January 1977
144
The Journal o f P E D I A T R I C S
Treatment of pulmonary infections in patients with cystic fibrosis: A comparative study of ticarcillin and gentamiein The effectiveness of ticarcillin against Pseudomonas aeruginosa in acute exacerbations of pulmonary infection in patients with cystic fibrosis was evaluated. Seventy-one percent of patients treated with ticarcillin alone responded favorably. The response rate was similar in patients treated with a combination of ticarcillin plus gentamicin or with gentamicin alone. Severity of the underlying disease was the most important determinant of response to treatment. Ticarcillin-resistant organisms were recovered during treatment in 50% of patients who received this drug; recover), of them was not prevented by the inclusion of gentamicin in the therapeutic regimen nor did they interfere with clinical improvement. The ticarcillinresistant strains persisted at follow-up, two to six months after completion of therapy, in only one of ten patients. No serious toxicity to ticarcillin was noted during the study period
M i c h a e l F. P a r r y , H a r o l d C. Neu,* Matin Merlino, P u r e z a F l o r G a e r l a n , Celia N. O r e s , and C a r o l y n R. Denning, N e w York, N. Y.
RESPIRATORY INFECTION due to Pseudomonas aeruginosa is a major cause of death in patients with cystic
fibrosis? :~ The introduction of carbenicillin in 1967' proved to be a major advance in the treatment of pulmonary infections due to Pseudomonas. Despite clinical improvement in some patients with cystic fibrosis treated with carbenicillin, alone or with an aminoglycoside antibiotic,:'-" Pseudomonas was not eliminated from the sputum. Furthermore, administration of 500 to 600 mg/kg of carbenicillin per day (4.7 meq Na +/gm) is a problem for patients with cor pulmonale. The availability of ticarcillin, a new semisynthetic thienylpenicillin derivative which is two- to fourfold more active against Pseudomonas aeruginosa strains than is carbenicillin,'" prompted us to evaluate its efficacy in patients with pulmonary exacerbations of cystic fibrosis from whom Pseudornonas was cultured. We have From the Departments of Medicine and Pediatrics, College of Physicians and Surgeons, Columbia Universi(v and Columbia-Presbyterian Medical Center. *Reprint address: Division of Infectious Diseases, Department of Medicine, Columbia University, 630 West 168th St., New York, NY 10032. Vol. 90, No. l, pp. 144-148
compared the effectiveness of ticarcillin alone, ticarcillin plus gentamicin, and gentamicin alone in patients with cystic fibrosis. We have attempted to define those factors responsible for success or failure of therapy, the frequency with which ticarcillin-resistant microorganisms are isolated during therapy, and the influence that the development of ticarcillin-carbenicillin-resistant strains has on the subsequent course of the pulmonary disease.
Abbreviations used MIC: minimum inhibitory concentrations BUN: blood urea nitrogen
MATERIALS AND METHODS Forty-two courses of antimicrobial therapy were evaluated in 28 patients with cystic fibrosis admitted to the Columbia-Presbyterian Medical Center for acute infectious exacerbations of their pulmonary disease. Patients with acute respiratory symptoms were selected for study on the basis of isolation of Pseudornonas aeruginosa in pretreatment cultures of sputum. Beginning in April, 1974, patients who qualified for the study were placed alternately on ticarcillin alone or
Volume 90 Number 1
Ticareillin and gentamicin in treatment of pulmonar), infections
ticarcillin plus gentamicin. The study was concluded in August, 1975, with 14 courses of treatment for each group. These were compared with 14 other episodes of infection treated with gentamicin alone during the study period. Written, informed consent was obtained from each adult subject or parents of minors (children) prior to administration of ticarcillin. Ticarcillin, as the disodium salt (4.7 mEq Na+/gm), was supplied by Beecham-Massengill Pharmaceuticals, Bristol, Tenn. The drug was reconstituted with sterile water and diluted further with 50 to 200 ml of 5% dextrose in water for intravenous administration. Patients received 300 mg of ticarcillin per kg of body weight per day in equally divided doses intravenously every four hours. Gentamicin was administered as the commercially available preparation (Schering Corp., Kemilworth, N.J.), in a dose of 3 to 4 m g / k g / d a y in adult patients and 4 to 7 mg/ kg/day in children, either intravenously or intramuscularly. Most patients had been treated unsuccessfully with other oral and nebulized antibiotics prior to admission. These antibiotics were not continued during the study period. Physical therapy to the chest, bronchial drainage, and aerosol therapy with mucolytic agents were administered to all patients. Digitalis and diuretics were given for congestive heart failure. Complete blood count, sedimentation rate, urinalysis, serum electrolytes, blood urea nitrogen, creatinine, liver function tests, chest radiographs, and blood gas determinations were performed before therapy, at least weekly during therapy, and at the end of therapy. Pulmonary function tests were performed when possible. Ivy bleeding times were performed in six patients receiving ticarcillin. Sputum cultures were obtained before, during, and at the end of therapy, as well as two to six months after completion of therapy. These cultures were incubated for 72 to 96 hours, since we have observed that, after only 24 hours of incubation, growth of Pseudomonas species is often scant and easily overlooked. Organisms were identified by standard laboratory techniques,' .... and disc sensitivity tests to carbenicillin, ticarciltin, and gentamicin were performed by the method of Bauer and associates. '~ Minimum inhibitory concentrations of carbenicillin and ticarcillin for the isolated organisms were determined by agar dilution studies as previously described. 1~ Ticarcillin concentrations were assayed in serum and sputum by the agar plate technique '~ using Pseudomonas aeruginosa NCTC 10701 as the assay organism. Patients were classified as clinically improved or not improved after therapy. Response was assessed by evaluating changes in cough and sputum production, temperature, respiratory rate, physical findings, and body weight, together with alterations in sedimentation rate
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144
The Journal o f P E D I A T R I C S
Treatment of pulmonary infections in patients with cystic fibrosis: A comparative study of ticarcillin and gentamiein The effectiveness of ticarcillin against Pseudomonas aeruginosa in acute exacerbations of pulmonary infection in patients with cystic fibrosis was evaluated. Seventy-one percent of patients treated with ticarcillin alone responded favorably. The response rate was similar in patients treated with a combination of ticarcillin plus gentamicin or with gentamicin alone. Severity of the underlying disease was the most important determinant of response to treatment. Ticarcillin-resistant organisms were recovered during treatment in 50% of patients who received this drug; recover), of them was not prevented by the inclusion of gentamicin in the therapeutic regimen nor did they interfere with clinical improvement. The ticarcillinresistant strains persisted at follow-up, two to six months after completion of therapy, in only one of ten patients. No serious toxicity to ticarcillin was noted during the study period
M i c h a e l F. P a r r y , H a r o l d C. Neu,* Matin Merlino, P u r e z a F l o r G a e r l a n , Celia N. O r e s , and C a r o l y n R. Denning, N e w York, N. Y.
RESPIRATORY INFECTION due to Pseudomonas aeruginosa is a major cause of death in patients with cystic
fibrosis? :~ The introduction of carbenicillin in 1967' proved to be a major advance in the treatment of pulmonary infections due to Pseudomonas. Despite clinical improvement in some patients with cystic fibrosis treated with carbenicillin, alone or with an aminoglycoside antibiotic,:'-" Pseudomonas was not eliminated from the sputum. Furthermore, administration of 500 to 600 mg/kg of carbenicillin per day (4.7 meq Na +/gm) is a problem for patients with cor pulmonale. The availability of ticarcillin, a new semisynthetic thienylpenicillin derivative which is two- to fourfold more active against Pseudomonas aeruginosa strains than is carbenicillin,'" prompted us to evaluate its efficacy in patients with pulmonary exacerbations of cystic fibrosis from whom Pseudornonas was cultured. We have From the Departments of Medicine and Pediatrics, College of Physicians and Surgeons, Columbia Universi(v and Columbia-Presbyterian Medical Center. *Reprint address: Division of Infectious Diseases, Department of Medicine, Columbia University, 630 West 168th St., New York, NY 10032. Vol. 90, No. l, pp. 144-148
compared the effectiveness of ticarcillin alone, ticarcillin plus gentamicin, and gentamicin alone in patients with cystic fibrosis. We have attempted to define those factors responsible for success or failure of therapy, the frequency with which ticarcillin-resistant microorganisms are isolated during therapy, and the influence that the development of ticarcillin-carbenicillin-resistant strains has on the subsequent course of the pulmonary disease.
Abbreviations used MIC: minimum inhibitory concentrations BUN: blood urea nitrogen
MATERIALS AND METHODS Forty-two courses of antimicrobial therapy were evaluated in 28 patients with cystic fibrosis admitted to the Columbia-Presbyterian Medical Center for acute infectious exacerbations of their pulmonary disease. Patients with acute respiratory symptoms were selected for study on the basis of isolation of Pseudornonas aeruginosa in pretreatment cultures of sputum. Beginning in April, 1974, patients who qualified for the study were placed alternately on ticarcillin alone or
Volume 90 Number 1
Ticareillin and gentamicin in treatment of pulmonar), infections
ticarcillin plus gentamicin. The study was concluded in August, 1975, with 14 courses of treatment for each group. These were compared with 14 other episodes of infection treated with gentamicin alone during the study period. Written, informed consent was obtained from each adult subject or parents of minors (children) prior to administration of ticarcillin. Ticarcillin, as the disodium salt (4.7 mEq Na+/gm), was supplied by Beecham-Massengill Pharmaceuticals, Bristol, Tenn. The drug was reconstituted with sterile water and diluted further with 50 to 200 ml of 5% dextrose in water for intravenous administration. Patients received 300 mg of ticarcillin per kg of body weight per day in equally divided doses intravenously every four hours. Gentamicin was administered as the commercially available preparation (Schering Corp., Kemilworth, N.J.), in a dose of 3 to 4 m g / k g / d a y in adult patients and 4 to 7 mg/ kg/day in children, either intravenously or intramuscularly. Most patients had been treated unsuccessfully with other oral and nebulized antibiotics prior to admission. These antibiotics were not continued during the study period. Physical therapy to the chest, bronchial drainage, and aerosol therapy with mucolytic agents were administered to all patients. Digitalis and diuretics were given for congestive heart failure. Complete blood count, sedimentation rate, urinalysis, serum electrolytes, blood urea nitrogen, creatinine, liver function tests, chest radiographs, and blood gas determinations were performed before therapy, at least weekly during therapy, and at the end of therapy. Pulmonary function tests were performed when possible. Ivy bleeding times were performed in six patients receiving ticarcillin. Sputum cultures were obtained before, during, and at the end of therapy, as well as two to six months after completion of therapy. These cultures were incubated for 72 to 96 hours, since we have observed that, after only 24 hours of incubation, growth of Pseudomonas species is often scant and easily overlooked. Organisms were identified by standard laboratory techniques,' .... and disc sensitivity tests to carbenicillin, ticarciltin, and gentamicin were performed by the method of Bauer and associates. '~ Minimum inhibitory concentrations of carbenicillin and ticarcillin for the isolated organisms were determined by agar dilution studies as previously described. 1~ Ticarcillin concentrations were assayed in serum and sputum by the agar plate technique '~ using Pseudomonas aeruginosa NCTC 10701 as the assay organism. Patients were classified as clinically improved or not improved after therapy. Response was assessed by evaluating changes in cough and sputum production, temperature, respiratory rate, physical findings, and body weight, together with alterations in sedimentation rate
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