Ronald Gold

Pseudomonas cepacia infection in cystic fibrosis: An emerging problem

The prevalence of Pseudomonas cepacia infection increased from 10% in 1971 to 18% by 1981 in a population of approximately 500 patients with cystic fibrosis. Carriage of P. aeruginosa has remained unchanged at 70% to 80% over the same period. Patients infected with P. cepacia have greater impairment of pulmonary function than those with P. aeruginosa. A syndrome characterized by high fever, severe progressive respiratory failure, leukocytosis, and elevated erythrocyte sedimentation rate has occurred in eight patients over the past 3 years, with a 62% fatality rate. Because P. cepacia strains are uniformly resistant to ticarcillin, piperacillin, and aminoglycosides, and because ceftazidime is ineffective despite in vitro activity, treatment of these infections is very difficult. Prevention of acquisition and effective treatment of P. cepacia in patients with cystic fibrosis are now major clinical problems in our clinic.

Efficacy of inhaled tobramycin in the treatment of pulmonary exacerbations in children with cystic fibrosis.

Two forms of treatment of acute pulmonary exacerbations in patients with cystic fibrosis were compared: intravenous ticarcillin (300 mg drug per kg per day) and tobramycin (10 mg drug per kg per day) versus the same intravenous antibiotic therapy plus inhaled tobramycin (80 mg three times per day). The 16 patients in the intravenous plus inhaled tobramycin group were similar to the 12 control patients in age, sex, Schwachman scores, pulmonary function and pretreatment colony counts of Pseudomonas aeruginosa in sputum. Treatment resulted in significant improvement in clinical status and pulmonary function without any apparent differences in the two groups. However, intravenous plus inhaled tobramycin resulted in temporary eradication of P. aeruginosa in 63% of the patients compared to 25% in the intravenous only group (P = 0.03). Suppression of P. aeruginosa in sputum cultures did not correlate with clinical response to treatment. No renal toxicity or elevations of serum tobramycin were observed in the intravenous plus inhaled tobramycin group.

Antibiotic prophylaxis in cystic fibrosis: Inhaled cephaloridine as an adjunct to oral cloxacillin

The effect of prophylactic antibiotics on bacterial colonization of the respiratory tract and on general progression of cystic fibrosis was studied in a two-year prospective study of 47 mildly to moderately affected patients. One group of patients received inhaled cephaloridine and the other received no inhaled antibiotic; both groups received cloxacillin orally. Carriage of Haemophilus influenzae was greater in the group not receiving inhaled antibiotic (55% vs 20%). Rates of carriage of Staphylococcus aureus (23%). Pseudomonas aeruginosa (greater than 90%). Pseudomonas cepacia (45%), and other organisms were similar in both groups. There were no significant differences between the two groups in incidence of respiratory tract infections or hospital admissions, clinical scores, radiologic scores, or rate of change of pulmonary function. Although continuous antistaphylococcal antibiotic prophylaxis may be successful in suppressing colonization with S. aureus, it may also contribute to the high rates of carriage of Ps. aeruginosa and Ps. cepacia observed in patients with cystic fibrosis.

Ceftazidime disposition in acute and stable cystic fibrosis

Ceftazidime disposition after an intravenous dose of 50 mg/kg infused over 20 min was followed in 10 subjects with cystic fibrosis (CF) hospitalized with acute pulmonary exacerbations and in 10 healthy subjects. Serum ceftazidime elimination t½ decreased from 105.3 ± 12.4 min (X̄ ± SD) in controls to 90.0 ± 11.1 min in subjects with CF. Calculated distribution volumes were both larger in subjects with CF. When normalized for body surface area, total body clearance (Cl) was 41.9% greater in the CF group (142.4 ± 16.9 and 100.5 ± 10.3 ml/min/1.73 m2). Normalization for body weight revealed 64.8% greater Cl in subjects with CF. Fraction of dose recovered in urine was of the same order for each group, while renal clearance (ClR) was 40.9% greater in the subjects with CF (130.1 ± 11.4 and 92.7 ± 11.6 ml/min/1.73 m2). Five subjects with CF were restudied while infection‐free 119 to 219 days after the original study day. With the exception of a 10% increase in the volume of distribution at steady state while infection‐free, kinetic parameters were much the same. No changes in Cl or ClR were evident from one study day to the next. Acute pulmonary infection does not appear to alter ceftazidime clearance in CF. The mechanism underlying increased ceftazidime Cl and ClR in CF is not apparent from the present data.

Randomized trial of ceftazidime versus placebo in the management of acute respiratory exacerbations in patients with cystic fibrosis

A randomized trial of ceftazidime versus placebo was conducted in patients with cystic fibrosis hospitalized for acute respiratory exacerbations. Patients 12 years of age or older were included if they had mild to moderately severe illness according to the following criteria: erythrocyte sedimentation rate less than or equal to 50 mm/hr and less than three other abnormalities (leukocyte count greater than or equal to 15,000/microliter, pulse greater than or equal to 100 beats/min, respirations greater than or equal to 30/min, or temperature greater than or equal to 38.5 degrees C). In all 16 episodes treated with ceftazidime, the patients were rated improved in comparison with 10 of 12 patients treated with placebo. Three placebo-treated patients dropped out of the study within 3 to 5 days because they wanted antibiotic therapy. None of the 15 placebo-treated patients showed clinical deterioration. There were no significant differences in rate of improvement of symptom score, weight gain, or pulmonary function between the two treatment groups. There was no difference in the course during the 6 to 24 months after the study period. Intravenous antibiotics are not essential in the management of all acute respiratory exacerbations of mild to moderate severity in patients with cystic fibrosis.

Inhaled antibiotics in cystic fibrosis: Is there a therapeutic effect?

Antibiotics are administered to patients with cystic fibrosis to eliminate or suppress sputum bacteria. Aerosol administration is attractive because it delivers antibiotic directly to the site of infection. Effective aerosol administration is compromised by the inefficiency of nebulizers to generate small-particle aerosols, adverse airway reaction to the drug, potential emergence of resistant bacteria, and cost. Studies evaluating aerosol treatment have not always controlled for confounding factors and have used a variety of outcome indicators. Results of controlled studies are contradictory with regard to the beneficial effect of aerosol therapy on pulmonary function, sputum bacterial density, and frequency of hospitalization. Therefore, until additional well-controlled trials are completed, routine aerosol administration of antibiotics in cystic fibrosis is not warranted because of cost, potential side effects, and the propensity to select resistant organisms.

Cloxacillin absorption and disposition in cystic fibrosis

Because of reports of lowered antibiotic serum concentrations in patients with cystic fibrosis (CF), a bioavailability and pharmacokinetic study of cloxacillin was conducted in 12 control and 16 patients with CF after intravenously and orally administered doses of cloxacillin 25 mg/kg. The patients had mild to moderate CF and were in stable condition. Significantly lower serum concentrations in CF were a result of a 78% increase in total body clearance (P less than 0.005) and a 38% increase in the apparent volume of distribution (P less than 0.025). The bioavailability in CF (0.50) was not significantly different than in controls (0.38), but more variability was seen in the group with CF. After the intravenously given dose the fraction of cloxacillin excreted in the urine unchanged was similar in controls (0.644) and patients with CF (0.547). Compared with that in the control subjects, the mean renal clearance in patients with CF was 30% greater (P less than 0.10) and the nonrenal clearance was 144% greater (P less than 0.07). Enhanced nonrenal clearance explains most of the demonstrated difference between serum concentrations in controls and patients with CF after identical weight-adjusted doses. The data suggest enhanced cloxacillin biotransformation in CF.

The management of central intravenous catheter infections.

Catheter-associated infection is a frequent complication in patients with indwelling intravenous catheters used for administration of total parenteral nutrition and/or cancer chemotherapy. Thirty-seven catheter-associated infections in 19 patients were identified in our retrospective survey conducted for the period from January 1, 1982, through December 31, 1982. Fourteen patients were receiving total parenteral nutrition for gastrointestinal disorders, and five were receiving total parenteral nutrition and chemotherapy for underlying malignancy. Coagulase-negative staphylococci were isolated from 65% of catheter-associated bacteremias, as a single species (18 cases) or as one of multiple species (6 cases). Ten of 33 coagulase-negative staphylococcal isolates (30%) were methicillin-resistant. Twenty-one infections (57%) were initially treated with antibiotics administered through the central venous catheter. There were three failures with this treatment; in two cases the catheter was removed because of continued fever and positive blood cultures despite antibiotics, and one patient developed a pyogenic granuloma. The remaining 18 (86%) catheter-associated infections were cured without catheter removal. However, a new infection occurred subsequently in two of these patients. We recommend that vancomycin and an aminoglycoside be the initial empiric therapy for suspected catheter-associated sepsis. Lack of defervescence or continued positive blood cultures for 2 to 4 days despite antibiotics are indications for catheter removal. Otherwise antibiotics should be continued for 14 to 21 days.

Controlled trial of ceftazidime vs. ticarcillin and tobramycin in the treatment of acute respiratory exacerbations in patients with cystic fibrosis

A randomized controlled trial was undertaken to compare ceftazidime vs. the combination of ticarcillin and tobramycin in the treatment of acute respiratory exacerbations of mild to moderate severity in patients with cystic fibrosis. The two antibiotic regimens were equally effective in terms of clinical improvement: 16 of 17 in the ceftazidime group and 11 of 13 in the ticarcillin/tobramycin group were judged to be improved by the patients and attending physicians and were observed to show improvement in symptom scores, vital signs, body weight and pulmonary function. Ceftazidime was more effective bacteriologically in reducing colony counts of Pseudomonas aeruginosa in the sputum. Neither regimen affected Pseudomonas cepacia. Resistance to multiple antibiotics developed in six of 12 isolates of nonmucoid P. aeruginosa in patients receiving ticarcillin/tobramycin, which was significantly more than occurred in the ceftazidime group. There was no correlation between clinical and bacteriologic outcomes in either treatment group. No clinically important adverse effects were observed.

Disseminated Legionella pneumophila infection in an infant with severe combined immunodeficiency

LEGIONNAIRE DISEASE, unrecognized before 1976, has since received global attention, with over 1,000 cases reported. ~ Although most individuals who developed the disease were previously healthy, this infection frequently occurs in immunocompromise d patients? M ost cases have been described in adults, but children can be affected. 3,4 We report a case of fatal Legionnaire disease in an infant with severe combined immunodeficiency who developed disseminated infection involving the lungs, liver, and brain. CASE REPORT