Comparative, multicenter studies of cefixime and amoxicillin in the treatment of respiratory tract infections

Comparative, Multicenter Studies of Cefixime and Amoxicillin in the Treatment of Respiratory Tract Infections REZA KIANI, M.D. Chicago, ///imis DEBORAH JOHNSON, M.D., BENNIE NELSON, M.A.* Pear/ Rivel; New York

A total of 560 patients were treated in two double-blind, randomized multicenter studies to compare the safety and efficacy of cefixime (400 mg administered once daily) and amoxicillin (250 or 500 mg administered three times daily) for the treatment of bacterial respiratory tract infections. Eighty percent of the 244 patients treated in the lower respiratory tract infections (LRTI) study had acute bronchitis. Streptococcus pneumoniae (13 percent), Haemophilus influenzue (28 percent), and Escherichia coli (10 percent) were the pathogens most frequently isolated from sputum in these patients. Among evaluable patients with positive bacterial culture results at baseline, a favorable clinical response (cured or improved) was obtained in 100 percent of the cefixime- treated patients (22 of 22) and in 96 percent of the amoxicillin-treated patients (23 of 24). Bacte- riologic eradication rates were 100 percent and 83 percent for cefixime and amoxicillin, respectively. In the upper respiratory tract infections CURT11 study, 316 patients with pharyngitis (80 percent) or tonsillitis (14 percent) were treated. Group A, beta-hemolytic Streptococcus (69 percent) and H. influenzae (8 percent) were the pathogens most frequently isolated from the throat culture specimens of these patients. Favor- able clinical results were obtained in 99 percent of the evaluable cefixime-treated group (n = 73) and in 98 percent of the amoxicillin-treated group (n = 66). The bacteriologic eradication rates were 93 percent and 100 percent, respectively. The adverse experiences reported during both studies were similar in nature and frequency to those reported for other beta-la&am antibiotics with the exception of a higher incidence of altered bowel movement (diarrhea and stool changes) with both drugs. These episodes usually resolved without remedial medication when the treatment was withdrawn. No significant adverse laboratory findings were observed. Results of these trials demonstrate that cefixime at a dosage of 400 mg once daily is an effective and safe oral antibiotic for the treatment of acute respiratory tract infections.

From the Department of Medicine, University of Illinois Hospital, Chicago, Illinois, and Medical Research Division, Amencan Cyanamid Company, Pearl River, New York. Requests for reprints should be addressed to Dr. Reza Kiani, Director of Outpatient Clinic and Emergency Room, University of Illinois Hospital, 840 South Wood Street, Chicago, Illinois 60612.

I( *A lkst of additional investigators IS provided at the and of this article. I 1 I

C efixime (also designated as FR17027, FK027, and CL 284, 653 in the literature) is an oral third-

generation cephalosporin that has a broad antibacte- rial spectrum and appears more potent in vitro than cefaclor, cephalexin, and amoxicillin against a wide variety of pathogens, including Haemophilus influenxae, Escherichia coli, and Klebsiella pneumoniae [1,2]. It also has a high level of bactericidal activity against group A and B streptococcus, Streptococcus pneumoniae, and Branhamella catarrhalis and is sta- ble to both penicillinase- and cephalosporinase-type beta-laetamases [2]. Clinical pharmacologic and pharmacokinetic studies have demonstrated that cefixime is well-absorbed orally, has a long plasma half-life for a cephalosporin (three to four hours), and has a good therapeutic index in a variety of infections [3]. These findings have been further supported by clinical studies conducted in patients with a variety of infections [4-6-J.

The wide bactericidal spectrum and potent in vitro activity of cefixime against common respiratory tract pathogens suggest that it should constitute effective treatment for infections caused by organisms that are increasingly becoming more resistant to commonly used antibiotics. Its safety profile, long half-life, and good oral absorption permit once-daily dosing and should increase patient compliance in the outpatient setting. To evaluate these potential advantages, two multicenter trials were conducted. These separate studies involved patients with either lower or upper respiratory tract infections (LRTI and URTI). The effectiveness of cefixime was compared with that of amoxicillin for each of these infections. The results of these studies are presented in this report.

PATIENTS AND METHODS Study Design

Two multicenter studies (one for LRTI and one for URTI) were conducted in 41 sites in the United States from October 1985 to May 1986 using a double-blind, randomized, two-treatment, comparative design. The protocol was approved by the institutional review board of each participating site and informed consent was obtained from each patient (or legal guardian) prior to enrollment. All patients were scheduled for at least three office visits: a baseline visit within three days prior to the first dose; an on-therapy visit within three to five days following the first dose; and an end- of-therapy visit within 72 hours after the last dose. Physical examinations, medical history, and laboratory studies for serum chemistry, hematology, and urinalysis were performed at baseline and end of therapy. Sputum or throat cultures for bacteriologic evaluation were scheduled for each assessment visit. Chest radiographic examinations were required at baseline for patients with a LRTI and repeated at end-of-therapy for patients treated for pneumonia.

6 September 16, 1988 The American Journal of Medicine Volume 85 (suppl 3A)

Patient Selection Susceptibility Testing Male and female inpatients or outpatients, 13 years

of age or older with clinical evidence of a respiratory tract infection, were admitted into the study. Patients were excluded from enrollment if they had a history of alcoholism, chronic severe systemic disease, hyper- sensitivity to cephalosporins or penicillins, abnormal renal or hepatic function parameters, or severe acute concurrent disease or other sites of bacterial infection. Pregnant women, nursing mothers, or women of childbearing potential not practicing an effective method of birth control were also excluded. In addi- tion to the entry criteria, patients in the LRTI trial had to have a diagnosis of an acute lower respiratory tract infection, which could include pneumonia, and were required to have had a sputum culture performed within three days prior to the first dose. Pa- tients were eligible for the URTI study if they had a diagnosis of acute pharyngitis and/or tonsillitis. Pre- treatment throat cultures were also required. If a bacterial pathogen was isolated, susceptibility to cefixime and amoxicillin was determined.

All isolates were tested for susceptibility to cefixime and amoxicillin by measurement of the mini- mal inhibitory concentrations (MIC) utilizing Gibco Sensititre microdilution panels and by zones of inhibition using the disk diffusion test with BBL or Difco 30-pg cefixime or lO+g ampicillin disks. For all organisms, zones less than 23 mm and MICs greater than 1 pg/ml for cefixime indicated resistance. For amoxicillin, zones less than 14 mm and MICs more than 8 pglml indicated resistance for Enterobacteria- ceae, Branhamella, and Neisseria. MICs more than 0.25 pg/ml amoxicillin indicated resistance for Strepto- coccus and Staphylococcus species: zones less than 23 mm for Streptococcus and zones less than 29 mm for Staphylococcus indicated resistance to amoxicillin. For cases in which susceptibility results were incon- sistent between MICs and zones, the zone of inhibition diameter was considered to be more reliable.

Safety Assessments

Dosage and Administration Under the LRTI protocol, eligible patients were

randomly assigned to receive cefixime 400 mg once daily or amoxicillin 500 mg three times daily for 14 days. Under the URTI protocol, patients were randomly assigned to treatment with cefixime, 400 mg once daily, or amoxicillin, 250 mg three times daily for 10 days. Cefixime was administered as two ZOO-mg capsules in the morning and placebo capsules for the afternoon and evening doses. In the LRTI study, amoxicillin was administered as two 250-mg capsules morning, afternoon, and evening. In the URTI study, amoxicillin was given as one 250-mg capsule and one placebo capsule in the morning and one 250-mg capsule in the afternoon and one in the evening. All patients were instructed to take the study medication with meals. No other systemic antimicrobial agent was permitted during the course of the study.

Patients were required to record daily any adverse experiences on their diary cards. The patients were also interviewed by study personnel for adverse experiences at each visit. If laboratory values showed significant deviations from normal limits, the patient was re-tested and monitored until the values were normal or had returned to baseline level. For any adverse experiences reported, the time of onset, duration, and severity were noted. For clinical and laboratory adverse changes, the relationship to study drug (defi- nite, probable, possible, remote, or definitely not), any action taken, and the final outcome were re- corded.

Statistical Methodology

Efficacy Assessments Patients were considered evaluable for the efficacy

analysis if they satisfied the entrance criteria: had at least one bacterial pathogen (obtained from an appro- priate specimen) that demonstrated susceptibility to both study drugs; had a post-therapy culture (unless the LRTI patient was no longer producing sputum); had a minimum of five (URTI group) or seven (LRTI group) consecutive treatment days in the first seven to 10 days of therapy; had no concomitant antimicrobial therapy; and had no serious, chronic underlying conditions that could interfere with the therapeutic outcome.

Clinical efficacy was determined independently of bacteriologic efficacy for each patient. Clinical response was assessed at each visit, but only the response at the end-of-therapy was used for the efficacy analysis. Clinical response was characterized as cured, improved, relapsed, failed, or not evaluated (with reason specified). Bacteriologic response was rated as eradication (elimination of originally isolated pathogens), persistence (presence of originally isolated pathogen at the post-therapy evaluation), or not evaluated (reason specified). Isolation of organisms other than the baseline pathogens was noted but not evaluated.

Adverse drug reaction rates and demography analyses were performed for all treated patients. These analyses and efficacy rates were calculated for all evaluable patients. The homogeneity of the data across centers was assessed to determine the validity of pooling of data from all study sites within the protocol. Treatment groups were compared with respect to clinical and bacteriologic response rates using ordered categorical (Wilcoxon two sample test) or binomial data analysis methods (Fisher’s exact test). Treat- ment differences for demographic characteristics were analyzed as follows: non-ordered categorical data using Chi-squared tests, ordered categorical data using the Wilcoxon two sample test, and continuous data using a two-tailed Student t test. The absence/ severity distribution of each adverse experience oc- curring with an incidence of at least 2 percent was compared between groups using the Wilcoxon two sample test. Similar analyses compared treatment groups for each adverse experience category (e.g., gastrointestinal) and for the overall adverse experience absence/severity distributions. Two-tailed test procedures were used for treatment comparisons and statistical significance was tested at the p = 0.05 level.

RESULTS Study Population

In total, 560 patients from 41 centers were treated in these two multicenter trials: 244 patients from 22 centers participated in the protocol for lower respiratory tract infections (LRTI) and 316 patients from 19

SYMPOSIUM ON CEFIXIMEI KIANI ET AL

September 16, 1988 The Amencan Journal of Medicine Volume 85 (suppl 3A) 7

SYMPOSIUM ON CEFlXlME/ KIANI ET AL

TABLE I

Patient Characteristics of Evaluable Patients*

Cefixime-Treated AmoxiciMTreated

LRTI URTI LRTI URTI

n (“lo) n @I n (“/o) n M

Nu;:; of evaluable patients

Women

22 ii ‘l$i

24 15 15 ‘q E ‘~~~~

7 (32) 39 (53) 9 (38) 43 (65)

Mean age (years) 53.6 27.5 49.7 24.8

Mean weight [kg) 75.4 71.3 76.3 69.3

Race White Black Other

18 60 19 (791 56 (85) 2 11 E (21) 9 (141 2 (9) 2 (31 1 M

Diagnosis LRTI

Bronchitis Pneumonia Other

URTI Pharyngitis Tonsillitis

Infection severity Mild (9)

4: 7

Moderate (101

Severe 1191

11 I:;/ 21 (28) 5 (21) iepresents a subset of the total enrollment of the LRTI study (122 cefixime, 122 amoxlcillin) and the URTI study (160 cefixime, 156 amoxicillin).

centers participated in the protocol for upper respiratory tract infections (URTI).

In the LRTI study, 244 patients were randomly assigned to receive a 14-day course of 400 mg of cefixime once daily (n = 122) or 500 mg of amoxicillin three times daily (n = 122). Based on the capsule counts of returned medication, the majority of patients complied with and completed the fixed-dosage regimen. One hundred (82 percent) cefixime-treated and 89 (73 percent) amoxicillin-treated patients completed the lkday course of therapy. Of the 55 patients (22 cefixime, 33 amoxicillin) who did not complete therapy, the most common reasons included dropout/lost to follow-up (nine cefixime, 12 amoxicillin) and adverse experiences (three cefixime, five amoxicillin). The 122 cefixime-treated patients included 71(58 percent) men and 51 (42 percent) women. The mean age was 49.7 years and the mean weight was 75.2 kg. Ninety-six (79 percent) where white, 21 (17 percent) were black, one (1 percent) was Oriental, and four (3 percent) were classified as other. The 122 amoxicillin- treated patients were comprised of 66 (54 percent) men and 56 (46 percent) women. The mean age was 46.9 years and the mean weight was 73.6 kg. Ninety- five (78 percent) were white, 24 (20 percent) were black, one (1 percent) was Oriental, and two (2 percent) were classified as other. There were no statistically significant differences between treatment groups for any of these demographic characteristics. Eighty-two of the 122 cefixime-treated and 86 of the 122 amoxicillin-treated patients had at least one underlying condition reported. The most prevalent conditions were in the cardiovascular (29 to 32 percent), respiratory (42 to 36 percent), and gastrointestinal (13 to 17 percent) categories. Demographic chasacteris-

tics for evaluable patients were similar to those of the total study population. Patient characteristics of the evaluable patients are summarized in Table I.

In the URTI study, 160 patients received 400 mg of cefixime once daily and 156 received 250 mg of amoxicillin three times daily for 10 days. Capsule counts of returned medication indicated that study patients complied, in general, with the fixed dosage require- ment regimen prescribed in the protocol. One hundred thirty-four (84 percent) cefixime-treated and 131 (84 percent) amoxicillin-treated patients completed the lo-day course of therapy. For the 51 patients (25 cefixime, 26 amoxicillin) who did not complete therapy, the most common reasons reported were no baseline pathogen (seven cefixime, seven amoxicillin); lost to follow-up (seven cefixime, seven amoxicillin); and adverse experiences (three cefixime, four amoxicillin). There were no statistically significant differences in the demographic characteristics of the two treatment groups. Eighty-five (26 percent) of the 316 patients (46 cefixime [2S percent] and 39 amoxicillin-treated [25 percent] patients) had at least one underlying condition reported. The most common conditions were in the cardiovascular (8 percent in both treatments), respiratory (2 to 3 percent), and gastrointestinal (3 to 4 percent) body system categories. Demographic characteristics for evaluable patients were not significantly different from those of the total study population. Patient characteristics of the evaluable patients are summarized in Table I.

Efficacy Forty-six (19 percent) evaluable cases were col-

lected from 12 of the 22 LRTI study sites for efficacy analysis: 22 (18 percent) of these patients received


SYMPOSIUM ON CEFIXIME / KIANI ET AL

TABLE II

Evaluability Status of All Treated Patients

status

Cefixime.Treated Amoxicillin~Trkated

LRTI URTI ~RTI URTI

n (“4 n (“fd n 6) n (%I

Total number of treated patients 122 WI 160 (1001 122 (1001 156 ilOO)

Total number of evaluable patients 22 (18) 13 (46) 24 POJ 66 1421

Total number of nonevaluable patients 100 (84 87 (54) 98 (801 90 VI

Reasons No pretherapypathogen Resistant pretherapy pathogen No pretherapy culture No sensibvities done

No posttherapy culture Other

TABLE Ill

Bacteriologic Response by Pathogen Pretherapy Isolates from Evaluable LRTI Patients*

LRTI Pathogeh Number of Pithogens

Cefixime

Eradication Persistence

n 61 n b)

Arnoxicillin

Eradication Persistence Riumber of Pathogens n (%) n (“10)

H. influenzae E i

WO) 6 167) 3 133) E. co/i S. pheunomae

i 3 liiil

i i

i ; d (86) 1 (14)

S pyogenes Haemophilus parainfluenzae Neiken menmgitidis i

j l l i l j 0 - - - :

7 2 iig a

S. au& - - - Enterobacter agglomerans i 1’ i tij i Proteus vulgaris Enterobacter cioacae !

t - -

i

(ii, j

iii!/ i - -

Hafma alvei 0 Pseudomonas aerupnosa ;

1 i

iif/ 0 i 0 i (100)

B. catarrhals i

(1001 Serfatia marcescens - - -

! !

i;i; l i

Streptococcus agalactiae i

- - - Beta-hemolytic Streptococcus - 1 i (1001 ; Streptocokxs hemolybc non-A or-B

i - - - I1001

Proteus mirabik - - i ! UOO) i Citrobacter freund 0 - - - 1 1 (100) 0

LRTI subtotal 25 (100) 25 (100) 0 29 (100) 24 (831 5 (17 These data are derived from the 22 evaluable patients treated with cefixime and 24 evaluable patients treated with amoxlcillin.

ceflxime and 24 (20 percent) received amoxicillin. The URTI study provided 139 (44 percent) evaluable patients from 16 of the 19 URTI sites: ‘73 patients received cefixime and 66 received amoxicillin.

cal improvement with treatment and were permitted to complete the course of therapy.

Bacteriologic Efficacy Of the 560 patients in these two studies, 365 were In the LRTI study, a total of 54 pathogens were

excluded from the efficacy analysis: 198 of 244 were isolated; 25 from the 22 cefixime-treated evaluable excluded from the LRTI,study and 177 of 316 patients patients and 29 from the 24 amoxicillin-treated pa- were excluded from the LJRTI study. In both studies, tients. The eradication rate was 100 percent (25 of 25) the most common reasons for exclusion involved the for the cefixime-treated patients and 83 percent (24 of outcome of the baseline culture (i.e., negative culture ‘29) for the amoxicillin-treated patients. H. influenxae results, resistant pathogens, culture or sensitivity not was the predominant pathogen: six of six pathogens done), which was not known at the time of the first eradicated for the cefixime-treated patients and six of dose. These reasons accounted for 94 percent of the nine pathogens eradicated for the amoxicillin-treated excluded ljatients in the LRTI study and 88 percent of patients (Table III). Five patients treated with the excluded patients in the URTI study. The reasons cefixime and eight patients treated with amoxicillin for exclusion are summarized in Table II. Although it had multiple pathogens. All pathogens were eradi- was known early during therapy that these patients cated in the cefixime-treated patients and in seven of did not qualify for analysis, most of them showed clini- the eight amoxicillin-treated patients. One amoxi-

September 16, 1988 The American Journal of Medicine Volume 85 (suppl 3A) 9

SYMPOSIUM ON CEFIXIME I KIANI ET AL

TABLE IV

Bacteriologic Response by Pathogen of Pretherapy Isolates from Evaluable URTI Patients*

URTI Pathogens Number of Pathogens

Cefixime


n (%) n N Number of Pathogens

Amoxicillin


n (%) n (“4

H. influenzae S pyogenes Beta-hemolytic Streptococcus Strepfococcus-beta group C S. agalacfiae Streptococcus-beta group F Streptococcus group G Streptococcus eguisimilis S. pneumoniae Streptococcus non-A or -D

4 59 3

f

5: (100) 0 2 E1 :

(51 (33)

: (67) 133) WJ) A

-i (100) 0 : IW

I!:;; i

1 0

URTI subtotal 74 69 (93) 5 m 68 68 (100) 0

*These data are derived from the 73 evaluable patients treated with cefixime and 66 evaluable patients treated with amoxicillin.

cillin-treated patient had a mixed response (eradica- were cured, four (6 percent) improved, and one (2 per- tion and persistence). cent) relapsed (Table V).

In the URTI study, ‘73 of the cefixime-treated (46 percent) and 66 of the amoxicillin-treated patients (42 percent) were included in the efficacy analysis. A total of 142 pathogens were isolated: 74 from the cefixime- treated patients and 68 from the amoxicillin-treated patients. The eradication rate for the cefixime-treated patients was 93 percent (69 of 74) and 100 percent (68 of 68) for the amoxicillin-treated patients. Streptococ- cus pyogenes was the predominant pathogen: 59 pathogens eradicated (95 percent; 56 of 59 eradicated) for the cefixime-treated patients and 50 pathogens eradicated (100 percent; 50 of 50 eradicated) for the amoxicillin-treated patients (Table IV). One of the cefixime- treated patients had two pathogens. Two of the amoxicillin-treated patients had two pathogens each. All of these pathogens were eradicated by the end of therapy.

Microbiologic Results The predominant pathogens isolated in the LRTI

study were H. influenxae (28 percent), S. pneumoniae (13 percent), and E. coli (10 percent). Over 70 percent of all the pre-study sputum isolates obtained in this study were tested in vitro to determine susceptibility to the study drugs. In both the microdilution and the disk diffusion test systems, more pathogens were sensitive to cefixime than to amoxicillin (88 of 128 169 percent] sensitive to cefixime versus 65 of 128 [51 percent] sensitive to amoxicillin).

Four (two cefixime, two amoxicillin) of the 46 evaluable patients in the LRTI study and only one (amoxicillin) of the 139 evaluable patients in the URTI study had organisms other than the initial pathogen isolated during or after therapy. In both groups, the patients were assessed as cured or improved at the end of therapy. None of the new organisms was considered to have caused a super-infection.

The in viko susceptibility rates were somewhat different in the URTI study, in which the most frequently isolated pathogens were beta-hemolytic Streptococcus, primarily group A, (68 percent); Hae- mophilus species (7 percent), and Staphylococcus aureus (6 percent). Overall sensitivity rates were 83 percent (166 of 199) for cefixime and 90 percent (161 of 178) for amoxicillin. Most isolates of Staphylococcus were resistant to both drugs. In the in vitro tests, group A Streptococcus had a resistance rate of 7 percent (nine of 129) for cefixime and 0.8 percent (1 of 121) for amoxicillin. Nevertheless, clinical cures were achieved in all patients with these isolates.

Overall, the bacteriologic response data from the evaluable pathogens demonstrate a pathogen eradication rate ranging from 95 percent to 100 percent for cefixime-treated patients with respiratory tract infections as compared with a similar group of amoxicillin- treated patients in whom the eradication rate was 83 percent to 100 percent.

Adverse Drug Reactions

Clinical Efficacy For the LRTI study, 13 (59 percent) of the 22

cefixime-treated patients were cured and nine (41 percent) improved. Fourteen (58 percent) of the amoxicillin-treated patients were cured, nine (38 percent) improved, and one (4 perent) relapsed.

For the URTI study, 69 (95 percent) of the 73 cefixime-treated patients were cured, three (4 percent) improved, and one (1 percent) relapsed. Sixty- one (92 percent) of the 66 amoxicillin-treated patients

The adverse experiences reported during both studies were similar in nature and frequency to those reported for other beta-la&am antibiotics. In the LRTI study, the overall incidence of adverse experiences was 43.4 percent (53 of 122) for cefixime-treated patients, and 47.5 percent (58 of 122) for amoxicillin- treated patients. Significantly more cefixime-treated patients reported stool changes (soft, loose., or in- creased frequency of stools), whereas significantly more amoxicillin-treated patients reported rashes. One cefixime-treated patient who completed therapy had diarrhea with a positive Clostridium difficile titer. The patient was treated with Vancomycin and the diarrhea resolved six days later. More amoxicillin- treated patients experienced abdominal pain, but this difference was of borderline statistical significance.


SYMPOSIUM ON CEFIXIME / KlANl ET AL

TABLE V

Clinical Response by Diagnosis in Evaluable Patients

Diagnosis

Cefixime Amoxicillin

Cure Improvement Relapse Cure Improvement Number of ___ ___ -

Relapse Number of ___ ___ ___

Patients n (sb) n (%) n [p/,1 Patients n (O/O) n PO) n Pd

LRTI

Bronchitis Pneumonia Asthmatic bronchitis Bronchopneumonia

LRTI total 22 13 (59) 9 (41) 0 24 14 (581 9 (381 1 (4) URTI

Pharyngitis Tonsillitis

58 56 56 51 15

(911 13 (71 10 10 (1001

ii (71 :, (2)

URTI total 73 69 WI 3 141 1 (1) 66 61 (921 4 (6) 1 (21

TABLE VI

Adverse Experiences with an Incidence of 2 Percent or Greater in Treated Patients

Adverse Experience Category

CefiximeTreated AmoxicilliwTreated

LRTI (n = 122) URTI (n = 160) LRTI (n = 122) URTI (n = 156)

n b) n 6) n Pd n (oi,)

Overall incidence

Gastrointestinal Diarrhea Stool changes Nausea Abdominal parn Dyspepsia Vomiting

53 (431 69 (43) 58 (48) 64 (41)

16 15 l! [ii/ 24

iii/ ‘\ii ;

(5) (61

i (3) 11 (7) ; (71 11 (71 (4 0

; i 14) f

0 8 (51

2 0

Central nervous system Headache Dizziness

11 PI 27 6 (5) 3

Skin and appendages Rash Pruritus :

(61 (4) (31 i

Other Dry mouth Somnolence Fatigue Malaise Rhinitis

Table VI summarizes the adverse experiences reported with an incidence of 2 percent or greater.

Three cefixime- and five amoxicillin-treated patients discontinued treatment early because of adverse experiences. The three eefixime-treated patients all discontinued therapy because of gastrointestinal events, whereas the five amoxicillin-treated patients discontinued therapy because of various adverse experiences, including gastrointestinal events (n = Z), sinusitis (n = l), nosebleeds (n = l), and rash (n = 1). All recovered after termination of therapy.

In the URTI study, the overall incidence of adverse experiences for each treatment group was compara- ble: 69 of 160 (43 percent) cefixime-treated patients and 64 of 156 (41 percent) amoxicillin-treated patients.

Cefixime-treated patients had significantly (p ~0.01) more gastrointestinal disturbances than the amoxicillin-treated patients (54 [34 percent] versus 32 [Zl percent] patients). The amoxicillin group experienced more rash and dry mouth but the difference was of borderline statistical significance. Headaches occurred more frequently in the amoxicillin-treated patients (17 percent) than in the cefixime-treated patients (11 percent); this difference was not statistically significant.

Three cefixime- and four amoxicillin-treated patients discontinued therapy because of adverse experiences. The three cefixime-treated patients discontinued therapy because of moderate urticaria, severe diarrhea, and moderate dizziness with gastrointesti-

September 16, 1988 The American Journal of Medicine Volume 85 (suppl 3A) 11

nal problems. The four amoxicillin-treated patients discontinued therapy because of moderate rash and moderate dizziness. All patients recovered quickly after stopping the study drug.

Adverse Laboratory Changes A few clinically significant adverse laboratory

changes were observed for both treatments. None of the drug-related changes required remedial treatment or warranted discontinuation of therapy.

SUMMARY AND DISCUSSION Results showed that cefixime administered once

daily for 10 to 14 days was as effective as amoxicillin given three times daily for treatment of both lower and upper respiratory tract infections. In the LRTI study, where the predominant diagnosis was acute bronchitis, the evaluable group of cefixime-treated patients had an overall clinical response of 59 percent clinically cured, 41 percent clinically improved, and 1 percent relapse. The bacteriologic eradication rate in this group was 100 percent. Amoxicillin (500 mg three times daily) effected similar responses: 58 percent cured, 38 percent improved, 4 percent relapse; bacte- riologit testing, however, revealed only 83 percent eradication.

In the URTI study, in which most of the patients had streptococcal pharyngitis, the evaluable patients had a clinical response of 95 percent clinically cured and 4 percent improved for cefixime, and for amoxicillin (250 mg three times daily), 92 percent cured and 6 percent clinically improved. Bacteriologic eradication rates were 93 and 100 percent for cefixime and amoxicillin, respectively.

No significant differences in efficacy parameters were observed between treatments in either study. These results were consistent with those of other studies in which amoxicillin and other cephalosporins were used in the treatment of respirator-v tract infections [7--141.

The number of patients considered in the efficacy analysis was low in both studies: only 20 percent (46 of 244) of the. LRTI patients and 46 percent (192 of 316) of the URTI patients were included. This was primarily due to the fact that presumptive therapy was permitted in these trials. For LRTIs, these are typical rates due to the difficulty in obtaining specimens for pathogen isolation. Most nonevaluable patients were excluded from analysis because their baseline culture specimen provided no pathogen: 71 of 122 (58 percent) cefixime-treated and 60 of 122 (49 percent) amoxicillin-treated patients were excluded in the LRTI study and 45 of 160 (28 percent) cefixime-treated and 54 of 156 (35 percent) amoxicillin-treated patients were excluded in the URTI study. Patients were also excluded because their baseline pathogen was not susceptible to both study drugs. This occurred in 13 percent (32 of 244 [14 cefixime, 18 amoxicillin]) of the LRTI patients and 10 percent (32 of 316 [18 cefixime, 14 amoxicillin]) of the URTI patients. The remaining 14 to 15 percent of the patients were excluded for various other reasons (e.g., protocol violations, with- drawal from the study, susceptibility testing not done).

The general outcome of nonevaluable patients sup- ports the results demonstrated by the evaluable pa-

SYMPOSIUM ON CEFIXIME / KlANl ET AL

tients. The clinical outcome of nonevaluable patients who were clinically evaluated was favorable (cure and improved rates combined) for both treatments (94 percent cefixime, 95 percent amoxicillin) in the LRTI and URTI (96 percent cefixime, 92 percent amoxicillin) studies. Additionally, patients in the LRTI study who were excluded because their baseline pathogen was resistant to one or both study drugs had eradication rates of 85 and 83 percent for cefixime and amoxicillin, respectively; eradication rates for patients in the URTI study were 95 and 93 percent,, respectively.

In vitro results, determined by MICs and zones, showed that most of these pathogens associated with community-acquired URTIs and LRTIs were susceptible to cefixime. In these. studies, the most resistant organisms were Staphylococcus and Pseudomonas. The infections were generally associated with a favor: able clinical outcome. Superinfections did not appear to be a problem in these studies.

The safety profile of cefixime was similar to that reported for other beta-la&am antibiotics [l&17]. Results of these. studies agreed with those described by Norrby [16] in his review of newer cephalosporins. Skin reactions, drug fever, headaches, and the more severe laboratory abnormalities (hematologic reactions, hepato-ti and nephrotoxicity) occurred with low frequency, whereas the incidence of bowel changes appeared higher than for other antibiotics. Norrby [16] suggests this increase may be associated with the degree of oral absorption and a high degree of biliary excretion, which leads to higher concentrations of ac- tive antibiotic in the bowel. In these studies, the incidence and nature of side effects were similar for both treatments ivith the exception of a somewhat higher incidence of bowel problems in the cefixime group. The most frequently reported adverse experiences associated with cefixime were diarrhea (10 to 14 percent) and stool changes (13 to 15 percent), whereas diarrhea (5 to 12 percent) and headaches (9 to 1’7 percent) were more often associated with amoxicillin. The adverse effects of diarrhea and other stool changes were very much like those described by Norrby [16] for other oral cephalosporins, and the incidence was within the range given by Alanis [15] for gastrointestinal reactions with oral penicillins and cephalosporins. A total of six cefixime-treated and nine amoxicillin- treated patients discontinued treatment because of adverse effects. The cefixime-treated patients discontinued treatment because of diarrhea andlor nausea (five patients) and rash (one patient). Amoxicillin- treated patients discontinued treatment because of rash (four patients), diarrhea (two patients), and one each for dizziness, nosebleed, and sinusitis. No significant adverse laboratory findings were observed for either treatment group in these studies.

In summary, the results of these multicenter trials demonstrate that: (1) cefixime is as effective an antibiotic as amoxicillin for the treatment of community- acquired upper and lower respiratory tract infections; (2) cefixime administered as a once-daily regimen is safe and effective; (3) pathogens associated with the majority of community-acquired respiratory tract infections are susceptible to cefixime; and (4) the adverse effects generally associated with cefixime were lower gastrointestinal tract reactions that usually resolved without remedial therapy and disappeared when cefixime treatment was discontinued. Its anti-


SYMPOSIUM ON CEFIXIME I KIANI ET AL

bacterial spectrum of activity, its long half-life, and the advantage of once-daily dosing in terms of patient compliance confirm the value of cefixime as a new oral antibiotic.

ADDITIONAL INVESTIGATORS The LRTI multicenter trial was conducted by the

following principal investigators: S. Salzman (private practice, Miami, Florida), R. Thacker (private practice, St. Petersburg, Florida), L. Seebach (private practice, San Francisco, California), M. Barash (private practice, Fremont, California), L. Repsher (Lu- theran Medical Center, Wheat Ridge, Colorado), B. Kim (Scripps Hospital, La Jolla, California), J. McMil- lian, (private practice, Camp Hill, Pennsylvania), R. Snepar (private practice, Highland Park, New Jer- sey), L. Coulson (West Side Veterans Hospital, Chi- cago, Illinois), D. Epstein (Huron Road Hospital, East Cleveland, Ohio), E. Wilkins (private practice, Raleigh, North Carolina), A. Erickson (Veterans Administration Medical Center, Davis Park, Provi- dence, Rhode Island), R. Kiani (University of Illinois Hospital, Chicago, Illinois), R. Fairshter (Irvine Med- ical Center, Orange, Cahfornia), E. Petsonk (West Virginia University Medical Center, Morgantown, West Virginia), T. Taylor (Veterans Administration Medical Center, White River Junction, Vermont), L. Rossoff (Long Island Jewish Hillside Medical Center, New Hyde Park, New York), C. Sanders (Lousiana State University Medical Center, New Orleans, Lousiana), W. Tomford (Cleveland Metro Medical Center, Cleveland, Ohio), B. Hartman (The New York Hospital, Cornell Medical Center, New York, New York), W. Klaustermeyer (Wadsworth Medical Center, Los Angeles, California), and R. Cuthbertson (Sequaro Medical Center, Ltd., Phoenix, Arizona).

The URTI multicenter trial was conducted by the following principal investigators: A. Kneitel (private practice, Suffern, New York), L. Coulson (West Side Veterans Administration Hospital, Chicago, Illinois), H. Wilner (private practice, Los Angeles, California), R. Cuthbertson (Sequaro Medical Center, Phoenix, Arizona), G. Bliss (Seattle Medical Associates, Seat- tle, Washington), H. Kimmerling (private practice, Dallas, Texas), E. Bloom (private practice, Miami, Florida), T. Nolen (Columbiana Clinic, P.C., Colum- biana, Alabama), H. Wilbur (Glenville Health Associ- ates, Cleveland, Ohio), R. Kiani (University of Illi- nois, Chicago, Illinois), L. Lilienfield (Georgetown

University, Washington, D.C.), J. Davis (Norwood Hospital, Norwood, Massachusetts), J. Palmer (Marshfield Medical Center, Marshfield, Wisconsin), R. Scott (private practice, Cleveland, Ohio), K. Smith (Medical College of Wisconsin, Milwaukee, Wiscon- sin), J. Watson (University of Connecticut, Storrs, Connecticut), W. Featherstone (Family Practice Cen- ter, Houston, Texas), H. Beckman (Wayne State Uni- versity, Detroit, Michigan), and E. Lewin (Henry Ford Hospital, Detroit, Michigan).

REFERENCES 1. Jones RN. Barrv AL. Fuchs PC. Thornsberrv C: In vitro evaluation of FK027 icefiximel. a new broad spectrum cephalosporin, against fiSA Isolates. In: Moellerrng RC Jr: Shimada K (eds). Review of new oral cephems. Proceedings Workshop at the 14th ICC. Kyoto: Univer- srty of Tokyo Press, 1985; 17-21. 2. Neu HC, Chin N-X, Labthavikul P: Comparative in wlro activity and B-lactamase stability of FR17027, a new orally actrve cephalosporin. J Antimicrob Chemother 1984; 26 (2): 174-180. 3. Brrttain DC, Scully BE, Hrrose T, Neu HC: The pharmacokinetic and bacterrcrdal characteristics of oral cefixrme. Clan Pharmacol Ther 1985; 38 (5): 590-594. 4. Oizumi K, Saito A, Hayashi I: Therapeutic efficacy of FK027 in the treatment of respiratorv tract infectrons. In: Moellenne PC Jr. Shimada K feds). Review of new oral ceohems. Proceedrngs Workshop at the 14th ICC. Kyoto: University of Tokyo Press, 1985; 41-45. 5. Levenstein J, Summerbeld PJ, Fourre S, Brink G, Michaelides-Murray E, Naidoo N: Comparison of ceflxime and co-trimoxazole in acute uncomplicated urinary tract infection. A double-blind general oractlce studv. S Afr Med J 1986: 70 (8): 455-460. 6. Konishi K, Tamura M: Cknical stud,& of FK027, a new oral cephaiosporin In respiratory tract infections, and its pharmacokinetics. In: lshigamr J, ed. Recent advances in chemo- therapy. Proceedings of the 14th ICC. Kyoto: University of Tokyo Press, 1985; 1157-1158. 7. Brodie NH, McGhie RC, O’Hara H, O’Hara J, Rahman MK, Valle-Jones JC: A double-blind studv comoarlne cefaclor and amoxicrllin in the treatment of respiratorv tract infectrons in general practice. Pharmacotherapeutica 1980; 2 (2): 494-498. ’ 8. Hurst DJ: A comparison of cefaclor and tetracycline in the treatment of bacterial bronchitis. Clin Ther 1984; 6 (2): 163-169. 9. Jaffe GV, Grimshaw JJ: Comparatrve study of cefaclor and amoxicillin In the treatment of respiratory tract infections in general practice. Curr Med Res Open 1980; 6 (8): 569- 572. 10. Yango BG, Palumbo JA, Nolen T. Lifland PW, Schleupner CJ: Comparative mulbcentre evaluation of the safety and efficacy of ceftazidime versus cefamandole for pneumonra. J Antlmicrob Chemother 1986; 4: 521-529. 11. Cooper TJ, Ladusans E, Williams PE, Polychronopoulos V, Gaya H, Rudd RM: A compar- Ison of oral cefuroxime axetil and oral amoxyciilin rn lower respiratory tract infections. J Antimrcrob Chemother 1985; 3: 373-378. 12. Potgieter PD, Lrnton DM, Forder AA, Plumb H: Ceftriaxone therapy in adults wfth severe lower respiratory tract mfectrons. S Air Med J 1986; 69 (8): 495-497. 13. Gerber MA, Randolph MF, Chanatry J, Wright LL, Anderson LR, Kaplan EL: Once daily therapy for streptococcal pharyngibs wrth cefadroxil. J Pediatr 1986; 109 (3): 531-537. 14. Abbate GP, Alagia I, Graqumto E, et al; Treatment of lower respiratory tract infectrons wrth ceftriaxone and cefotaxime. Respiration 1986; 49 (3): 222-230. 15. Alanis A.’ Weinstein AJ: Adverse reactions associated with the use of oral oenicillins and cephalosporins. Med Clan North Am 1983; 67 (1): 113-129. 16. Norrby SR: Adverse reactions and interactions with newer cephaiosponn and cephamycrn antibiotics. Med Tox 1986; 1: 32-46. 17. Kramer MS. Hutchmson TA. Maimark L. Contardi R. Fleeel KM. Leduc DG: Antrbiobc- associated gastromtestinal symptoms In general pediatric oujpatrents. Pediatrics 1985; 76 (3): 365-370.

September 16, 1988 The American Journal of Medicme Volume 85 (suppl 3A) 13

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Comparative, multicenter studies of cefixime and amoxicillin in the treatment of respiratory tract infections