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Randomized double-blind trial of the comparative efficacy and safety of cefpodoxime proxetil and cefaclor in the treatment of acute community-acquired pneumonia
CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 9, SEPTEMBER 1994
R A N D O M I Z E D D O U B L E - B L I N D T R I A L OF T H E C O M P A R A T I V E E F F I C A C Y A N D S A F E T Y OF C E F P O D O X I M E P R O X E T I L A N D CEFACLOR IN THE TREATMENT OF ACUTE COMMUNITY-ACQUIRED PNEUMONIA J O N A. G R E E N , 1 T H O M A S BUTLER, 2 AND W E S L E Y M A R K TODD 3
UC Davis School of Medicine, Davis, and the Department of Veterans Affairs, Northern California System of Clinics, Pleasant Hill, California, 2Texas Tech University Health Sciences Center, Lubbock, Texas, and 3The Upjohn Company, Kalamazoo, Michigan
ABSTRACT
A randomized, controlled, double-blind, double-dummy, multicenter study compared the efficacy and safety of cefpodoxime proxetil with that of cefaclor in the outpatient treatment of community-acquired pneumonia. A total of 325 patients received 7 to 14 days of either 200 mg of cefpodoxime as eefpodoxime proxetil twice daily (n = 216) or 500 mg of cefaclor three times daily (n = 109). All study criteria were met by 125 patients (cefpodoxime, 77; cefaclor, 48). Streptococcus pneumoniae and Haemophilus influenzae were the most commonly identified pathogens. Of 198 pathogenic bacteria isolated from sputum, cefpodoxime susceptibility was tested in 178 and cefaclor susceptibility in 181. Isolates were more susceptible to cefpodoxime than to cefaclor (P = 0.001): 94% were susceptible to cefpodoxime and 82% to cefaelor; 3% were moderately susceptible to cefpodoxime and 5% to cefaclor; 3% were resistant to cefpodoxime and 13% were resistant to cefaclor. Clin 1 ical outcome in the two treatment groups was similar: 77% of cefpodoxime-treated patients and 71% of cefaclor-treated patients were cured; 19% of cefpodoxime-treated and 25% of cefaclor-treated patients improved; and 4% of patients in each group were considered treatment failures. Gastrointestinal complaints were the most frequently reported drug-related adverse event (10%) in the cefpodoxime group, and dermatologic problems (5%) were the most commonly encountered drug-related adverse event in the eefaclor group. Overall frequencies of drug-related adverse events were similar (16% for cefpodoxime vs 14% for cefaclor) in the two groups. Cefpodoxime proxetil was as effective and as well tolerated as cefaclor in the outpatient treatment of community-acquired pneumonia. INTRODUCTION
P n e u m o n i a is t h e fifth m o s t f r e q u e n t l y r e p o r t e d c a u s e of d e a t h in t h e U n i t e d S t a t e s . 1 F a c t o r s c o n t r i b u t i n g to m o r t a l i t y include infection c a u s e d b y n o n b a c t e r i a l p a t h o g e n s , s e r i o u s u n d e r l y i n g illness, i m p a i r e d h o s t deAddress correspondence to: Jon A. Green, MD, PhD, 150 Muir Road, Martinez, CA 94553.
Received for publication on June 17, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1003
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EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
fense mechanisms, and delay in the institution of effective antimicrobial therapy. 2 Precise identification of causative infectious agents and their susceptibility to antibiotics is neither practical nor possible in most circumstances, and therapy is essentially empiric, designed to include the known antibiotic sensitivities of common respiratory pathogens. 3 Empiric therapy of community-acquired pneumonia has to include gram-negative bacteria 4 and accommodate the increasing resistance of major respiratory pathogens, particularly Streptococcus pneumoniae and Haemophilus influenzae, to commonly used antibiotics. 5 In recent years S pneumoniae has demonstrated resistance to penicillins and to erythromycin, which are considered by many to be the antibiotics of choice for the initial treatment of community-acquired pneumonia. 6 Continuing changes in the types and antibiotic sensitivity patterns of bacterial respiratory pathogens support the need to identify alternative agents for empiric therapy of communityacquired pneumonia. Cefpodoxime proxetil is an orally administered, broad-spectrum thirdgeneration cephalosporin, with many characteristics that make it suitable for the oral outpatient treatment of community-acquired pneumonia. Patient compliance is likely to be enhanced by twice-daily dosing and the requirement that cefpodoxime be taken with food rather than on an empty stomach. 7 Cefpodoxime is active in vitro against common respiratory pathogens such as H influenzae and S pneumoniae, including isolates resistant to penicillin antibiotics. S'9 In adults, plasma levels of cefpodoxime reach 2.2 ~g/mL after a 200-mg dose of cefpodoxime administered as cefpodoxime proxetil, a pro-drug that is hydrolyzed to free cefpodoxime by the gastrointestinal mucosa. 1° Oral administration of cefpodoxime proxetil produces lung tissue cefpodoxime concentrations of 0.63 mg/kg, 11 which exceed the minimum inhibitory concentration (MIC) of common pneumonia-causing pathogens. The present study was conducted to compare the efficacy and safety of orally administered cefpodoxime proxetil and cefaclor in the outpatient treatment of culture-proven acute community-acquired pneumonia. PATIENTS
AND METHODS
Patient Population Male and female patients aged/>14 years with signs and symptoms indicative of acute community-acquired pneumonia (radiographic evidence of pulmonary infiltrate, Gram's stain indicating purulent sputum, and cough or fever) were enrolled in the study. Female patients were required not to be pregnant or breast-feeding and to have a negative pregnancy test within 8 hours of enrollment and receipt of study drug. Patients 1004
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were excluded if t h e y had hypersensitivity to cephalosporins, cephamycins, or penicillin; neutropenia (leukocytes <2000/mm3), moderate-tosevere renal impairment (serum creatinine >2.5 mg/dL), or hepatic dysfunction (serum g l u t a m i c - p y r u v i c t r a n s a m i n a s e >200 U/L or total bilirubin > 3.0 mg/dL); had a history of or active immunologic or neoplastic disease or severe vascular insufficiency; had received antimicrobial therapy within 5 days of study entry (except antituberculous therapy); or were of child-bearing potential and not practicing an acceptable contraceptive method. Patients who were currently enrolled in any other investigational protocol, were previously enrolled in a cefpodoxime proxetil study, or weighed <90 lb (40.9 kg) were also ineligible for inclusion in the study. All patients (or parents/legal guardians of minors) were required to sign an informed consent form. All patients who received any study drug were included in the safety analysis. To be eligible for evaluation (ie, included in the efficacy analyses), patients had to have a bacterial pathogen isolated from preadmission sputum or blood cultures that was sensitive to both cefpodoxime and cefaclor; taken at least 80% of their assigned medication without missing more t h a n 2 consecutive doses of cefpodoxime or 3 consecutive doses of cefaclor; been evaluated 0 to 7 days after completion of therapy; and avoided using any nonstudy systemic antimicrobials between study admission and posttherapy follow-up. Patients with a negative pretreatment culture who had gram-positive diplococci present in the sputum were considered provisionally suitable for clinical analysis.
Microbiologic Cultures and Susceptibility Testing Respiratory tract cultures were obtained at the pretreatment, interim, and end-of-therapy visits, as well as at the final visit if there were recurrent symptoms. At the pretreatment visit, sputum was obtained for Gram's stain, aerobic culture, and susceptibility testing. A blood sample was also drawn for culture. If blood cultures were initially positive, cultures were repeated at subsequent visits until negative. Susceptibility testing of isolated organisms was performed using 10~g cefpodoxime or 30-~g cefaclor disks. (Before J u l y 1990, 30-,xg class [cephalothin] disks were used because cefaclor disks were unavailable.) Susceptibility on the basis of zone diameter of inhibition was defined as follows12: susceptible, cefpodoxime t> 21 m m and cefaclor ~> 18 mm; resistant, cefpodoxime ~< 17 m m and cefaclor ~< 14 mm. Criteria for susceptibility were defined according to recommendations by the National Committee for Clinical Laboratory Standards 12 (cefaclor, 1>32 ~g/mL resistant; <~8 ~g/mL susceptible) and by Jones and Barry 13 (cefpodoxime,/>8 ~g/mL resistant; 4 2 ~g/mL susceptible). Susceptibility results were confirmed using MIC testing performed by a central reference laboratory at Thomas 1005
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
Jefferson University, Philadelphia. When disk zone inhibition information was not available, MIC data were used to evaluate isolate antibiotic susceptibility.
Study Design In this multiclinic, double-blind, double-dummy study, outpatients were randomized (2:1) to receive either cefpodoxime proxetil (equivalent to 200 mg of cefpodoxime) twice daily with food or 500 mg of cefaclor every 8 hours on an empty stomach for 7 to 14 days. Cefpodoxime proxetil was supplied as tablets (The Upjohn Company, Kalamazoo, Michigan); cefaclor as capsules (Eli Lilly and Company, Indianapolis, Indiana). Each patient received a blister pack containing both capsules and tablets, and each patient took two capsules and three tablets each day, regardless of which drug they were randomized to receive. Individual patient packets had one pill (tablet or capsule) containing active medication and the other (tablet or capsule) was a placebo or a dummy. This design accommodated the different dosing forms of the two antibiotics in a manner that blinded patient and investigator to the identity of the antibiotics being used. At visit 1 (admission visit, study day 1), medical histories were recorded and patients underwent physical examination (including measurement of vital signs and clinical observations of the signs of pneumonia), laboratory tests (hematology, serum chemistry, urinalysis, and pregnancy test when applicable), chest roentgenogram (posteroanterior and lateral), respiratory tract culture, and blood culture. Direct Coombs' test, Gram's stain of sputum or aspirate, and susceptibility testing of isolated pathogens were also performed. At visit 2 (interim visit, study day 7 to 10), the clinical progress of the patient was assessed (signs and symptoms of pneumonia, vital signs, and physical examination); when indicated, sputum Gram's stain and culture, and blood cultures were obtained. Susceptibility testing of isolated pathogens, laboratory tests, and direct Coombs' test were performed. At visits 3 (end-of-therapy visit, study day 15 to 18) and 4 (follow-up visit, study day 28 to 35), these procedures were repeated, and clinical and bacteriologic assessments of the efficacy of therapy were made. Microbiologic response was defined as follows: cure, all initial pathogens eradicated; partial cure, eradication of at least one, but not all, initial pathogens; and failure, no initial pathogens eradicated. Recurrence was defined as eradication of pathogen at the end-of-therapy visit with reculture of the same pathogen at the follow-up visit. Superinfection was defined as the presence of a new respiratory pathogen isolated at the interim or end-of-therapy visit in a patient who was not clinically cured. Clinical outcome was determined independently of microbiologic outcome. Clinical response was defined as follows: cure, complete resolution of signs and symptoms of pneumonia; improvement, substantial improve1006
J.A. GREEN ET AL.
ment in the signs and symptoms of pneumonia; failure, no response to therapy (unchanged or worse). Clinical recurrence was defined as improvement or cure at the end-of-therapy visit with subsequent appearance or worsening of the signs and symptoms of pneumonia by the follow-up visit. Adverse events were classified by the investigators as severe (substantial risk to patient's well-being, likely to require medical intervention), moderate (posed some risk to patient's well-being; intervention may have been considered), or mild (events were of little concern).
Statistical Analysis All statistical tests were two-sided; probabilities <0.05 were considered significant. An analysis of variance was used to analyze age, body weight, pretreatment vital signs, and continuous clinical laboratory assay variables. Continuous variables (vital signs and continuous laboratory assays) were tested over time within each treatment group, using a paired t test. Any measure with a significant (P < 0.02) mean change was analyzed using the basic model. Weighted least squares were used to analyze categorical variables (race, sex, cure rates, and overall and pathogen-specific end-of-therapy microbiologic eradication rate). In addition, these variables were evaluated using a mean score response function 14 or a logit model, i5 Fisher's exact test was computed to evaluate adverse event frequencies and to compare t r e a t m e n t groups (2 x 2 tables) regarding pulmonary disease frequencies, other medical condition frequencies, and pretreatment physical examination abnormalities. RESULTS
Of the 325 patients enrolled in the study, 216 were randomly assigned to cefpodoxime and 109 to cefaclor. Among the cefpodoxime-treated patients, 63% were male, 37% female; 78% were white, 13% black, 6% Hispanic, and 2% other; and their mean (-+SD) age was 53.8 +- 19.5 years. Among the cefaclor-treated patients, 56% were male, 44% female; 80% were white, 14% black, and 6% Hispanic; and their mean (-+SD) age was 49.9 _+ 19.0 years. Between-group differences in age, sex, race, body weight, or history of asthma, chronic bronchitis, emphysema, pneumonia, or tuberculosis were not significant. However, significantly more of the cefpodoxime group reported past or current gastrointestinal disease (29% vs 18% of the cefaclor group; P < 0.05). Most patients (164 cefpodoxime, 81 cefaclor) completed treatment as planned. Treatment was evaluated in 77 (36%) of the 216 patients in the cefpodoxime group and 48 (44%) of the 109 patients in the cefaclor group. The most common reason for exclusion from the efficacy evaluation was 1007
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
negative pretreatment culture (in 90 cefpodoxime patients and in 41 cefaclor patients). Other reasons included failure to meet entry criteria (22 patients), occurrence of resistant pathogens (21 patients), and no susceptibility testing (14 patients). Patients who had negative pretreatment cultures, but whose sputum contained gram-positive diplococci consistent with S pneumoniae, were considered suitable for provisional evaluation in the clinical analysis; these included 63 patients in the cefpodoxime group and 27 in the cefaclor group. Most patients (88% of the cefpodoxime and 92% of the cefaclor patients) who completed treatment took medication for at least 7 days; the mean duration of treatment was 11 and 12 days, respectively. Pill count determined that the mean total dose taken was 4.4 g of cefpodoxime proxetil and 17.8 g of cefaclor.
Microbiologic Results Spneumoniae and H influenzae were the most common of 198 isolates recovered from the patients. In vitro MIC susceptibility data for these isolates are reported in Table I. Significantly more isolates were susceptible to cefpodoxime than to cefaclor (figure): 94% of 178 isolates reported for cefpodoxime were susceptible, 3% moderately susceptible, and 3% resistant; and 82% of 181 isolates reported for cefaclor were susceptible, 5% moderately susceptible, and 13% resistant (P = 0.001). Three isolates of Pseudomonas species were resistant to both study drugs. At the end-of-therapy visit, all 88 pathogens were eradicated in the 77 cefpodoxime patients and 46 (92%) of 50 pathogens were eradicated in the 48 cefaclor patients (P = 0.06). Bacteriologic outcomes were similar in patients with single and multiple pathogens: in patients with single pathogens, all 66 were eradicated in the cefpodoxime group and 91% of 46 in the cefaclor group; in patients with multiple pathogens, the eradication rate was 100% for both groups. Clinical Results Patients with culture-positive pneumonia and those with sputum Gram's stains demonstrating gram-positive diplococci but negative pretreatment cultures were evaluated clinically. Both oral antibiotic regimens produced comparable cure rates: among patients with culture-proven pneumonia, 77% of the cefpodoxime-treated and 71% of the cefaclortreated patients were cured, 19% and 25% were improved, and 4% in each group were treatment failures. Similar clinical responses to cefpodoxime and cefaclor occurred in patients with Gram-stain evidence of S pneumoniae and negative pretreatment cultures (Table II). All patients enrolled in the study had radiographic confirmation of pulmonary infiltrates at enrollment. Of the 70 cefpodoxime and 44 cefaclor 1008
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Table I. In vitro susceptibility of Haemophilus influenzae and Streptococcus pneumoniae to cefpodoxime and cefaclor (cumulative percentages).
MIC (~g/mL)
Cefpodoxime (n = 47) %
Cefaclor (n = 47) %
23 7O 85 91 96 98 98 100 100 100 100 100
0 0 0 0 0 0 23 40 66 79 89 100
Haemophilus~fluenzae 0.03 0.06 0.12 0.25 0.50 1.00 2.00 4.00 8~00 16.00 32.00 64.00
(n = 29)* %
(n=29)* %
Strep~coccuspneumon~e 0.03 0.06 0.12 0.25 0.50 1.00 2.00 4.00 32,00
66 76 86 86 86 93 100 100 100
0 0 7 38 62 76 86 97 100
MIC = minimum inhibitory concentration. * Total = 43; data for 14 not reported.
patients who had a chest roentgenogram at the end-of-therapy visit, 56% versus 76% had no radiographic evidence of infiltrate. Radiographs were not obtained at the follow-up visit. In the cefpodoxime group, microbiologic eradication of 99% of assessable pathogens was maintained between end-of-therapy and follow-up. H influenzae was the only recurring pathogen. End-of-therapy eradication was maintained in all cefaclor patients. At follow-up, recurrence of clinical symptoms of infection in patients with assessable responses was similar in the two treatment groups: 3% of 69 in the cefpodoxime group and 0% of 41 in the cefaclor group. Superinfection was diagnosed in four evaluated cefpodoxime patients and two evaluated cefaclor patients.
Safety Adverse events judged to be probably or possibly related to the study drugs were reported by 16% of the 216 patients in the cefpodoxime group and by 14% of the 109 patients in the cefaclor group. Most adverse events 1009
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
100 -
94%
9080t.D
70-
m
m
c ,, or
600 t~
50403020-
13%
10-
3%
5%
3%
OSusceptible
Moderately SusceptiblQ
Resistant
Figure. In vitro susceptibility of p r e t r e a t m e n t respiratory isolates. Isolates were significantly more susceptible to cefpodoxime t h a n to cefaclor (P = 0.001).
reported were mild. Gastrointestinal complaints were the most frequently reported drug-related adverse events in the cefpodoxime group, affecting 10% of patients, compared with 3% of the cefaclor patients (P < 0.05); the most common gastrointestinal complaint was diarrhea, reported by 4% of the cefpodoxime patients and 2% of the cefaclor patients. The most frequently reported drug-related events among cefaclor-treated patients were dermatologic (pruritus, rash, or urticaria in 5%); 1% of cefpodoxime patients reported dermatologic symptoms. Table II. Clinical responses in patients treated with cefpodoxime or cefaclor.
Cefpodoxime
Cefaclor Ratable Patients
Cured Improved Failed
(n = 77) %
(n = 48) %
77 19 4
71 25 4
Provisionally Ratable Patients* (n = 63) (n = 27) % % Cured Improved Failed
70 22 8
59 33 7
* Negative respiratory tract culture at admission, but presence of gram-negative diplococci typical of Strep-
tococcus pneumoniae seen in respiratory secretions.
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Vital signs data revealed no evidence of study drug toxicity in either treatment group. The only clinically significant changes in vital signs observed during the course of the study were those consistent with infection resolution. Mean body temperature was elevated at study admission and normalized with therapy in both treatment groups. The decrease in respiration rate in the cefpodoxime group was significantly greater than in the cefaclor group at the interim visit (P < 0.05). Some patients (9% of the cefpodoxime and 8% of the cefaclor patients) had laboratory assays (blood urea nitrogen, platelet count, hemoglobin, alkaline phosphatase, white blood cells, transaminases, prothrombin time, partial thromboplastin time, glucose) that became substantially abnormal over the course of therapy. Changes in laboratory values were not related to antibiotic therapy. DISCUSSION
Results of the current study demonstrate that cefpodoxime is as effective as cefaclor in the t r e a t m e n t of mild-to-moderate acute communityacquired pneumonia. Bacterial pathogens isolated from sputum were proportionately more sensitive to cefpodoxime than to cefaclor (P = 0.001). The greater in vitro antibacterial activity of cefpodoxime may have contributed to the trend toward higher microbiologic eradication rates in cefpodoxime-treated patients (P = 0.06). Elevated respiratory rate, which has been shown to correlate with severity of pneumonia, 16 returned to preinfection levels more rapidly in cefpodoxime-treated patients. The finding of a statistically significant improvement in respiratory rate suggests the existence of an enhanced cefpodoxime-induced clinical response that may become apparent with greater use. In general, both drugs were well tolerated. The higher frequency of gastrointestinal side effects experienced by cefpodoxime-treated patients is difficult to evaluate since patients randomized to receive this drug had a significantly higher incidence of gastrointestinal disease before participating in the study. The study design required identification of a specific etiologic agent; however, it is a widely accepted practice to treat community-acquired pneumonia in the absence of bacterial cultures, a This approach is necessitated by the absence of reliable methods for identifying specific causative organisms in patients with acute community-acquired pneumonia. 4'17 In the current study, sputum cultures were negative or nondiagnostic in 41% of cases, which is less than the 48% reported by others.17 Empiric antibiotic selection designed to include S pneumoniae, which accounts for 40% to 80% of cases, now has to acknowledge the increasing importance o f H influenzae. is This change is supported by the fact that H influenzae was the most i011
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
commonly identified pathogen recovered from evaluated patients in the current study. The bacterial pathogens associated with acute community-acquired pneumonia are changing, is The antibiotic sensitivity and resistance patterns of these organisms are also in flux. 6 Two important changes have been observed: S pneumoniae resistant to penicillin, penicillin derivatives, and erythromycin are being identified with increased frequency,ls-21 and, although gram-negative bacilli accounted for few isolates in the current study, they have been identified as etiologic pathogens in as many as 35% of pneumonias. 4 A continued increase in the prevalence of gramnegative bacillary pneumonia is expected to reflect increased oropharyngeal colonization in the institutionalized elderly, diabetic patients, and other chronically ill persons. 22'23 The emergence o f H influenzae and gram-negative bacteria, as well as relatively and absolutely penicillin-resistant S pneumoniae, as common causes of pneumonia warrants the use of an agent that specifically covers these organisms. The MIC ranges ofcefpodoxime and cefaclor are lower for several bacteria that are increasingly recognized as etiologic agents in community-acquired pneumonia, particularly H influenzae, than are those of amoxicillin or amoxicillin plus clavulanic acid. s Mendelman et al ~ demonstrated that cefpodoxime had greater in vitro activity against most strains of H influenzae than cefaclor. In our study, the proportion of isolates susceptible to cefpodoxime was significantly greater than that to cefaclor, and cefpodoxime was better at eradicating H influenzae than was cefaclor (100% vs 86% eradication rate in evaluated patients). In addition, results of other studies indicate that cefpodoxime may be the sole oral agent with activity against relatively penicillin-resistant S pneumoniae. 24 A paucity of oral agents currently available for the outpatient treatment of pneumonia caused by S pneumoniae resistant to penicillin, erythromycin, or multiple antibiotics, supports the continued evaluation of cefpodoxime and other oral agents for this purpose. Ultimately, lack of effective oral antibiotics could require hospitalization solely for intravenous administration of antibiotics to patients otherwise suited for outpatient therapy. Financial costs may be substantial when community-acquired pneumonia is treated in the hospital, is Outpatient treatment significantly reduces those costs. It is axiomatic that the decision to use outpatient treatment will not jeopardize patient well-being, and that good physician judgment will be exercised in making such a decision. Several recent studies 16'25'26 have identified conditions associated with or predictive of a poor outcome (complications or death) of community-acquired pneumonia. Farr et a116 concluded that tachypnea, diastolic hypotension, and an elevated blood urea nitrogen were independent predictors of death from pneumonia. Fine et a125'26 identified age greater than 65 years, comorbid illness, temperature higher than 38.3 °C (101 °F), immunosuppression, and high-risk 1012
J.A. GREEN ET AL.
etiology (staphylococcal, gram-negative rod, aspiration, or postobstructive pneumonia) as conditions associated with a high risk of complications. Fine et a125 concluded that patients with more than one of these risk factors should be hospitalized, but that outpatient treatment was preferable to hospitalization for those with only one or no risk factors. The low incidence of complications in our study supports their conclusion that physicians can correctly identify patients likely to benefit from oral antibiotic therapy, and that mild-to-moderate acute community-acquired pneumonia can be treated successfully on an outpatient basis. In choosing an antibiotic for outpatient treatment of acute community-acquired pneumonia, both the antimicrobial spectrum of the agent and the likelihood that the patient will comply with the regimen need to be considered. Patient compliance in taking cefpodoxime should be enhanced by twice-a-day dosing and the requirement that it be taken with food. Previous studies have established a 24% improvement in compliance as the prescribed dose frequency was decreased from a thrice-daily to a twicedaily regimen. 7'27 There is an intuitive sense that patients are more likely to take oral medications when the dose schedule is associated with eating. There appears to be a logical contradiction when patients are told to take oral medications (an act associated with eating) on an empty stomach. CONCLUSIONS
The pathogens isolated in our study, including H influenzae and S pneumoniae, were significantly more susceptible in vitro to cefpodoxime than to cefaclor. Cefpodoxime proxetil was as effective as cefaclor in the eradication of bacterial pathogens in patients with pneumonia, and in the production of clinical cures in these patients. Both agents were generally well tolerated.
Acknowledgments The research was conducted by the following investigators: Lawrence E. Alberti, MD, Aurora, Illinois; James J. Ball, MD, Auburn, Washington; Larry D. Beaty, MD, Des Moines, Iowa; Robert L. Bjurstrom, MD, Bellevue, Washington; Thomas C. Butler, MD, Lubbock, Texas; Rohit A. Desai, MD, Covina, California; Mark O. Farber, MD, Indianapolis, Indiana; James V. Felicetta, MD, Phoenix, Arizona; Aaron E. Glatt, MD, East Meadow, New York; Jon Green, MD, PhD, Martinez, California; Richard C. Hebert, MD, Baton Rouge, Louisiana; Michael K. Hill, MD, New Orleans, Louisiana; David E. Johnson, MD, Anniston, Alabama; Richard B. Kohler, MD, Indianapolis, Indiana; Benjamin A. Lipsky, MD, Seattle, Washington; Barry L. Marmorstein, MD, Bellevue, Washington; Anthony 1013
EFFICACYANDSAFETYOFCEFPODOXIMEPROXETILVERSUSCEFACLOR
J. Meier, MD, East Lansing, Michigan; Joseph C. Muhler, II, MD, Fort Wayne, Indiana; Dwight Keith Perkins, PharmD, Kansas City, Missouri; John A. Powell, MD, MC, Fort Tucker, Alabama; John M. Quale, MD, Brooklyn, New York; Michael P. Rosenthal, MD, Philadelphia, Pennsylvania; James H. Schultz, MD, Escondido, California; Gregory Semerdjian, MD, San Diego, California; Eric Solomon, MD, Birmingham, Alabama; John Stafford, MD, St. Joseph, Michigan; James F. Stanford, MD, Kansas City, Missouri; Judith M. Strymish, MD, West Roxbury, Massachusetts; Dennis L. Swartout, MD, Keene, New Hampshire; Matthew M. Tignor, MD, Virginia Beach, Virginia; Carl P. Weidenbach, MD, Plainview, Texas; and Michael Ziter, MD, Cadillac, Michigan. This study was supported in part by The Upjohn Company, Kalamazoo, Michigan. References: 1. The National Data Book. 110th ed. Washington, DC: Statistical Abstracts of the United States; 1990:82. 2. Torres A, Serra-Batilles J, Ferrer A, et al. Severe community acquired pneumonia: Epidemiology and prognostic factors. Am Rev Respir Dis. 1991;144;312-318. 3. Feckety R, Lynch JP III. Community acquired pneumonia: What role for new antibiotics? J Respir Dis. 1994;15:132-147. 4. McKeller PP. Treatment of community-acquired pneumonias.Am J Med. 1985;79:25-31. 5. Finch RG. Epidemiological features and chemotherapy of community-acquired respiratory tract infections. J Antimicrob Chemother. 1990;26:53-61. 6. Kunin CM. Resistance to antimicrobial drugs--a worldwide calamity. Ann Intern Med. 1993;118:557-561. 7. Eisen SA, Miller DK, Woodward RS, et al. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med. 1990;150:1881-1884. 8. Fass RJ, Helsel VL. In vitro activity of U-76,252 (CS-807), a new oral cephalosporin. Antimicrob Agents Chemother. 1988;32:1082-1085. 9. Mendelman PM, Henritzy LL, Chaffin DO, et al. In vitro activities and targets of three cephem antibiotics against Haemophilus influenzae. Antimicrob Agents Chemother. 1989; 33:1878-1882. 10. Borin MT, Hughes GS, Spillers CR, Patel RK. Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrob Agents Chemother. 1990;34:1094-1099. 11. Couraud L, Andrews JM, Lecoeur H, et al. Concentrations of cefpodoxime in plasma and lung tissue after a single oral dose of cefpodoxime proxetil. J Antimicrob Chemother. 1990;26(Suppl E):35-40. 12. National Committee for Clinical Laboratory Standards, Antimicrobial Susceptibility Testing. Committee Report. Vol. 5, No. 22, M7-A. Villanova, Pa: NCCLS, 1985. 13. Jones RN, Barry AL. Antimicrobial activity and disk diffusion susceptibility testing of U-76,253A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS807). Antimicrob Agents Chemother. 1988;32:443-449. 1014
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14. Grizzle JE, Starmer CF, Koch GG. Analysis of categorical data by linear models. Biometrics. 1969;25:489-504. 15. Feinberg SE. The Analysis of Cross-Classified Categorical Data. 2nd ed. Cambridge, Mass: MIT Press; 1980. 16. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized for communityacquired pneumonia. Ann Intern Med. 1991;115:428-436. 17. Lentino JR, Lucks DA. Nonvalue of sputum culture in the management of lower respiratory tract infections. J Clin Microbiol. 1987;25:758-762. 18. Fang GD, Fine M, Orloff J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: A prospective multicenter study of 359 cases. Medicine. 1990;60:307-316. 19. Lonks JR, Medeiros AA. High rate oferythromycin and clarithromycin resistance among Streptococcus pneumoniae isolates from blood cultures from Providence, R.I. Antimicrob Agents Chemother. 1993;37:1742-1745. 20. Sempera MA, Gomez J, Ruiz J. Resistance of Streptococcus pneumoniae to erythromycin in adults and children. J Antimicrob Chemother. 1992;29:348-349. 21. Mason EO Jr, Kaplan LB, Lamberth LB, et al. Increased rate of isolation of penicillinresistant Streptococcus pneumoniae in a children's hospital and in vitro susceptibilities to antibiotics of potential therapeutic use. Antimicrob Agents Chemother. 1992;36:17031707. 22. Valenti WM, Trudell RG, Bently DW. Factors predisposing to oropharyngeal colonization with gram-negative bacilli in the aged. NEJM. 1978;298:1108-1111. 23. Johanson WG, Pierce AK, Sanford JP, Thomas GD. Nosocomial respiratory infections with gram-negative bacilli: The significance of colonization of the respiratory tract. Ann Intern Med. 1972;77:701-706. 24. Whittier S, Barnes D, Wait K, et al. Streptococcus pneumoniae: Antibiotic resistance patterns among children in day care. Presented at the 32nd Intersciences Conference on Antimicrobial Agents and Chemotherapy, Anaheim, California, October 11-14, 1992. Abstract 1018. 25. Fine MJ, Smith DN, Singer DE. Hospitalization decision in patients with communityacquired pneumonia: A prospective cohort study. Am J Med. 1990;89:713-721. 26. Fine MJ, OrloffJJ, Arisumi D, et al. Prognosis of patients hospitalized with communityacquired pneumonia. Am J Med. 1990;88(network 5N):5-1N-5-8N. 27. Pullar T, Birtwell AJ, Wiles PG, et al. Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily. Clin Pharmacol Ther. 1988;44:540-545.
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R A N D O M I Z E D D O U B L E - B L I N D T R I A L OF T H E C O M P A R A T I V E E F F I C A C Y A N D S A F E T Y OF C E F P O D O X I M E P R O X E T I L A N D CEFACLOR IN THE TREATMENT OF ACUTE COMMUNITY-ACQUIRED PNEUMONIA J O N A. G R E E N , 1 T H O M A S BUTLER, 2 AND W E S L E Y M A R K TODD 3
UC Davis School of Medicine, Davis, and the Department of Veterans Affairs, Northern California System of Clinics, Pleasant Hill, California, 2Texas Tech University Health Sciences Center, Lubbock, Texas, and 3The Upjohn Company, Kalamazoo, Michigan
ABSTRACT
A randomized, controlled, double-blind, double-dummy, multicenter study compared the efficacy and safety of cefpodoxime proxetil with that of cefaclor in the outpatient treatment of community-acquired pneumonia. A total of 325 patients received 7 to 14 days of either 200 mg of cefpodoxime as eefpodoxime proxetil twice daily (n = 216) or 500 mg of cefaclor three times daily (n = 109). All study criteria were met by 125 patients (cefpodoxime, 77; cefaclor, 48). Streptococcus pneumoniae and Haemophilus influenzae were the most commonly identified pathogens. Of 198 pathogenic bacteria isolated from sputum, cefpodoxime susceptibility was tested in 178 and cefaclor susceptibility in 181. Isolates were more susceptible to cefpodoxime than to cefaclor (P = 0.001): 94% were susceptible to cefpodoxime and 82% to cefaelor; 3% were moderately susceptible to cefpodoxime and 5% to cefaclor; 3% were resistant to cefpodoxime and 13% were resistant to cefaclor. Clin 1 ical outcome in the two treatment groups was similar: 77% of cefpodoxime-treated patients and 71% of cefaclor-treated patients were cured; 19% of cefpodoxime-treated and 25% of cefaclor-treated patients improved; and 4% of patients in each group were considered treatment failures. Gastrointestinal complaints were the most frequently reported drug-related adverse event (10%) in the cefpodoxime group, and dermatologic problems (5%) were the most commonly encountered drug-related adverse event in the eefaclor group. Overall frequencies of drug-related adverse events were similar (16% for cefpodoxime vs 14% for cefaclor) in the two groups. Cefpodoxime proxetil was as effective and as well tolerated as cefaclor in the outpatient treatment of community-acquired pneumonia. INTRODUCTION
P n e u m o n i a is t h e fifth m o s t f r e q u e n t l y r e p o r t e d c a u s e of d e a t h in t h e U n i t e d S t a t e s . 1 F a c t o r s c o n t r i b u t i n g to m o r t a l i t y include infection c a u s e d b y n o n b a c t e r i a l p a t h o g e n s , s e r i o u s u n d e r l y i n g illness, i m p a i r e d h o s t deAddress correspondence to: Jon A. Green, MD, PhD, 150 Muir Road, Martinez, CA 94553.
Received for publication on June 17, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1003
0011-393x/94/$3.50
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
fense mechanisms, and delay in the institution of effective antimicrobial therapy. 2 Precise identification of causative infectious agents and their susceptibility to antibiotics is neither practical nor possible in most circumstances, and therapy is essentially empiric, designed to include the known antibiotic sensitivities of common respiratory pathogens. 3 Empiric therapy of community-acquired pneumonia has to include gram-negative bacteria 4 and accommodate the increasing resistance of major respiratory pathogens, particularly Streptococcus pneumoniae and Haemophilus influenzae, to commonly used antibiotics. 5 In recent years S pneumoniae has demonstrated resistance to penicillins and to erythromycin, which are considered by many to be the antibiotics of choice for the initial treatment of community-acquired pneumonia. 6 Continuing changes in the types and antibiotic sensitivity patterns of bacterial respiratory pathogens support the need to identify alternative agents for empiric therapy of communityacquired pneumonia. Cefpodoxime proxetil is an orally administered, broad-spectrum thirdgeneration cephalosporin, with many characteristics that make it suitable for the oral outpatient treatment of community-acquired pneumonia. Patient compliance is likely to be enhanced by twice-daily dosing and the requirement that cefpodoxime be taken with food rather than on an empty stomach. 7 Cefpodoxime is active in vitro against common respiratory pathogens such as H influenzae and S pneumoniae, including isolates resistant to penicillin antibiotics. S'9 In adults, plasma levels of cefpodoxime reach 2.2 ~g/mL after a 200-mg dose of cefpodoxime administered as cefpodoxime proxetil, a pro-drug that is hydrolyzed to free cefpodoxime by the gastrointestinal mucosa. 1° Oral administration of cefpodoxime proxetil produces lung tissue cefpodoxime concentrations of 0.63 mg/kg, 11 which exceed the minimum inhibitory concentration (MIC) of common pneumonia-causing pathogens. The present study was conducted to compare the efficacy and safety of orally administered cefpodoxime proxetil and cefaclor in the outpatient treatment of culture-proven acute community-acquired pneumonia. PATIENTS
AND METHODS
Patient Population Male and female patients aged/>14 years with signs and symptoms indicative of acute community-acquired pneumonia (radiographic evidence of pulmonary infiltrate, Gram's stain indicating purulent sputum, and cough or fever) were enrolled in the study. Female patients were required not to be pregnant or breast-feeding and to have a negative pregnancy test within 8 hours of enrollment and receipt of study drug. Patients 1004
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were excluded if t h e y had hypersensitivity to cephalosporins, cephamycins, or penicillin; neutropenia (leukocytes <2000/mm3), moderate-tosevere renal impairment (serum creatinine >2.5 mg/dL), or hepatic dysfunction (serum g l u t a m i c - p y r u v i c t r a n s a m i n a s e >200 U/L or total bilirubin > 3.0 mg/dL); had a history of or active immunologic or neoplastic disease or severe vascular insufficiency; had received antimicrobial therapy within 5 days of study entry (except antituberculous therapy); or were of child-bearing potential and not practicing an acceptable contraceptive method. Patients who were currently enrolled in any other investigational protocol, were previously enrolled in a cefpodoxime proxetil study, or weighed <90 lb (40.9 kg) were also ineligible for inclusion in the study. All patients (or parents/legal guardians of minors) were required to sign an informed consent form. All patients who received any study drug were included in the safety analysis. To be eligible for evaluation (ie, included in the efficacy analyses), patients had to have a bacterial pathogen isolated from preadmission sputum or blood cultures that was sensitive to both cefpodoxime and cefaclor; taken at least 80% of their assigned medication without missing more t h a n 2 consecutive doses of cefpodoxime or 3 consecutive doses of cefaclor; been evaluated 0 to 7 days after completion of therapy; and avoided using any nonstudy systemic antimicrobials between study admission and posttherapy follow-up. Patients with a negative pretreatment culture who had gram-positive diplococci present in the sputum were considered provisionally suitable for clinical analysis.
Microbiologic Cultures and Susceptibility Testing Respiratory tract cultures were obtained at the pretreatment, interim, and end-of-therapy visits, as well as at the final visit if there were recurrent symptoms. At the pretreatment visit, sputum was obtained for Gram's stain, aerobic culture, and susceptibility testing. A blood sample was also drawn for culture. If blood cultures were initially positive, cultures were repeated at subsequent visits until negative. Susceptibility testing of isolated organisms was performed using 10~g cefpodoxime or 30-~g cefaclor disks. (Before J u l y 1990, 30-,xg class [cephalothin] disks were used because cefaclor disks were unavailable.) Susceptibility on the basis of zone diameter of inhibition was defined as follows12: susceptible, cefpodoxime t> 21 m m and cefaclor ~> 18 mm; resistant, cefpodoxime ~< 17 m m and cefaclor ~< 14 mm. Criteria for susceptibility were defined according to recommendations by the National Committee for Clinical Laboratory Standards 12 (cefaclor, 1>32 ~g/mL resistant; <~8 ~g/mL susceptible) and by Jones and Barry 13 (cefpodoxime,/>8 ~g/mL resistant; 4 2 ~g/mL susceptible). Susceptibility results were confirmed using MIC testing performed by a central reference laboratory at Thomas 1005
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
Jefferson University, Philadelphia. When disk zone inhibition information was not available, MIC data were used to evaluate isolate antibiotic susceptibility.
Study Design In this multiclinic, double-blind, double-dummy study, outpatients were randomized (2:1) to receive either cefpodoxime proxetil (equivalent to 200 mg of cefpodoxime) twice daily with food or 500 mg of cefaclor every 8 hours on an empty stomach for 7 to 14 days. Cefpodoxime proxetil was supplied as tablets (The Upjohn Company, Kalamazoo, Michigan); cefaclor as capsules (Eli Lilly and Company, Indianapolis, Indiana). Each patient received a blister pack containing both capsules and tablets, and each patient took two capsules and three tablets each day, regardless of which drug they were randomized to receive. Individual patient packets had one pill (tablet or capsule) containing active medication and the other (tablet or capsule) was a placebo or a dummy. This design accommodated the different dosing forms of the two antibiotics in a manner that blinded patient and investigator to the identity of the antibiotics being used. At visit 1 (admission visit, study day 1), medical histories were recorded and patients underwent physical examination (including measurement of vital signs and clinical observations of the signs of pneumonia), laboratory tests (hematology, serum chemistry, urinalysis, and pregnancy test when applicable), chest roentgenogram (posteroanterior and lateral), respiratory tract culture, and blood culture. Direct Coombs' test, Gram's stain of sputum or aspirate, and susceptibility testing of isolated pathogens were also performed. At visit 2 (interim visit, study day 7 to 10), the clinical progress of the patient was assessed (signs and symptoms of pneumonia, vital signs, and physical examination); when indicated, sputum Gram's stain and culture, and blood cultures were obtained. Susceptibility testing of isolated pathogens, laboratory tests, and direct Coombs' test were performed. At visits 3 (end-of-therapy visit, study day 15 to 18) and 4 (follow-up visit, study day 28 to 35), these procedures were repeated, and clinical and bacteriologic assessments of the efficacy of therapy were made. Microbiologic response was defined as follows: cure, all initial pathogens eradicated; partial cure, eradication of at least one, but not all, initial pathogens; and failure, no initial pathogens eradicated. Recurrence was defined as eradication of pathogen at the end-of-therapy visit with reculture of the same pathogen at the follow-up visit. Superinfection was defined as the presence of a new respiratory pathogen isolated at the interim or end-of-therapy visit in a patient who was not clinically cured. Clinical outcome was determined independently of microbiologic outcome. Clinical response was defined as follows: cure, complete resolution of signs and symptoms of pneumonia; improvement, substantial improve1006
J.A. GREEN ET AL.
ment in the signs and symptoms of pneumonia; failure, no response to therapy (unchanged or worse). Clinical recurrence was defined as improvement or cure at the end-of-therapy visit with subsequent appearance or worsening of the signs and symptoms of pneumonia by the follow-up visit. Adverse events were classified by the investigators as severe (substantial risk to patient's well-being, likely to require medical intervention), moderate (posed some risk to patient's well-being; intervention may have been considered), or mild (events were of little concern).
Statistical Analysis All statistical tests were two-sided; probabilities <0.05 were considered significant. An analysis of variance was used to analyze age, body weight, pretreatment vital signs, and continuous clinical laboratory assay variables. Continuous variables (vital signs and continuous laboratory assays) were tested over time within each treatment group, using a paired t test. Any measure with a significant (P < 0.02) mean change was analyzed using the basic model. Weighted least squares were used to analyze categorical variables (race, sex, cure rates, and overall and pathogen-specific end-of-therapy microbiologic eradication rate). In addition, these variables were evaluated using a mean score response function 14 or a logit model, i5 Fisher's exact test was computed to evaluate adverse event frequencies and to compare t r e a t m e n t groups (2 x 2 tables) regarding pulmonary disease frequencies, other medical condition frequencies, and pretreatment physical examination abnormalities. RESULTS
Of the 325 patients enrolled in the study, 216 were randomly assigned to cefpodoxime and 109 to cefaclor. Among the cefpodoxime-treated patients, 63% were male, 37% female; 78% were white, 13% black, 6% Hispanic, and 2% other; and their mean (-+SD) age was 53.8 +- 19.5 years. Among the cefaclor-treated patients, 56% were male, 44% female; 80% were white, 14% black, and 6% Hispanic; and their mean (-+SD) age was 49.9 _+ 19.0 years. Between-group differences in age, sex, race, body weight, or history of asthma, chronic bronchitis, emphysema, pneumonia, or tuberculosis were not significant. However, significantly more of the cefpodoxime group reported past or current gastrointestinal disease (29% vs 18% of the cefaclor group; P < 0.05). Most patients (164 cefpodoxime, 81 cefaclor) completed treatment as planned. Treatment was evaluated in 77 (36%) of the 216 patients in the cefpodoxime group and 48 (44%) of the 109 patients in the cefaclor group. The most common reason for exclusion from the efficacy evaluation was 1007
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
negative pretreatment culture (in 90 cefpodoxime patients and in 41 cefaclor patients). Other reasons included failure to meet entry criteria (22 patients), occurrence of resistant pathogens (21 patients), and no susceptibility testing (14 patients). Patients who had negative pretreatment cultures, but whose sputum contained gram-positive diplococci consistent with S pneumoniae, were considered suitable for provisional evaluation in the clinical analysis; these included 63 patients in the cefpodoxime group and 27 in the cefaclor group. Most patients (88% of the cefpodoxime and 92% of the cefaclor patients) who completed treatment took medication for at least 7 days; the mean duration of treatment was 11 and 12 days, respectively. Pill count determined that the mean total dose taken was 4.4 g of cefpodoxime proxetil and 17.8 g of cefaclor.
Microbiologic Results Spneumoniae and H influenzae were the most common of 198 isolates recovered from the patients. In vitro MIC susceptibility data for these isolates are reported in Table I. Significantly more isolates were susceptible to cefpodoxime than to cefaclor (figure): 94% of 178 isolates reported for cefpodoxime were susceptible, 3% moderately susceptible, and 3% resistant; and 82% of 181 isolates reported for cefaclor were susceptible, 5% moderately susceptible, and 13% resistant (P = 0.001). Three isolates of Pseudomonas species were resistant to both study drugs. At the end-of-therapy visit, all 88 pathogens were eradicated in the 77 cefpodoxime patients and 46 (92%) of 50 pathogens were eradicated in the 48 cefaclor patients (P = 0.06). Bacteriologic outcomes were similar in patients with single and multiple pathogens: in patients with single pathogens, all 66 were eradicated in the cefpodoxime group and 91% of 46 in the cefaclor group; in patients with multiple pathogens, the eradication rate was 100% for both groups. Clinical Results Patients with culture-positive pneumonia and those with sputum Gram's stains demonstrating gram-positive diplococci but negative pretreatment cultures were evaluated clinically. Both oral antibiotic regimens produced comparable cure rates: among patients with culture-proven pneumonia, 77% of the cefpodoxime-treated and 71% of the cefaclortreated patients were cured, 19% and 25% were improved, and 4% in each group were treatment failures. Similar clinical responses to cefpodoxime and cefaclor occurred in patients with Gram-stain evidence of S pneumoniae and negative pretreatment cultures (Table II). All patients enrolled in the study had radiographic confirmation of pulmonary infiltrates at enrollment. Of the 70 cefpodoxime and 44 cefaclor 1008
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Table I. In vitro susceptibility of Haemophilus influenzae and Streptococcus pneumoniae to cefpodoxime and cefaclor (cumulative percentages).
MIC (~g/mL)
Cefpodoxime (n = 47) %
Cefaclor (n = 47) %
23 7O 85 91 96 98 98 100 100 100 100 100
0 0 0 0 0 0 23 40 66 79 89 100
Haemophilus~fluenzae 0.03 0.06 0.12 0.25 0.50 1.00 2.00 4.00 8~00 16.00 32.00 64.00
(n = 29)* %
(n=29)* %
Strep~coccuspneumon~e 0.03 0.06 0.12 0.25 0.50 1.00 2.00 4.00 32,00
66 76 86 86 86 93 100 100 100
0 0 7 38 62 76 86 97 100
MIC = minimum inhibitory concentration. * Total = 43; data for 14 not reported.
patients who had a chest roentgenogram at the end-of-therapy visit, 56% versus 76% had no radiographic evidence of infiltrate. Radiographs were not obtained at the follow-up visit. In the cefpodoxime group, microbiologic eradication of 99% of assessable pathogens was maintained between end-of-therapy and follow-up. H influenzae was the only recurring pathogen. End-of-therapy eradication was maintained in all cefaclor patients. At follow-up, recurrence of clinical symptoms of infection in patients with assessable responses was similar in the two treatment groups: 3% of 69 in the cefpodoxime group and 0% of 41 in the cefaclor group. Superinfection was diagnosed in four evaluated cefpodoxime patients and two evaluated cefaclor patients.
Safety Adverse events judged to be probably or possibly related to the study drugs were reported by 16% of the 216 patients in the cefpodoxime group and by 14% of the 109 patients in the cefaclor group. Most adverse events 1009
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
100 -
94%
9080t.D
70-
m
m
c ,, or
600 t~
50403020-
13%
10-
3%
5%
3%
OSusceptible
Moderately SusceptiblQ
Resistant
Figure. In vitro susceptibility of p r e t r e a t m e n t respiratory isolates. Isolates were significantly more susceptible to cefpodoxime t h a n to cefaclor (P = 0.001).
reported were mild. Gastrointestinal complaints were the most frequently reported drug-related adverse events in the cefpodoxime group, affecting 10% of patients, compared with 3% of the cefaclor patients (P < 0.05); the most common gastrointestinal complaint was diarrhea, reported by 4% of the cefpodoxime patients and 2% of the cefaclor patients. The most frequently reported drug-related events among cefaclor-treated patients were dermatologic (pruritus, rash, or urticaria in 5%); 1% of cefpodoxime patients reported dermatologic symptoms. Table II. Clinical responses in patients treated with cefpodoxime or cefaclor.
Cefpodoxime
Cefaclor Ratable Patients
Cured Improved Failed
(n = 77) %
(n = 48) %
77 19 4
71 25 4
Provisionally Ratable Patients* (n = 63) (n = 27) % % Cured Improved Failed
70 22 8
59 33 7
* Negative respiratory tract culture at admission, but presence of gram-negative diplococci typical of Strep-
tococcus pneumoniae seen in respiratory secretions.
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Vital signs data revealed no evidence of study drug toxicity in either treatment group. The only clinically significant changes in vital signs observed during the course of the study were those consistent with infection resolution. Mean body temperature was elevated at study admission and normalized with therapy in both treatment groups. The decrease in respiration rate in the cefpodoxime group was significantly greater than in the cefaclor group at the interim visit (P < 0.05). Some patients (9% of the cefpodoxime and 8% of the cefaclor patients) had laboratory assays (blood urea nitrogen, platelet count, hemoglobin, alkaline phosphatase, white blood cells, transaminases, prothrombin time, partial thromboplastin time, glucose) that became substantially abnormal over the course of therapy. Changes in laboratory values were not related to antibiotic therapy. DISCUSSION
Results of the current study demonstrate that cefpodoxime is as effective as cefaclor in the t r e a t m e n t of mild-to-moderate acute communityacquired pneumonia. Bacterial pathogens isolated from sputum were proportionately more sensitive to cefpodoxime than to cefaclor (P = 0.001). The greater in vitro antibacterial activity of cefpodoxime may have contributed to the trend toward higher microbiologic eradication rates in cefpodoxime-treated patients (P = 0.06). Elevated respiratory rate, which has been shown to correlate with severity of pneumonia, 16 returned to preinfection levels more rapidly in cefpodoxime-treated patients. The finding of a statistically significant improvement in respiratory rate suggests the existence of an enhanced cefpodoxime-induced clinical response that may become apparent with greater use. In general, both drugs were well tolerated. The higher frequency of gastrointestinal side effects experienced by cefpodoxime-treated patients is difficult to evaluate since patients randomized to receive this drug had a significantly higher incidence of gastrointestinal disease before participating in the study. The study design required identification of a specific etiologic agent; however, it is a widely accepted practice to treat community-acquired pneumonia in the absence of bacterial cultures, a This approach is necessitated by the absence of reliable methods for identifying specific causative organisms in patients with acute community-acquired pneumonia. 4'17 In the current study, sputum cultures were negative or nondiagnostic in 41% of cases, which is less than the 48% reported by others.17 Empiric antibiotic selection designed to include S pneumoniae, which accounts for 40% to 80% of cases, now has to acknowledge the increasing importance o f H influenzae. is This change is supported by the fact that H influenzae was the most i011
EFFICACY AND SAFETY OF CEFPODOXIME PROXETIL VERSUS CEFACLOR
commonly identified pathogen recovered from evaluated patients in the current study. The bacterial pathogens associated with acute community-acquired pneumonia are changing, is The antibiotic sensitivity and resistance patterns of these organisms are also in flux. 6 Two important changes have been observed: S pneumoniae resistant to penicillin, penicillin derivatives, and erythromycin are being identified with increased frequency,ls-21 and, although gram-negative bacilli accounted for few isolates in the current study, they have been identified as etiologic pathogens in as many as 35% of pneumonias. 4 A continued increase in the prevalence of gramnegative bacillary pneumonia is expected to reflect increased oropharyngeal colonization in the institutionalized elderly, diabetic patients, and other chronically ill persons. 22'23 The emergence o f H influenzae and gram-negative bacteria, as well as relatively and absolutely penicillin-resistant S pneumoniae, as common causes of pneumonia warrants the use of an agent that specifically covers these organisms. The MIC ranges ofcefpodoxime and cefaclor are lower for several bacteria that are increasingly recognized as etiologic agents in community-acquired pneumonia, particularly H influenzae, than are those of amoxicillin or amoxicillin plus clavulanic acid. s Mendelman et al ~ demonstrated that cefpodoxime had greater in vitro activity against most strains of H influenzae than cefaclor. In our study, the proportion of isolates susceptible to cefpodoxime was significantly greater than that to cefaclor, and cefpodoxime was better at eradicating H influenzae than was cefaclor (100% vs 86% eradication rate in evaluated patients). In addition, results of other studies indicate that cefpodoxime may be the sole oral agent with activity against relatively penicillin-resistant S pneumoniae. 24 A paucity of oral agents currently available for the outpatient treatment of pneumonia caused by S pneumoniae resistant to penicillin, erythromycin, or multiple antibiotics, supports the continued evaluation of cefpodoxime and other oral agents for this purpose. Ultimately, lack of effective oral antibiotics could require hospitalization solely for intravenous administration of antibiotics to patients otherwise suited for outpatient therapy. Financial costs may be substantial when community-acquired pneumonia is treated in the hospital, is Outpatient treatment significantly reduces those costs. It is axiomatic that the decision to use outpatient treatment will not jeopardize patient well-being, and that good physician judgment will be exercised in making such a decision. Several recent studies 16'25'26 have identified conditions associated with or predictive of a poor outcome (complications or death) of community-acquired pneumonia. Farr et a116 concluded that tachypnea, diastolic hypotension, and an elevated blood urea nitrogen were independent predictors of death from pneumonia. Fine et a125'26 identified age greater than 65 years, comorbid illness, temperature higher than 38.3 °C (101 °F), immunosuppression, and high-risk 1012
J.A. GREEN ET AL.
etiology (staphylococcal, gram-negative rod, aspiration, or postobstructive pneumonia) as conditions associated with a high risk of complications. Fine et a125 concluded that patients with more than one of these risk factors should be hospitalized, but that outpatient treatment was preferable to hospitalization for those with only one or no risk factors. The low incidence of complications in our study supports their conclusion that physicians can correctly identify patients likely to benefit from oral antibiotic therapy, and that mild-to-moderate acute community-acquired pneumonia can be treated successfully on an outpatient basis. In choosing an antibiotic for outpatient treatment of acute community-acquired pneumonia, both the antimicrobial spectrum of the agent and the likelihood that the patient will comply with the regimen need to be considered. Patient compliance in taking cefpodoxime should be enhanced by twice-a-day dosing and the requirement that it be taken with food. Previous studies have established a 24% improvement in compliance as the prescribed dose frequency was decreased from a thrice-daily to a twicedaily regimen. 7'27 There is an intuitive sense that patients are more likely to take oral medications when the dose schedule is associated with eating. There appears to be a logical contradiction when patients are told to take oral medications (an act associated with eating) on an empty stomach. CONCLUSIONS
The pathogens isolated in our study, including H influenzae and S pneumoniae, were significantly more susceptible in vitro to cefpodoxime than to cefaclor. Cefpodoxime proxetil was as effective as cefaclor in the eradication of bacterial pathogens in patients with pneumonia, and in the production of clinical cures in these patients. Both agents were generally well tolerated.
Acknowledgments The research was conducted by the following investigators: Lawrence E. Alberti, MD, Aurora, Illinois; James J. Ball, MD, Auburn, Washington; Larry D. Beaty, MD, Des Moines, Iowa; Robert L. Bjurstrom, MD, Bellevue, Washington; Thomas C. Butler, MD, Lubbock, Texas; Rohit A. Desai, MD, Covina, California; Mark O. Farber, MD, Indianapolis, Indiana; James V. Felicetta, MD, Phoenix, Arizona; Aaron E. Glatt, MD, East Meadow, New York; Jon Green, MD, PhD, Martinez, California; Richard C. Hebert, MD, Baton Rouge, Louisiana; Michael K. Hill, MD, New Orleans, Louisiana; David E. Johnson, MD, Anniston, Alabama; Richard B. Kohler, MD, Indianapolis, Indiana; Benjamin A. Lipsky, MD, Seattle, Washington; Barry L. Marmorstein, MD, Bellevue, Washington; Anthony 1013
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J. Meier, MD, East Lansing, Michigan; Joseph C. Muhler, II, MD, Fort Wayne, Indiana; Dwight Keith Perkins, PharmD, Kansas City, Missouri; John A. Powell, MD, MC, Fort Tucker, Alabama; John M. Quale, MD, Brooklyn, New York; Michael P. Rosenthal, MD, Philadelphia, Pennsylvania; James H. Schultz, MD, Escondido, California; Gregory Semerdjian, MD, San Diego, California; Eric Solomon, MD, Birmingham, Alabama; John Stafford, MD, St. Joseph, Michigan; James F. Stanford, MD, Kansas City, Missouri; Judith M. Strymish, MD, West Roxbury, Massachusetts; Dennis L. Swartout, MD, Keene, New Hampshire; Matthew M. Tignor, MD, Virginia Beach, Virginia; Carl P. Weidenbach, MD, Plainview, Texas; and Michael Ziter, MD, Cadillac, Michigan. This study was supported in part by The Upjohn Company, Kalamazoo, Michigan. References: 1. The National Data Book. 110th ed. Washington, DC: Statistical Abstracts of the United States; 1990:82. 2. Torres A, Serra-Batilles J, Ferrer A, et al. Severe community acquired pneumonia: Epidemiology and prognostic factors. Am Rev Respir Dis. 1991;144;312-318. 3. Feckety R, Lynch JP III. Community acquired pneumonia: What role for new antibiotics? J Respir Dis. 1994;15:132-147. 4. McKeller PP. Treatment of community-acquired pneumonias.Am J Med. 1985;79:25-31. 5. Finch RG. Epidemiological features and chemotherapy of community-acquired respiratory tract infections. J Antimicrob Chemother. 1990;26:53-61. 6. Kunin CM. Resistance to antimicrobial drugs--a worldwide calamity. Ann Intern Med. 1993;118:557-561. 7. Eisen SA, Miller DK, Woodward RS, et al. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med. 1990;150:1881-1884. 8. Fass RJ, Helsel VL. In vitro activity of U-76,252 (CS-807), a new oral cephalosporin. Antimicrob Agents Chemother. 1988;32:1082-1085. 9. Mendelman PM, Henritzy LL, Chaffin DO, et al. In vitro activities and targets of three cephem antibiotics against Haemophilus influenzae. Antimicrob Agents Chemother. 1989; 33:1878-1882. 10. Borin MT, Hughes GS, Spillers CR, Patel RK. Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrob Agents Chemother. 1990;34:1094-1099. 11. Couraud L, Andrews JM, Lecoeur H, et al. Concentrations of cefpodoxime in plasma and lung tissue after a single oral dose of cefpodoxime proxetil. J Antimicrob Chemother. 1990;26(Suppl E):35-40. 12. National Committee for Clinical Laboratory Standards, Antimicrobial Susceptibility Testing. Committee Report. Vol. 5, No. 22, M7-A. Villanova, Pa: NCCLS, 1985. 13. Jones RN, Barry AL. Antimicrobial activity and disk diffusion susceptibility testing of U-76,253A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS807). Antimicrob Agents Chemother. 1988;32:443-449. 1014
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14. Grizzle JE, Starmer CF, Koch GG. Analysis of categorical data by linear models. Biometrics. 1969;25:489-504. 15. Feinberg SE. The Analysis of Cross-Classified Categorical Data. 2nd ed. Cambridge, Mass: MIT Press; 1980. 16. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized for communityacquired pneumonia. Ann Intern Med. 1991;115:428-436. 17. Lentino JR, Lucks DA. Nonvalue of sputum culture in the management of lower respiratory tract infections. J Clin Microbiol. 1987;25:758-762. 18. Fang GD, Fine M, Orloff J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: A prospective multicenter study of 359 cases. Medicine. 1990;60:307-316. 19. Lonks JR, Medeiros AA. High rate oferythromycin and clarithromycin resistance among Streptococcus pneumoniae isolates from blood cultures from Providence, R.I. Antimicrob Agents Chemother. 1993;37:1742-1745. 20. Sempera MA, Gomez J, Ruiz J. Resistance of Streptococcus pneumoniae to erythromycin in adults and children. J Antimicrob Chemother. 1992;29:348-349. 21. Mason EO Jr, Kaplan LB, Lamberth LB, et al. Increased rate of isolation of penicillinresistant Streptococcus pneumoniae in a children's hospital and in vitro susceptibilities to antibiotics of potential therapeutic use. Antimicrob Agents Chemother. 1992;36:17031707. 22. Valenti WM, Trudell RG, Bently DW. Factors predisposing to oropharyngeal colonization with gram-negative bacilli in the aged. NEJM. 1978;298:1108-1111. 23. Johanson WG, Pierce AK, Sanford JP, Thomas GD. Nosocomial respiratory infections with gram-negative bacilli: The significance of colonization of the respiratory tract. Ann Intern Med. 1972;77:701-706. 24. Whittier S, Barnes D, Wait K, et al. Streptococcus pneumoniae: Antibiotic resistance patterns among children in day care. Presented at the 32nd Intersciences Conference on Antimicrobial Agents and Chemotherapy, Anaheim, California, October 11-14, 1992. Abstract 1018. 25. Fine MJ, Smith DN, Singer DE. Hospitalization decision in patients with communityacquired pneumonia: A prospective cohort study. Am J Med. 1990;89:713-721. 26. Fine MJ, OrloffJJ, Arisumi D, et al. Prognosis of patients hospitalized with communityacquired pneumonia. Am J Med. 1990;88(network 5N):5-1N-5-8N. 27. Pullar T, Birtwell AJ, Wiles PG, et al. Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily. Clin Pharmacol Ther. 1988;44:540-545.
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