, MD; J. Mitchell Simpson, MD; Bernard M. Sklar, MD; David A.Smith, MD; William Smith, MD; Rodney Snow, MD; Irwin Spim, MD; Harry Steinberg, MD; Lance Sterman, MD; J. Christopher Stringer, MD; Frederick A. Tolle, MD; Helen B. Trop, MD; Mark L. Vandewalker, MD; Robert Van Hook, MD; Gilbert Weisman, DO; David B. Wilhelm, MD; Jack Zaremba, MD; Jay Zdunek, DO; and Chris Zuschke, MD.

2. Statistical Abstract of the US. 108th ed. Washington, DC: US Department of Commerce, Bureau of Census; 1988.

Address correspondence to: Gerald R. Donowitz, MD, MR4, #2112, 300 Park Place, University of Virginia Health Sciences Center, Charlottesville, VA 22908.

Woodhead MA, MacFarlane JT. Comparative clinical and laboratory features of Legionella with pneumococcal and Mycoplasma pneumonias. Br J Dis Chest. 1987;81:133-139.

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