Use of Ampicillin/Sulbactam (Sultamicillin) in the Management of Pediatric Infections
Sultamicillin is a semisynthetic double ester that combines ampicillin with the beta-lactamase inhibitor sulbactam. It is hydrolyzed in the gastrointestinal tract after oral administration to release equimolar quantities of ampicillin and sulbactam. Sultamicillin has been shown to be effective against a wide range of Gram-positive and Gram-negative bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae b and non-b (both beta-lactamase-positive and beta-lactamase-negative strains), Moraxella catarrhalis and Gram-negative rods and related species.1, 2 These microorganisms are relatively common in pediatric patients and many are resistant to the majority of beta-lactam antibiotics as a result of beta-lactamase production. The combination of sulbactam with the beta-lactam antibiotic ampicillin restores the bactericidal activity of ampicillin.
This article describes the clinical use of sultamicillin in infants and children with known or suspected mild to moderate acute upper respiratory tract or skin and soft tissue infections in a prospective, open, noncomparative multicenter study in Argentina designed to assess the efficacy and tolerability of oral sultamicillin.
COMMON PATHOGENIC MICROORGANISMS IN ARGENTINIAN CHILDREN
Studies have shown that the microorganisms isolated from pediatric patients at the Buenos Aires Hospital can be different from those reported in the English language literature.3, 4 For example Table 1 shows the pathogenic microorganisms isolated from patients suffering from otitis media; the incidence of M. catarrhalis is considerably lower than that cited in the English language publications. Because H. influenzae was found to be the major pathogen in otitis media, the antibiotic susceptibility of H. influenzae strains isolated in the hospital was examined. The majority of strains isolated were non-type b. During the period 1994 to 1995, 7 of 50 strains (14%) isolated were beta-lactamase producers and were resistant to beta-lactam antibiotics in comparison with 6 of 66 strains (9%) isolated between 1990 and 1991. A similar increase was found in penicillin resistance among strains of S. pneumoniae isolated from middle ear fluid. During 1994 and 1995, 10 of 39 strains (25.6%) were resistant to penicillin, in comparison with only 1 of 64 strains (1.5%) during 1990 and 1991 (P < 0.01).
As is the case almost everywhere else in the world, Escherichia coli is the most common pathogen in pediatric urinary tract infections in the Buenos Aires Hospital, being responsible for ∼80% of cases and 90% of first infections. The second most common pathogens are Klebsiella pneumoniae (6%) and Staphylococcus saprophyticus in adolescents and young women (5%). Pseudomonas species (1%) and Proteus species (29%) are seen occasionally (1%). In Argentina >60% of E. coli isolates causing urinary tract infections are resistant to ampicillin, and >40% are resistant to cotrimoxazole (trimethoprim/sulfamethoxazole, the drug used most commonly throughout the world for empiric treatment of urinary tract infections). In comparison the resistance rate for ampicillin/sulbactam was found to be only 10%. The pattern is similar for Proteus mirabilis, with resistance to ampicillin, for many years the treatment of choice against this species, at nearly 30% and resistance to cotrimoxazole at 23%; resistance to ampicillin/sulbactam is only 8%.
These in vitro results with ampicillin/sulbactam are in agreement with clinical findings of >86% clinical efficacy and >85% bacterial response with ampicillin/sulbactam in pediatric patients with upper and lower respiratory tract infections, skin and soft tissue infections and otitis media/sinusitis5(Table 2).
CLINICAL USE OF AMPICILLIN/SULBACTAM IN ARGENTINIAN CHILDREN
Methods. This study was designed to assess the efficacy and tolerability of ampicillin/sulbactam (sultamicillin) in pediatric ambulatory patients in Argentina. Children 5 months to 16 years old with known or suspected mild to moderate upper respiratory tract infections, skin and soft tissue infections and urinary tract infections, etc., were enrolled. The study was open in design, prospective and noncomparative and ran in 10 centers. The recommended daily dose of sultamicillin to be given (orally) was 25 to 50 mg/kg twice a day for 7 to 14 days. Only patients treated for at least 5 days at the recommended dose were considered evaluable. Whenever possible, bacteriologic cultures were taken from the infection sites. Clinical outcome was defined as cure (total remission of symptoms), improvement (decline in intensity of symptoms but not total remission) or failure (persistence or worsening of symptoms).
Results. Of the 500 children recruited 467 were evaluated (one was lost to follow-up so that clinical efficacy was assessed in 466 patients). The mean age of the children was 53 ± 36 months, of whom 74% were <2 years old; 62% were male and 38% were female. The infections found in these patients are shown in Table 3. As expected the most common infections were upper respiratory tract infections, the most frequent of these being acute otitis media.
Cultures were taken from ∼41% of the patients; ∼65% of these were positive (N = 124 patients). Grampositive bacteria were isolated from 88 patients (Table 4), the most frequent of these being Streptococcus pyogenes from the pharynx and skin. Gram-negative bacteria were isolated from 36 patients (Table 5), the most common being E. coli from the urine. As shown in Table 5, M. catarrhalis, as mentioned above, is a rare causal agent of acute otitis media in Argentina.
Of the 466 evaluable patients cure was recorded in 416 (89%), improvement in 37 (8%) and failure in only 13 (3%). Bacteriologic eradication was assessed in 95 (76.6%) of the 124 patients from whom cultures were positive, a reasonable percentage given that these were outpatients. Apart from one case a urinary tract infection attributed to Pseudomonas aeruginosa, bacteriologic eradication was recorded in all cases in which it was assessed.
Side effects were reported in 90 patients (19%). Mild diarrhea was the most common side effect, accounting for 76% of the 90 cases, i.e. 15% of the treated children. None of these patients was forced to discontinue treatment. Vomiting and abdominal cramps (21.9%) and Candida albicans infection in the form of thrush (2.1%) were the other side effects noted. All these side effects were relatively slight.
This large, open, noncomparative study showed that oral administration of ampicillin/sulbactam in the form of sultamicillin is a useful therapeutic option for the treatment of mild to moderate pediatric infections. The drug offered high clinical and bacteriologic cure rates in the outpatients treated in this study, with a low incidence of (relatively minor) side effects similar to those reported in other studies of sultamicillin.6
The increase in beta-lactamase production in pathogenic microorganisms in Argentina has meant that as in the rest of the world, many of the bacteria causing pediatric infections are resistant to the beta-lactam antibiotics that have been used for many years for empiric therapy. Sultamicillin, a mutual prodrug of ampicillin and the beta-lactamase inhibitor sulbactam, has been shown to be active against a wide range of Gram-negative and Gram-positive bacteria against which ampicillin on its own would be ineffective. An open, noncomparative study in a large number of Argentinian children has demonstrated sultamicillin to be an effective treatment for a range of mild to moderate pediatric infections such as otitis media and urinary tract infections. High clinical cure rates and high rates of bacteriologic eradication were recorded. Side effects were mild and infrequent. Ampicillin/sulbactam is a useful treatment option in children with mild to moderate bacterial infections caused by beta-lactamase-producing pathogens.
The following investigators participated in the clinical study: Eduardo L. López. M.D. (Chairman), Noemí A. Rivas, M.D. (Co-Chairman), Ernestina de Apra, M.D., Rodolfo Binelli, M.D., Susana Blacher, M.D., Emilio Cecchini, M.D., Alejandro Fuentes, M.D., Susana de Gimeno, M.D., Rubén Paolucci, M.D., Carlos Posse, M.D., Roberto Santoro, M.D., Miguel Tregnaghi, M.D.
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Proceedings of the Symposium held at the First World Congress of Pediatric Infectious Disease; Acapulco, Mexico; December, 1996
Keywords:© Williams & Wilkins 1998. All Rights Reserved.
Beta-lactamase; sultamicillin; sulbactam; ampicillin; pediatric infections