Cefaclor

In this multicenter, observer-blinded study, 301 patients with signs and symptoms of acute bacterial exacerbation of COPD were randomized (2:1) to receive either cefpodoxime proxetil (200 mg, bid) or cefaclor (250 mg, tid) for 10 days. Clinical and microbiologic evaluations were performed before treatment, during therapy study days 3 to 5), at the end of therapy (3 to 7 days posttreatment), and at long-term follow-up (4 weeks posttreatment). The most common pretreatment isolates were Haemophilus influenzae, Haemophilus parainfluenzae, and Streptococcus pneumoniae. Significantly (p <0.001) more bacterial isolates were susceptible in vitro to cefpodoxime (233 of 256, 91 percent) than to cefaclor (215 of 255, 84 percent). There were no statistically significant differences between the two drug regimens in eradication of the initial pathogen (cefpodoxime, 116 of 128, 91 percent; cefaclor, 59 of 64, 92 percent) or end-of-therapy clinical response (cure + improved; cefpodoxime, 99 of 100, 99 percent; cefaclor, 45 of 49, 92 percent) rates for evaluable patients. Both drug treatments were well-tolerated, with a similar incidence of drug-related adverse events (cefpodoxime 11 percent, cefaclor 12 percent). Cefpodoxime (bid) was as safe and effective as cefaclor (tid) in the treatment of acute exacerbation of COPD. The less frequent dosing regimen of cefpodoxime may improve patient compliance compared to those antibiotics that require three or four daily doses.

(Chest 1993; 104:1387-92) MIC = minimum inhibitory concentration

Chronic obstructive pulmonary disease is a general term for respiratory disorders, including asthma, emphysema, and chronic bronchitis, that decrease air flow. Acute bacterial infections of the respiratory tree in patients with COPD are common and associated with significant morbidity and mortality, often due to respiratory failure.[1,2]

Since pathogenic organisms may not be isolated from up to 50 percent of purulent sputum samples from patients with acute exacerbation of COPD, antibiotic therapy is often based on likely pathogens rather than the isolation of any specific causative agent(s).[3] Pathogens commonly associated with acute exacerbation of COPD have demonstrated increasing resistance to traditional therapies for respiratory infections. Therapeutic agents for acute exacerbation of COPD must, therefore, be effective against a wide range of pathogens including Streptococcus pneumoniae and [beta]-lactamase positive and negative strains of Haemophilus influenzae, Moraxella catarrhalis, and Haemophilus parainfluenzae.[6]

Cefpodoxime proxetil is an orally administered prodrug of cefpodoxime, an extended-spectrum cephalosporin.[,15] Cefpodoxime proxetil's methoxymethyl radical and esterified carboxyl function facilitate its gastrointestinal absorption and hydrolysis in the gastrointestinal mucosa to the active drug, cefpodoxime.[7] In vitro, cefpodoxime is active against pathogens commonly associated with exacerbation of COPD and is resistant to hydrolysis by [beta]-lactamases.[7,10] Levels of cefpodoxime demonstrated in plasma (2.2 [mu]g/ml), lung tissue (0.63 mg/kg), and sputum (0.16 [mu]g/ml) following a 200-mg free acid equivalent dose exceed the minimum inhibitory concentration [(MIC).sub.90] of common respiratory pathogens.[11-13] The results of preliminary studies indicate that cefpodoxime proxetil is a promising agent for the treatment for respiratory infections. This study was designed to compare the safety and efficacy of cefpodoxime proxetil in the treatment of acute bacterial exacerbation of COPD to that of cefaclor, another oral cephalosporin accepted as effective treatment for patients with both lower and upper respiratory tract infections.

Methods

Patient Population

Males and nonpregnant, non-breast-feeding women aged [is greater than or equal to] 18 years with a body weight [is greater than or equal to] 40 kg were eligible for this study if they presented with signs and symptoms indicative of acute exacerbation of COPD, including cough, fever (>37.7 [degrees] C, oral), or increased sputum production/purulent sputum and absence of pulmonary infiltrate on chest radiograph. Both hospitalized patients and outpatients were eligible for this study. Patients were excluded if they suffered from a severe respiratory tract infection that required parenteral antibiotic treatment; had hypersensitivity to cephalosporins or a history of anaphylaxis or severe reaction to penicillin; had received antimicrobial therapy within the previous 5 days, unless resistance to the previous treatment was documented by microbiologic susceptibility testing; were neutropenic (WBC <2,000 [mm.sup.3]); had moderate to severe renal impairment (serum creatinine >2.5 mg/dl) or hepatic dysfunction (SGOT >200 IU/L or total bilirubin >3.0 mg/dl); suffered from significant immunologic/neoplastic disease or severe vascular insufficiency; had a gastrointestinal disorder that might have affected absorption of study drug; were enrolled in any other investigational protocol or had been enrolled previously in a cefpodoxime proxetil study; or in women with child-bearing potential, were not practicing an acceptable contraceptive method. All patients, or if incompetent, their guardians, provided signed written informed consent prior to the initiation of any study-specific procedures.

Study Design

Patients were randomly assigned (2:1) to receive either cefpodoxime proxetil (tablet; equivalent of 200 mg cefpodoxime bid) or cefaclor (capsule; Ceclor, Eli Lilly; 250 mg tid) for 10 days. At admission (study day 0), written consent and medical history were obtained and the following evaluations performed: physical examination with vital signs, clinical laboratory tests (blood chemistry, platelets/differential, urinalysis with microscopic examination), pregnancy test if applicable, chest radiograph (posteroanterior, lateral), respiratory tract culture (and/or blood culture)/gram stain, susceptibility testing of isolated pathogens, and evaluation of clinical signs and symptoms. Evaluations of vital signs, clinical laboratory parameters, clinical status, and clinical signs and symptoms were repeated during therapy (study days 3 to 5), at the end of therapy (days 3 to 7 posttreatment), and at long-term follow-up (4 weeks after completion of therapy). Any laboratory finding that was abnormal at long-term follow-up was monitored until resolved. Physical examinations were repeated only at the end-of-therapy visit. Respiratory tract culture (and/or blood culture) with Gram stain and susceptibility testing of isolated pathogens were optional during therapy but were repeated at the end-of-therapy visit, as well as at long-term follow-up if recurrent symptoms were present.

Microbiologic Cultures and Susceptibility Testing

Specimens were obtained for aerobic culture, Gram stain, and susceptibility testing. Acceptable specimens included expectorated sputum with <10 squamous endothelial cells and >25 WBCs per high power field, transtracheal aspirate, protected brush endoscopic brushings, or blood culture isolates.

Isolated organisms were tested for susceptibility to study drugs according to the procedures of the National Committee for Clinical laboratory Standards (NCCLS).[17] Susceptibilities on the basis of zone diameter inhibition were defined" as follows: cefpodoxime (10 [mu]g/disk) - susceptible [is greater than or equal to] 21 mm, moderately susceptible 18 to 20 mm, resistant [is greater than or equal to] 17 mm; cefaclor (30 [mu]g/disk) - susceptible [is greater than or equal to] 18 mm (H influenzae [is greater than or equal to] 24 mm), moderately susceptible 15 to 17 mm (H influenzae 19 to 23 mm), resistant [is less than or equal to] 14 mm (H influenzae [is less than equal to] 18 mm).

Pathogens were also sent to a central microbiology laboratory at Thomas Jefferson University (Philadelphia) for MIC determinations. When disk zone inhibition information was not available, MIC data were used to determine evaluability based on criteria recommended by NCCLS[17] (cefaclor: susceptible [is less than or equal to] 8 [mu]g/ml, moderately susceptible 16 [mu]g/ml, resistant [is greater than or equal to] 32 [mu]g/ml) and those proposed by Jones and Barry[15] (cefpodoxime: susceptible [is less than or equal to] 2 [mu]g/ml, moderately susceptible 4 [mu]g/ml, resistant [is greater than or equal to] 8 [mu]g/ml). Only those patients with pretreatment pathogen(s) determined to be susceptible or moderately susceptible to their assigned study drug were retained in the study.

Statistical Analyses

All patients administered study medication were considered evaluable for safety analyses. To be considered evaluable for efficacy analyses, patients were required to have had the following: no major deviations from inclusion/exclusion criteria, radiographic absence of pulmonary infiltrate, a pretreatment culture taken [is less than or equal to] 3 days prior to the first dose of study drug, bacterial pathogen(s) isolated at admission from respiratory tract or blood culture that was susceptible or moderately susceptible to the assigned study drug, taken at least 80 percent of the assigned medication without missing two consecutive doses of cefpodoxime or three consecutive doses of cefaclor, treatment with study drug for at least 7 consecutive days (responders) or [is greater than or equal to] 3 days (nonresponders), evaluated 2 to 8 days after completion of therapy (interim and long-term follow-up evaluations were not required), and not used nonstudy systemic antimicrobials between study admission add end-of-therapy evaluation (except failures).

Primary efficacy parameters included clinical outcome, end-of-therapy microbiologic response, and microbiologic outcome for each pathogen. Clinical outcome was defined as clinical cure (complete disappearance or return to baseline of signs and symptoms), clinical improvement (significant improvement but not complete resolution of signs and symptoms), clinical failure (little or no response to therapy at study completion or time of withdrawal), or recurrence (requirement for antimicrobials between end-of-therapy and long-term follow-up visit). Patients who received another antimicrobial agent due to inadequate response by end of therapy were considered to be failures. Clinical outcomes were determined independently of microbiologic outcomes. Microbiologic response was defined as microbiologic cure (all evaluable pathogens eradicated, or no culturable material, or nonpurulent sputum), microbiologic partial cure (eradication of at least one, but not all, initial pathogens in cases of polymicrobial infections), or microbiologic failure (initial pathogen[s] not eradicated). Microbiologic outcome for each pathogen was defined as eradication (culture negative or unobtainable due to improvement/cure), recurrence (eradication at end of therapy with recurrence of same pathogen at long-term follow-up), or superinfection (isolation of new pathogen[s] from initial site of infection during or immediately after therapy).

Safety parameters that were monitored included changes in vital signs, results of clinical laboratory assays, and adverse events. Adverse events were classified by the investigators as to seriousness, severity (mild, moderate, or severe), and relationship to study drug (drug-related: reasonable possibility that the event was caused by the study drug).

All statistical tests were two-sided with p levels <0.05 considered to indicate statistical significance. All variables were analyzed using the model: result=mean (overall treatment mean)+treatment (effect of study drug) + error (random error symmetric about zero). Analysis of variance (ANOVA) was used to analyze age, height, weight, pretreatment vital signs, and continuous laboratory variables. The method of weighted least squares was used to compute test statistics for evaluability rate, race, sex, end-of-therapy microbiologic and clinical cure rates, and end-of-therapy microbiologic eradication rates. Ordered responses were computed using a mean s(,ore response function,[19] while responses that could not be ordered were computed using a logit model.[20] A Fisher's exact test for 2 x 2 tables was computed for medical history frequencies and pretreatment physical examination abnormalities. Fisher's exact tests were also used to analyze adverse event data. A [chi.sup.2] analysis was computed for severity of initial infection and in vitro susceptibility categories. Primary efficacy parameters were analyzed using ANOVA and confidence limit intervals. When normal ranges for clinical laboratory parameters were not supplied by each investigator's laboratory, normal ranges were taken from Halstead and Halstead.[21]

Results

Patient Population

A total of 301 patients, 194 administered cefpodoxime proxetil and 107 administered cefaclor, were enrolled in the study and included in the safety analyses. Among patients evaluable for safety, there were no significant differences between the two drug groups in demographics, infection severity, medical history, or physical examination abnormalities noted at admission. Approximately one half of the patients in both drug groups completed treatment as planned (cefpodoxime 111 of 194, 57 percent; cefaclor 56 of 107, 52 percent). The most common reason for premature study discontinuation was ineligibility after the start of study medication (cefpodoxime 65 of 194, 34 percent; cefaclor 39 of 107, 36 percent), generally as a result of a negative pretreatment culture.

No significant difference in the number of patients evaluable for efficacy analyses between cefpodoxime (100 of 194, 52 percent) and cefaclor (49 of 107, 46 percent) treatment groups was observed. The two most common reasons for nonevaluability were negative pretreatment cultures (cefpodoxime 66 of 194, 34 percent; cefaclor 39 of 107, 36 percent), and resistant pathogens (cefpodoxime 15 of 194, 8 percent; cefaclor 13 of 107, 12 percent). Evaluable patients in the two treatment groups were similar in age, weight, race, and infection severity (Table 1). Ninety-seven percent of cefpodoxime and 92 percent of cefaclor-evaluable patients received therapy for 10 or 11 days.

Microbiologic Results

Two hundred fifty-nine pathogens were isolated from all patients, with the most common isolates being H influenzae, H parainfluenzae, and S pneumoniae. The types of pathogens isolated were similar to those observed in other studies involving patients with acute exacerbation of chronic bronchitis.

In vitro susceptibility test results were reported for 256 isolates against cefpodoxime and 255 isolates against cefaclor. In vitro susceptibility results are based primarily on MIC criteria and secondarily on disk zone size. Significantly more (p<0.001) pretreatment isolates were susceptible and moderately susceptible to cefpodoxime than to cefaclor (233 of 256, 91 percent vs 215 of 255, 84 percent, respectively). Twenty-three pretreatment isolates (9 percent) were resistant to cefpodoxime, whereas 40 isolates (16 percent), including 6 strains of H influenzae, were resistant to cefaclor. Results for selected individual pathogens are listed in Table 2. The [MIC.sub.100] of cefpodoxime was lower than that of cefaclor against S pneumoniae, H influenzae ([beta]-lactamase positive or negative), and H parainfluenzae ([beta]-lactamase negative) isolates.

End-of-therapy eradication rates for pathogens in evaluable patients were similar between cefpodoxime proxetil (116 of 128, 91 percent) and cefaclor (59 of 64, 92 percent). Eradication rates for the most commonly identified pathogens are listed in Table 3.

There were no significant differences in end-of-therapy microbiologic outcomes of the two treatment groups. After microbiologic evaluation, 90 of 100 (90 percent) cefpodoxime-treated patients were considered cured, 7 of 100 (7 percent) partially cured, and 3 of 100 (3 percent) failed; the values for cefaclor-treated patients were 44 of 49 90 pereent), 2 of 49 (4 percent), and 3 of 49 (6 percent), respectively Evaluable patients presenting with a single pathogen had a higher microbiologic cure rate than those with multiple pathogens in both treatment groups.

Fifteen evaluable patients (10 of 100 evaluable cefpodoxime patients [10 percent]) 5 of 49 evaluable cefaclor patients [10 pereent]) had bacterial persistence at the end-of-therapy evaluation. Pathogens isolated from these patients at the end of therapy were still susceptible to both study drugs, except for a Citrobacter diversus isolate (resistant to both drugs by disk zone), an Acinetobacter anitratus isolate (resistant to cefpodoxime by both disk zone and MIC), and an Enterobacter cloacae isolate (resistant to cefaclor by MIC but not disk zone). These resistant pathogens were isolated from cefpodoxime-treated patients evaluated as clinically cured or improved at the end of therapy.

Maintenance of eradication from the end of therapy to long-term follow-up in evaluable patients was not significantly different between drug groups (cefpodoxime 96 of 96, 100 percent; cefaclor 47 of 50, 94 percent). Recurring pathogens in the cefaclor group were Streptococcus morbillorum, S pneumoniae, and [beta]-lactamase negative H influenzae. Twelve cefpodoxime-treated patients (12 percent) and 13 cefaclor-treated patients (27 percent) were diagnosed with superinfections at the interim or end-of-therapy visit.

Clinical Results

Most patient's cough, intensity of dyspnea, and sputum production and/or purulence decreased during the course of the study regardless of therapy. At the end of therapy, there were no sigificant differences in positive clinical response (cure + improved) rate (cefpodoxime 99 of 100, 99 percent; cefaclor 45 of 49, 92 percent) or in distribution of clinical outcomes between the two drug treatments. For the cefpodoxime-treated group, 65 of 100 patients (65 percent were evaluated as having had a clinical cure; 34 (34 percent) as showing clinical improvement; and I patient (1 percent) was considered a clinical failure. For the cefaclor-treated group, 28 of 49 (57 percent) patients were considered cured; 17 (35 percent) improved; and 4 (8 percent) failed. The sole clinical failure in the cefpodoxime group involved Escherichia coli; clinical failures in the cefaclor group involved S pneumoniae, S morbillorum, H influenzae ([beta]-lactamase negative), H parainfluenzae ([beta]-lactamase negative), and Serratia liquefaciens.

Recurrence at long-term follow-up was similar between the two drug groups, with 18 percent (16 of 90) of cefpodoxime-treated patients and 14 percent (6 of 43) of cefaclor-treated patients experiencing a recurrence of symptoms.

Safety Profile

There were no significant differences observed in the number of patients experiencing a drug-related adverse event (cefpodoxime 22 of 194, 11 percent; cefaclor 13 of 107, 12 percent) or in the number of drug-related adverse events (cefpodoxime 32, cefaclor 15) between the two treatment groups. Gastrointestinal complaints were the most commonly reported drug-related adverse events for both drug groups. There were no significant differences observed between treatment groups in the number of patients reporting drug-related gastrointestinal events (cefpodoxime 17 of 194, 9 percent; cefaclor 3 of 107, 3 percent). percent), diarrhea (cefpodoxime 10 of 194, 5 percent; cefaclor 3 of 107, 3 percent), or nausea (cefpodoxime 5 of 194, 3 percent; cefaclor 3 of 107, 3 percent).

The majority of drug-related events were mild or moderate for both treatment groups. One cefpodoxime patient reported severe diarrhea and stomach cramps. Four patients (3 cefpodoxime, 1 cefaclor) discontinued the study due to drug-related adverse events (cefpodoxime: nausea/vomiting, headache, abdominal cramps/diarrhea; cefaclor: nausea/heartburn/perioral numbness).

Changes consistent with resolution of infection were observed in vital signs and clinical laboratory parameters. Seven patients (five cefpodoxime, two cefaclor) experienced potentially clinically significant changes in laboratory values (increased SGOT, WBC, platelets) that appeared during the course of the study; the relationship of these abnormal values to study therapy is not known.

DISCUSSION

Chronic obstructive pulmonary disease is the fifth most frequently reported cause of death in the United States.[22] Bacterial exacerbation of COPD is associated with declines in respiratory function and significant morbidity and mortality; however, precise identification of causative pathogens through sputum culture is not possible in as many as 50 percent of the patients.[3] For example, in the present study, 35 percent of the patients had negative sputum cultures despite signs and symptoms consistent with acute bacterial exacerbation of COPD. Traditionally, therefore, acute exacerbation of COPD would be treated by the prompt initiation of broad-spectrum antibiotic therapy, with such agents as ampicillin, amoxicillin/clavulanate, ciprofloxacin, cefaclor, tetracycline, or trimethoprim/sulfamethoxazole.[6] Although recommended protocols using traditional agents are usually effective,[6] in recent years, pathogens commonly associated with acute exacerbation of COPD have increasingly become resistant to many of these therapies.[4,5] Continued development of new antimicrobial agents and improvement of currently available agents (eg, broad-spectrum cephalosporins) are, therefore, essential in order to minimize the effects of acute exacerbation of COPD through adequate antimicrobial therapy.

Cefpodoxime proxetil, a new orally administered prodrug of the extended-spectrum cephalosporin cefpodoxime, has a broad spectrum of in vitro activity against those pathogens commonly found in patients with exacerbation of COPD. In the present study, the [MIC.sub.100] of cefpodoxime was lower than that of cefaclor against S pneumoniae, H influenzae ([beta]-lactamase positive or negative), and H parainfluenzae isolates. In addition, significantly more bacterial isolates were susceptible in vitro to cefpodoxime than to cefaclor.

In the present study, cefpodoxime proxetil therapy resulted in excellent eradication of infecting pathogens (91 percent), including S pneumoniae, H influenzae, M catarrhalis, and H parainfluenzae, as well as excellent microbiologic cure rates (90 percent) and positive clinical response rates (99 percent). In addition, cefpodoxime proxetil administered twice a day was as effective as treatment with cefaclor three times a day.

Dosage frequency is an important determinant of drug compliance.[23,24] For example, in a study in which pill containers recorded medication usage, compliance rose from 59 percent on a tid regimen to 84 percent on a bid regimen.[23] Cefpodoxime proxetil's bid dosing regimen may help to improve compliance over antibiotic regimens that require more frequent dosing.

Compliance may also be influenced by the incidence and severity of side effects. In the present study, cefpodoxime and cefaclor were equally well tolerated. The most frequent side effects of either medication were gastrointestinal complaints of the type and frequency usually associated with oral antibiotics.

A potential limitation of any clinical trial is the population size. To ensure that we obtained sufficiently large samples (cefpodoxime- and cefaclor-treated patients), we generated a series of power curves. We used the assumptions that the true probability of success with cefaclor is 0.9 and the number of evaluable patients given cefpodoxime would be twice the number given cefaclor. With the sample sizes attained (100 evaluable cefpodoxime-treated patients and 49 evaluable cefaclor-treated patients), we calculated that the probability of correctly concluding that the rate of success for cefpodoxime proxetil is not more than 15 percent less than for ceclor was 0.89.

In summary, cefpodoxime proxetil is a safe and effective treatment for acute exacerbation of COPD. In this study, cefpodoxime and cefaclor were equally tolerated and demonstrated similar efficacy with regard to pathogen eradication, as well as positive clinical and microbiologic patient responses. Moreover, a significantly greater number of pathogens isolated before treatment were susceptible or moderately susceptible in vitro to cefpodoxime than to cefaclor.

REFERENCES

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