Worldwide pediatric experience with low-dose sultamicillin oral suspension

CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 5, MAY 1994

WORLDWIDE PEDIATRIC EXPERIENCE WITH LOW-DOSE SULTAMICILLIN ORAL SUSPENSION PIERRE RAILLARD,1 CHERYL FEINER,z VIRGINIA OTT,e GLENDA TREADWAY,3 AND YING WANG2 1Medical Operations, International Pharmaceuticals Group, 2pharmaceuticals Clinical Data Operations, and 3Antibiotics Development Team, International Pharmaceuticals Group, Pfizer Inc., New York, New York

ABSTRACT A total of 431 pediatric patients (233 boys [54%] and 198 girls [46%]) between the ages of 3 months and 16 years, with a diagnosis of upper or lower respiratory tract infections or skin and soft tissue infections, entered this international pediatric clinical program conducted by 14 investigators in nine countries in North, Central, and South Americas; Asia; and Europe. After informed consent was obtained from parents or legal guardians, all children were treated as outpatients and were to receive a daily dose of 25-mg/kg sultamicillin oral suspension, administered as two equally divided doses 12 hours apart. F o u r hundred eight children met all requirements for clinical efficacy evaluability and were included in the drug clinical efficacy assessment; 146 were both clinically and bacteriologically evaluable for efficacy. Three hundred eighty-two patients (94%) were reported as clinically cured, 15 (4%) as improved, and 11 (3%) as clinical failures. The bacteriologic eradication rate was 99%, or 153 of 155 isolated pathogens, including 38 of 39 beta-lactamase-producing strains. All 431 patients were evaluable for safety; 34 (8%) experienced 39 adverse drug reactions that were considered by the investigators to be drug-related or possibly drug-related. As expected with a beta-lactam antibiotic, side effects were mainly gastrointestinal in nature. The most frequent, diarrhea, was reported in 26 patients (6%). Drug discontinuation occurred in 9 patients (2%). Few laboratory abnormalities of potential clinical significance were recorded in any of the treated children. Sultamicillin pediatric suspension, administered orally twice daily at a dose of 25 mg/kg, confirms its efficacy and toleration in the t r e a t m e n t of mildto-moderate bacterial pediatric infections. INTRODUCTION

Sulbactam is an irreversible inhibitor of most of the clinically important types of beta-lactamase enzymes that can degrade penicillins and cephalosporins. 1 In combination with the beta-lactam antibiotic ampicillin, it restores and expands the antibacterial spectrum of the latter to include a Addresscorrespondenceto: Dr. GlendaTreadway,AntibioticsDevelopmentTeam, InternationalPharmaceuticals Group, Pfizer Inc., 235 E. 42nd St., New York, NY 10017. Received for publication on January 24, 1994. Printed in the U.S.A. Reproductionin whole or part is not permitted. 601

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SULTAMICILLIN ORAL SUSPENSION

wide range of gram-positive and gram-negative pathogens: Staphylococcus aureus and Staphylococcus epidermidis (including penicillin-resistant strains and some methicillin-resistant strains); Streptococcus pneumoniae, Streptococcus faecalis, and other Streptococcus species; Haemophilus influenzae and Haemophilus parainfluenzae (beta-lactamase-positive and beta-lactamase-negative strains); Moraxella (Branhamella) catarrhalis; anaerobes including Bacteroides fragilis and related species; Escherichia coli; Klebsiella species; Proteus species (both indole-positive and indolenegative); Enterobacter species; and Neisseria gonorrheae. 2 Sulbactam alone exhibits significant antibacterial activity only against Neisseriaceae, Acinetobacter calcoaceticus, ~-7 Bacteroides species, 4-6's M catarrhalis, 9 and Pseudomonas cepacia. 1° Sultamicillin* is a prodrug in which ampicillin and sulbactam are combined as a double ester. 11 The ester linkage between the two components is hydrolyzed during absorption and results in therapeutic plasma and tissue levels of both components. The respective plasma levels of ampicillin and sulbactam, when given as sultamicillin, have been reported to be two to three times higher than with equivalent doses of either drug administered alone. 12 The clinical efficacy and safety of sultamicillin administered at a daily dose of 50 mg/kg in the treatment of children with infections caused by susceptible organisms have been established by numerous studies. 2'13-17 This article discusses the results of an international clinical trials program conducted to evaluate the efficacy and safety of a 25-mg/kg sultamicillin daily-dose regimen in the treatment of mild-to-moderate pediatric infections. It incorporates data from open noncomparative studies conducted in 14 centers in Argentina, Costa Rica, France, Italy, Mexico, Panama, Taiwan, Turkey, and Venezuela. In the Italian center the protocol was originally designed as a comparative study versus amoxicillin but the investigator did a noncomparative study. Therefore, all protocols were basically similar with regard to design and methodology. Data from two interim reports were published in 1990 and 1992. ls'19 PATIENTSANDMETHODS Infants and children of both sexes, between the ages of 3 months and 16 years, with known or suspected upper or lower respiratory tract or skin and soft tissue infections, based on medical history and clinical findings, were eligible for entry into the clinical trials. Each patient's parent or legal guardian gave informed consent. All patients were outpatients and had a history taken and physical examina* Trademarks: Duocid ®, Unasyn®, U n a s y n a ® (Pfizer Inc., New York, New York).

602

P. RAILLARD ET AL.

tion before the first dose of the study drug was given. Laboratory determinations were left to the discretion of each of the 14 clinical investigators. Signs and symptoms of the infections were assessed and graded before (baseline), during (ie, 3 and 7 days after the first dose of study drug), and at the end of therapy. Whenever possible, appropriate bacteriologic cultures were taken from the infection sites and the pathogens isolated and identified. The isolates were tested for beta-lactamase production, when possible, and the in vitro susceptibility to both ampicillin and the sulbactam/ampicillin combination was determined using the disk susceptibility testing method. Exclusion criteria were: (1) treatment with another antimicrobial agent within 2 weeks before enrollment, unless there was documented failure of this antibiotic; (2) known hypersensitivity to any beta-lactam antibiotic; (3) treatment with any investigational drug; (4) infections requiring treatment with another antimicrobial agent; (5) urinary tract infections; (6) meningitis or suspected meningitis; (7) terminal illness or other disease state that precluded completion and evaluation of study drug therapy; (8) severe hepatic or renal impairment; (9) poorly controlled diabetes; and (10) if culture results were obtained before initiation of treatment, presence of pathogens exhibiting in vitro resistance to the sulbactam/ampicillin combination. Investigators were provided with glass bottles each containing 5.0 g sultamicillin powder for reconstitution with water, which was done by adding 67 mL of sterile water for injection to give 250 mg of sultamicillin/5 mL of suspension. The recommended dose was 25 mg/kg/d, administered in two equally divided doses, approximately 12 hours apart. The exact dose was determined from the patient's weight at the pretreatment physical examination. Duration of treatment depended on the type and severity of infection, and was expected to be within a 7 to 14-day range. Infections caused by beta-hemolytic streptococci were to be treated for at least 10 days to prevent the development of glomerulonephritis and rheumatic fever. Sultamicillin was the only antimicrobial agent allowed, and all concomitant conditions and/or corrective medications were to be recorded on the case report forms. The following laboratory tests were performed at the clinicians' discretion, at entry, and after completion of therapy: (1) hemoglobin; (2) hematocrit; (3) red and white blood cell counts and differential; (4) quantitative platelet count; 45) bilirubin; (6) total protein and albumin; (7) serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyl transferase (GGT), and creatine phosphokinase (CPK); (8) blood urea nitrogen (BUN) and creatinine; (9) alkaline phosphatase; and (10) urinalysis. To be considered evaluable for efficacy, each patient had to be treated 603

SULTAMICILLINORAL SUSPENSION

for a minimum of 5 days at the recommended daily dose (ie, 25 mg/kg). A patient was considered clinically cured when all pretreatment signs and symptoms of infection were eliminated at the end of treatment. Clinical improvement was defined as improvement in, or partial disappearance of, pretreatment signs and symptoms; failure was defined as no change or worsening in those signs and symptoms. Bacteriologic efficacy was assessed by comparing the pretreatment cultures with the end-of-treatment cultures. Eradication was defined as elimination of pretreatment pathogens from the infection site, and persistence was defined as the presence of pretherapy pathogens at the infection site. For skin and soft tissue infections, follow-up cultures are often not available due to wound healing. With otitis media, it is unethical to obtain follow-up middle-ear puncture cultures. For these indications, the terms eradication and persistence were used to reflect the clinical condition of patients at the end of treatment in some cases, and the actual eradication or persistence in other cases. If susceptibility testing was not done, with the exception of a priori resistant pathogens such as Pseudomonas aeruginosa, the organism's susceptibility to sulbactam/ampicillin was assumed. Regarding safety assessment, all clinicians recorded all clinical adverse events encountered, stating date of onset, duration, severity (mild, moderate, or severe), whether the event was considered drug-related (yes, no, or uncertain/unknown), and the outcome. The mean total severity score was calculated at baseline and at all subsequent visits for the 408 clinically evaluable patients. For each patient, the change in total severity score from baseline was calculated at each of the following visits. If a patient did not return for the end-oft r e a t m e n t visit b u t was seen at all three previous visits, the signs and symptoms data from the last visit (days 7 to 13) were repeated for the end-of-treatment visit. The one-sample t test was used for analysis of the changes in total severity score over time for these paired data. Because three comparisons were made (baseline vs 3 to 6 days, baseline vs days 7 to 13, and baseline vs end-of-treatment), a Bonferroni adjustment was made to the significance level. In order for the type I error level for all three comparisons to be less than 0.05, each individual paired comparison was declared statistically significant at P < 0.017. RESULTS

A total of 431 infants and children entered this clinical trials program; 408 met all requirements for clinical evaluability and were included in the clinical drug efficacy assessment. The study sample comprised 233 boys and 198 girls (sex ratio, 1.18). The mean age was 5.1 years (SD, 3.4 years), ranging from 3 months to 16 years (Table I). 604

P. RAILLARD ET AL.

Table I. Demographic characteristics. No. of Patients (%)

Age (yr) Mean SD Range Distribution (%) 3mo-1 yr >1-5 yr >5-10 yr >10-16 yr Not stated Race (%) WhiteBlack Oriental Hispanic Not stated BO~e~neight (kg) SD Range

Male 233 (54)

Female 198 (46)

All 431

5.1 3.5 <1-15

5.2 3.3 <1-16

5.1 3,4 <1-16

261~4/ 102 66 }~I{ 29 10 (43)

22/4~1 74 7315~1 16 13 (57)

48 176 139 45 23

1514I~{ 34 I~l 3

1528/~{ 16/3~/ 2

30312 50 5

34

16

50

2o.4

19.9

20.2

10.6 6-60

10.2 6-58

10.4 6-60

Table II shows the diagnoses of the 431 patients at entry into the clinical study. Twenty-three were excluded from overall efficacy evaluability (14 for incorrect dosing, 3 for inappropriate diagnosis, 3 for prohibited concomitant medication, 2 were lost to follow-up, and i because a resistant pathogen was isolated at baseline). The mean daily dose of sultamicillin for all patients was 26 mg/kg (SD, 4.8 mg/kg; range, 15 to 100 mg/kg; n = 431); the mean duration of therapy for evaluable patients was 10 days (SD, 2.9 days; range, 2 to 22 days; n = 408). Among the evaluable patients, the average length of therapy ranged from a mean of 9 days in children with lower respiratory tract infections to a mean of 12 days in those with otitis media and sinusitis (Table III). A total of 90 patients (21%) had one or more concurrent illnesses or secondary diagnoses. These conditions did not appear to increase the risk of therapeutic failure or to contribute to adverse drug reactions in these children. Two exceptions were a 7-month-old girl with congenital heart disease and an 18-month-old girl infected with the h u m a n immunodeficiency virus; clinical cure was reported in both patients, and no pathogen had been isolated at baseline. One hundred ninety-eight concomitant medications were administered to 146 children. The most frequently prescribed were antipyretics, cough preparations and expectorants, and antihistamine products.

Clinical Efficacy Results Of the 431 children entered into the clinical trials program, 408 were 605

SULTAMICILLIN ORAL SUSPENSION

Table II. Diagnoses. No. of Patients Diagnosis

Male

Female

All

Skin and soft tissue infections Cellulitis Local skin infection Impetigo Wound infection cPyodermatitis arbuncle Erysipela Otitis media Tonsillitis/pharyngitis Tonsillitis Pharyngitis Sinusitis Acute sinusitis Chronic sinusitis Lower respiratorytract infections Bronchitis Pneumonia Other Miscellaneous Lymphadenitis Epiglottitis Rhinitis Total patients

38 17 10 8 2 0 0 1 57 90 73 17 12 10 2 29 18 6 5 7 4 1 2 233

23 9 8 2 1 2 1 0 55 87 77 10 11 9 2 20 7 8 5 2 2 0 0 198

61 26 18 10 3 2 1 1 112 177 150 27 23 19 4 49 25 14 10 9 6 1 2 431

assessed for clinical efficacy and 146 were evaluable for both clinical and bacteriologic efficacy. The clinical investigators assessed 382 patients (94%) as cured, 15 (4%) as improved, and 11 (3%) as clinical failures. Clinical cure was observed in all 39 patients infected with ampicillin-resistant pathogens. Clinical cure rates broken down by diagnosis are presented in Table IV. Of the eleven children reported as clinical failures, 6 presented with Table III. Duration of treatment. Days Diagnosis

N

Mean

All patients Skin/soft tissue infections Otitis media Tonsillitis/pharyngitis Sinusitis Lower respiratorytract infections Miscellaneous

408* 54 105 169 23 49 8

11

SD

Range

2.9

3-22 6-16 5-18 5-15 7-17 3-14 6-22

10

3.2

12 10 12 9 12

2.6 2.2 2.5 2.5 4.9

* Number of evaluablepatients(ie, those who receivedat least 5 claysof treatmentat the recommended25 mg/kg/d dosage).Also includedwas a 6-year-oldfemalepatientwith pneumoniawho was consideredas a failure after only 3 days of treatment.

606

P. R A I L L A R D E T AL.

Table IV. Clinical efficacy. Clinical Response (%) Diagnosis

Total

Cured

Improved

Failed

Skin/soft tissue infections 0titis media Tonsillitis/pharyngitis Sinusitis Lower respiratory tract infection Miscellaneous Total patients

54 105 169 23 49 8 408

54 (100) 92/8~1 165 19/83 / 46 6 382

~/701

0/0 / 6 6 2 1

I;,'/

2 (1) 3(13) 1 /2 2 21 15 (4)

02 11

acute otitis media, 2 w i t h tonsillitis, 2 w i t h p n e u m o n i a , a n d 1 w i t h sinusitis. All 11 w e r e bacteriologically n o n e v a l u a b l e because no microbiology t e s t i n g was done for 9, a n d only t h r o a t c u l t u r e s showing n o r m a l p l a s m a a n d no growth, respectively, w e r e p e r f o r m e d in t h e r e m a i n i n g two p a t i e n t s t r e a t e d for p n e u m o n i a . T h e evolution of the t o t a l signs/symptoms score was s i m i l a r in e a c h diagnostic group, showing a statistically significant i m p r o v e m e n t as e a r l y as t h e first p o s t t r e a t m e n t visit (3 to 6 days p o s t t r e a t m e n t ) in all indications. F i g u r e s 1 and 2 i l l u s t r a t e t h e evolution of infection-related signs a n d s y m p t o m s in t h e two groups r e p r e s e n t i n g the b u l k of t h e p a t i e n t s (ie, tonsillitis a n d otitis media).

5 o

4

"6 I- 3 2

I

BASELINE

m i

+ DAYS 3-6

+DAYS 7-13

+END OF THERAPY

+ I M P R O V E M E N T FROM BASELINE Figure 1. Evolution of signs and symptoms of tonsillitis/pharyngitis (n = 169), including sore throat, tonsillar swelling/redness, fever, lethargy, dehydration, irritability, peritonsillar abscess, and vomiting. *Score: 3 = severe; 2 = moderate; 1 = mild; and 0 = absent, tP = 0.0001. 607

SULTAMICILLIN ORAL SUSPENSION

7 6

3

i

T M

BASELINE

+ DAYS 3-6

+

+DAYS 7-13

+END OF THERAPY

IMPROVEMENT FROM BASELINE

Figure 2. Evolution of signs and symptoms of otitis media (n = 105), including earache, fever, perforated ear drums, irritability, lethargy, vomiting, and dehydration. *Score: 3 = severe; 2 = moderate; 1 = mild; and 0 --- absent, t P = 0.0001.

Bacteriologic Efficacy Results

Eradication and persistence of pathogens isolated from the infection sites were assessed by comparing the pretreatment and the posttreatment culture results. In all cases where this was not acceptable and/or suitable (ie, repetition of middle-ear puncture or absence of culturable material due to healing of a wound), the clinical response was used to determine the bacteriologic efficacy. A total of 146 patients infected by 155 pathogens had baseline cultures and were evaluable for assessment of bacteriologic efficacy; 39 of those isolates were strains of ampicillin-resistant pathogens and 83 were considered ampicillin-sensitive. Thirty-two eradicated strains and one persistent strain were not tested for ampicillin sensitivity. Bacteriologic eradication rates by pathogen are illustrated in Table V. S aureus, streptococci including beta- and alpha-hemolytic streptococci, Streptococcus pyogenes, and S pneumoniae were the most frequently isolated pathogens. Twenty-six strains of S aureus and four strains of beta-hemolytic streptococci isolated at baseline were beta-lactamaseproducing strains resistant to ampicillin in vitro; they account for 77% of all the resistant strains isolated. The bacteriologic eradication rate for beta-lactamase-producing strains was 97% (38/39). One strain of ampicillin-resistant S aureus isolated in a 1-year-old child with purulent tonsillitis persisted despite treatment, although clinical outcome was reported 608

P. RAILLARDET AL.

T a b l e V. Bacteriologic efficacy. N u m b e r of efficacy e v a l u a b l e p a t i e n t s w h o h a d b a s e l i n e c u l t u r e = 146.

No. of Pathogens Baseline Pathogen Acinetobacter calcoaceticus (Anitratus) Enterobacter aerogenes Enterobacter sp Esche#chia coli Haemophilus influenzae Streptococci beta-hemolytic group C Streptococci beta-hemolytic group F Streptococci beta-hemolytic group G K/ebsie/la pneumoniae Proteus mirabilis Proteus sp Rods (negative) Staphylococcus aureus Staphylococcus epidermidis Coagulase-negative staphylococcus Staphylococcus sp Streptococcus pneumoniae (pneumococcus) Streptococcus pyogenes (group A) Beta-hemolytic streptococci Streptococcus viridans group (alpha-hemolytic) All pathogens

No. Eradicated (%)*

Ampicillin- AmpicillinTotal Sensitivet Resistant 1 1 1 4 3 4 1 1 1 3 1 2 37 1 9 2 6 25 39 13 155

-

-

---2 3 ---1 -8 1 5 5 22 27 9 83

1 1 1 2 ----

-

1 ---26 1 2 -4 39

Total (100) I

(i oo)

AmpicillinSensitive

AmpicillinResistant

--

] (100)

(100)

(lOO) 2 0oo) 3 (100) 3 (100) 4 (100) I (100) (100)

I(iooi (100)

=o,

1 uuO)

~ (ioo) (100)

~ (lOO) --

1]Tool

I (100)

(lOO) (95) (100)

(ioo) (100)

1 (100)

5 (ioo)

2~(100) (ioo) 225~Too) (100) 39 (100) 13 (100) 153 (99)

27 (100) 9 (100) 83 (100)

i0oo)

2 (100) 4 000) 38 ~ 7 )

* 32 eradicated strains were not tested for ampicillin sensitivity. 2 of 155 strains persisted: 1 ampicillin-resistant S aureus; 1 S aureus not tested for ampicillin sensitivity. t 19 strains were intermediate in ampicillin sensitivity and all were eradicated with treatment with sultamicillin. Because bacteriologic persistence was not observed in any intermediate strains, these are shown here as sensitive.

as a cure. In another patient, one strain of S a u r e u s isolated from a wound infection site and not tested for ampicillin sensitivity persisted. This patient was considered cured. Toleration

The investigators recorded all clinical adverse events encountered during the trial, stating the date of onset, duration, severity (graded as mild, moderate, or severe), causal relationship with study drug (yes, no, or uncertain/unknown), and the outcome. All 431 children entered into the study were evaluated for safety. Of those, 34 (8%) experienced 39 adverse reactions considered by the investigators to be drug related or possibly drug related. Diarrhea (26 citations, 6%) was the most frequent side effect, followed by cutaneous rash (5 citations, 1.2%). All other side effects had an incidence of less t h a n 1%. Nine patients (2%) discontinued t r e a t m e n t due to adverse drug reactions (gastrointestinal, 8; rash, 1) and no fatalities were reported. Details on reported adverse events related or possibly related to study drug are included in Table VI. All available laboratory test data for each patient were reviewed. For 609

SULTAMICILLIN ORAL SUSPENSION

Table VI. Summary of adverse experiences related or possibly related to study drug for all patients.

Gastrontestna 33/i Body System and Manifestation

Incidence No. of patients (%)

Number Mild _ _

Vomiting 3 0.7 Abdominal pain 1 0.2 Nausea 1 0.2 Diarrhea 26 6.C Feces discolored 1 0.~ Hepatic function abnormal 1 .~ Dermatologic 5 Rash 4/!i i Rash maculopapular 1 . Miscellaneous 1 Anorexia 1 (OIL Total no. of patients receiving sultamicillin: 431 Total no. of ADRs: 39 No. of patients with ADRs: 34 (8%) No. of patients discontinued due to ADR: 9 (2%)

Number Number Discontinued Moderate Severe due to ADR m

_ _

0 0 1 13 0 0

1 1 0 12 1 1

2 0 0 1 0 0

3 1

1 0

0 0

1

0

0

8

3 1 0 6 1 0 1 0 1 O 0

ADR = adverse drug reaction.

each parameter where results deviated from the normal range and represented clinically significant abnormalities, the results were reviewed in greater depth by a physician. Comparison of all available laboratory values to their normal range revealed very few abnormalities of potential clinical significance. A moderate increase in SGOT was reported in a 7-month-old boy and was considered as possibly related to a concomitant intestinal infection due to rotavirus and adenovirus. A significant increase (averaging three times normal) in alkaline phosphatase was reported in five children (4 girls, 1 boy), ranging in age from 5 to 8 years. Although assessed as possibly drug related, these abnormalities remained isolated during drug therapy and were not associated with any hepatic or nonhepatic clinical disorders. It is noteworthy that baseline values were not available for four of the five children but only values obtained after 2 or 3 days of treatment; in addition, all of these patients were recruited and monitored in the same center. In light of these findings and the absence of long-term follow-up information, we concluded that any further attempt to define the clinical relevance of these abnormalities would be speculative. It is also important to note that high values are normally seen in this age group. DISCUSSION

Sultamicillin has been shown to provide effective antibacterial efficacy against clinically important beta-lactamase-producing pathogens including S aureus, H influenzae, and M catarrhalis. 2'9 Bactericidal synergy 610

P. RAILLARD ET AL.

against beta-lactamase-producing strains of S aureus, H influenzae, B fragilis, and Bacteroides species has been demonstrated in vitro with 1:1 (w/w) and 1:2 (w/w) sulbactam/ampicillin combinations.2°'21 Pharmacokinetic studies have also established that ampicillin peak plasma concentrations achieved after oral administration of sultamicillin are approximately 3.5 times those obtained with an equimolar dose of oral ampicillin. 12 Lower daily doses of ampicillin were therefore theoretically expected to be effective when administered with sulbactam as the prodrug sultamicillin. Sultamicillin at a daily dose of 50 mg/kg (yielding the equivalent of approximately 29 mg/kg ampicillin) was shown to provide effective anti-infective therapy for community-acquired pediatric infections of the upper respiratory tract, skin and soft tissue, and the urinary tract. 2'1~-17 We recently reported similar clinical and bacteriologic efficacy cure rates in the treatment of mild-to-moderate community-acquired pediatric infections, using an even lower daily dose of sultamicillin (25 mg/kg), ls'19 These data reporting the initial clinical experience of the 25-mg/kg dose have been included in this review. The compound proved to be effective in the treatment of pediatric patients with a variety of upper and lower respiratory tract infections, and skin and soft tissue infections. Overall clinical and bacteriologic cure rates reported (94% and 99%, respectively) compare very favorably with those observed in previous sultamicillin studies using a similar, ls'19 or a higher average daily dose (50 mg/kg).2'13-17 Efficacy cure rates are basically similar across the various indications, and by the visit on day 3 to 6 m o s t - - i f not all--signs and symptoms of infection had subsided in all indications. Sultamicillin was in particular shown to successfully eradicate all but one of the ampicillin-resistant strains isolated at baseline. Sultamicillin safety was evaluated in 431 patients, and 34 children (8.0%) reported an adverse event. Diarrhea was the most frequently reported adverse drug reaction; it was in most cases mild to moderate in nature, and led to drug discontinuation in only six patients. Those figures are lower than the average incidence rates generally reported for this compound in the international literature when used at a daily dose of 50 mg/kg 2'13 and similar to those reported in studies having used the same daily dose of 25 mg/kg, ls'19 CONCLUSIONS

At a low daily dose of 25 mg/kg, sultamicillin pediatric oral suspension proved to be efficacious and well tolerated in the treatment of mild-tomoderate community-acquired pediatric infections, including infections of the upper and lower respiratolT tract and skin and soft tissue infections. Ninety-four percent of the 408 clinically evaluable children were 611

SULTAMICILLINORALSUSPENSION

cured; in 146 bacteriologically assessable patients, 153 of the 155 isolated pathogens were eradicated, including 38 of 39 ampicillin-resistant strains. Safety was assessed in all patients entered into the study, and the overall good toleration profile of sultamicillin in infants and children was confirmed.

Acknowledgments The authors wish to thank the investigators who participated in this international clinical study program: Dr. Mong-Ling Chu, Taipei, Taiwan; Dr. JF Duhamel, Caen, France; Dr. M. Guillot, Lisieux, France; Dr. E. Hasanoglu, Ankara, Turkey; Dr. G. Kose, Izmir, Turkey; Dr. D. Martini, Padova, Italy; Dr. R. Mata, Panama City, Panama; Dr. A. Morante, Caracas, Venezuela; Dr. I. Passarelli, Buenos Aires, Argentina; Dr. JF Quesada-Solano, Heredia, Costa Rica; Dr. E. Rodriguez-Niriega, Mexico City, Mexico; Dr. C. Saenz, Monterey, Mexico; Dr. F. Sanchez, Caracas, Venezuela, and Dr. Hsin-Chih Wang, Taipei, Taiwan. References: 1. English AR, Retsema JA, Girard AE, et al. CP-45,899, a beta-lactamase inhibitor that extends the spectrum of beta-lactams: Initial bacteriological characterization. Antimicrob Agents Chemother. 1978;14:414-419. 2. Friedel HA, Campoli-Richards DM, Goa KL. Sultamicillin: A review of its antibacterial ~ctivity, pharmacokinetic properties and therapeutic use. Drugs. 1989;37:491-522. 3. Venezia RA, Pisegna-Swift D, Hollick GE, Gregory WW. Rapid bactericidal activity of sulbactam for clinical isolates of Acinetobacter calcoaceticus. Proceedings of the Annual Meeting of the American Society for Microbiology. 1986;86:14. Abstract. 4. Strausbaugh I_J, Martin I.J, Gregory WW. Synergy of cefoperazone/sulbactam against gram-negative pathogens that exhibit reduced susceptibility to a third generation cephalosporin. Proceedings of the Annual Meeting of the American Society for Microbiology. 1986;86:17. Abstract. 5. Fass RJ, Gregory WW, D'Amato RF, et al. Synergy of cefoperazone plus sulbactam against cefoperazone-resistant Enterobacteriaceae and nonfermenters. Presented at the 16th International Congress on Chemotherapy. April 17-21, 1988; Rio de Janeiro, Brazil. Abstract. 6. Jones RN, Barry AL, Parker RR, et al. In vitro antimicrobial spectrum, occurrence of synergy, and recommendations for dilution susceptibility testing concentrations of the cefoperazone-sulbactam combination. J Clin Microbiol. 1986;25:1725-1729. 7. Jones RN, Wilson HW, Thornsberry C, Barry AL. In vitro antimicrobial activity of cefoperazone-sulbactam combinations against 554 clinical isolates, including a review and beta-lactamases studies. Diagn Microbiol Infect Dis. 1985;3:489-499. 8. Wexler HM, Finegold SM. In vitro activity of cefoperazone plus sulbactam compared with that of other antimicrobial agents against anaerobic bacteria. Antimicrob Agents Chemother. 1988;32:403-406. 612

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9. Doern GV, Siebers KG, Hallick LM, Morse SA. Antibiotic susceptibility of betalactamase-producing strains of Branhamella (Neisseria) catarrhalis. Antimicrob Agents Chemother. 1980;17:24-29. 10. Jacoby GA, Sutton L. Pseudomonas cepacia susceptibility to sulbactam. Antimicrob. Agents Chemother. 1989;33:583-584. 11. Baltzer B, Binderup E, Von Daehne E, et ah Mutual pro-drugs of beta-lactam antibiotics and beta-lactamases inhibitors. J Antibiot. 1980;33:1183-1192. 12. Lode H, Hampel B, Bruckner G, Koeppe P. The pharmacokinetics of sultamicillin. APMIS. 1989;97(Suppl 5):17-22. 13. Pitts NE, Gilbert GS, Knirsch AK, Noguchi Y. Worldwide clinical experience with sultamicillin. APMIS. 1989;97(Suppl 5):23-34. 14. Bluestone CD. Role of sulbactam/ampicillin and sultamicillin in the treatment of bacterial infections of the upper respiratory tract of children. APMIS. 1989;97(Suppl 5):35-40. 15. Chang ST, Chung HY, Pai SD, Lee JH. Sulbactam/ampicillinfollowed by oral treatment with sultamicillin for medical and surgical infections. Diagn Microbiol Infect Dis. 1989; 12:175s-178s. 16. Prosperi RJ, de Prosperi EC, Rodriquez JJP. Sulbactam plus ampicillin (sultamicillin) in the treatment of pediatric upper respiratory tract bacterial infections. Rev Med Costa Rica. 1990;47:13-16. 17. Sapan N, Cil E, Cavaloglu B. Oral sultamicillin in upper respiratory and urinary tract infections. Pediatr Cerrahi Derg. 1990;4:33-34. 18. Raillard P, Lee JCH. International clinical experience with low-dose sultamicillin in the treatment of mild to moderate pediatric infections. Curr Ther Res. 1990;48:334-347. 19. Raillard P, Kose G, Ozkan H, et al. Low-dose sultamicillin oral suspension in the treatment of mild to moderate pediatric infections in Turkey. J Int Med Res 1992;20(Suppl 1):12A-23A. 20. Van der Auwera P, Klastersky J. Serum bactericidal activity of ampicillin and mezlocillin with and without sulbactam. Drugs Exp Clin Res. 1984;10:333-343. 21. Ginsburg CM, McCracken Jr GH, Olsen K, Petruska M. Pharmacokinetics and bactericidal activity of sultamicillin in infants and children. J Antimicrob Chemother. 1985;15: 345-351.

613