Development of antibiotic resistance in Pseudomonas aeruginosa during two decades of antipseudomonal treatment at the Danish CF Center.

At the Danish CF Center patients with chronic Pseudomonas aeruginosa lung infection were treated 3-4 times a year (from 1976) with a 2-week intravenous antipseudomonal course which included preferentially an aminoglycoside and a beta-lactam antibiotic. We investigated the development of antibiotic resistance in P. aeruginosa strains isolated from Danish CF patients over a period of 18 years by testing the in vitro efficacy of carbenicillin, piperacillin, ceftazidime, tobramycin and ciprofloxacin against P. aeruginosa strains collected in 1973 (51 strains), 1980 (80 strains), 1985 (58 strains), and 1991 (100 strains). All the strains were screened and assayed semiquantitatively for beta-lactamase activity by use of nitrocefin. We found a significant (p < 0.005) increase in the MIC values of the P. aeruginosa strains against piperacillin and ceftazidime. However, no significant correlation was found between the MIC and the number of antipseudomonal courses of antibiotics. The proportion of resistant in vivo selected P. aeruginosa strains, presumed to be stably derepressed producers of chromosomal beta-lactamase, also increased significantly during the period studied. Our results confirm that the beta-lactamase production is an important mechanism of antibiotic resistance in P. aeruginosa.

Fluoroquinolones in the treatment of cystic fibrosis.

Cystic fibrosis patients suffer from recurrent and chronic lung infections mainly caused by Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. The fluoroquinolones, notably ciprofloxacin and ofloxacin, represent an important addition to the therapy of P. aeruginosa infections. They offer the possibility of effective oral treatment for early colonisation as well as chronic infections, even in children. They are associated with only few and mild adverse effects. Development of resistance represents an increasing problem.

Peroral treatment with ciprofloxacin of patients with spinal cord lesion and bacteriuria caused by multiply resistant bacteria.

Eleven patients, median age 38 years, with spinal cord lesion (SCL) and urinary tract infection (UTI) caused by multiply resistant bacteria entered an open clinical trial of peroral ciprofloxacin 250 mg b.i.d. for 6 days. P. aeruginosa was the most prevalent bacteria. Ciprofloxacin was clinically effective in all patients who had symptoms of UTI at entry. Bacterial eradication was achieved in 9 out of 11 patients immediately after treatment. At 4 weeks post-treatment 5 patients had relapse of bacteriuria with the initial micro-organism and only 2 had long term eradication. One patient had transient elevation of transaminases, but no other adverse reactions were noted. Pharmacokinetic analysis showed that ciprofloxacin was readily absorbed with a terminal half life of 2.5 hours and considerable nonrenal elimination. The urinary concentration of ciprofloxacin was high during the whole dosing interval. Oral treatment with ciprofloxacin is an alternative to parenteral antibiotics in SCL-patients with urinary tract infection caused by resistant bacteria.

Clinical efficacy of ciprofloxacin in lower respiratory tract infections.

The sputum pharmacokinetics and clinical efficacy of ciprofloxacin in lower respiratory tract infections is reviewed. Following intravenous administration, ciprofloxacin penetrates rapidly into bronchial tissue; the elimination half life is between 3 and 4 h and a dose dependency is seen. Following oral intake, the time to reach maximal concentrations is approximately two hours and after a dose of 750 mg the concentration may reach 1.7 mg/l in patients without cystic fibrosis and range from 0.5 to 3.4 mg/l in cystic fibrosis patients. Coadministration of ciprofloxacin increases serum levels and decreases total body clearance of theophylline. In controlled comparative clinical trials, ciprofloxacin has been found to have similar clinical efficacy as amoxycillin, ampicillin, cefalexin, doxycycline, co-trimoxazole, imipenem-cilastatin and ceftazidime for the treatment of a range of lower respiratory tract infections. Ciprofloxacin has been found to be superior in clinical efficacy to cefaclor. Experimental animal models suggest a role for ciprofloxacin in infections caused by Legionella pneumophila and Mycoplasma pneumoniae. The clinical and bacteriological efficacy of ciprofloxacin is less pronounced in lung infections caused by Pseudomonas aeruginosa, but is comparable to the combination of beta-lactams and aminoglycosides. Development of resistance is frequently observed during ciprofloxacin treatment of Ps. aeruginosa. Because of the availability of other oral and effective agents, ciprofloxacin is not recommended for empirical treatment of community acquired lower respiratory infections, but should be reserved for infections caused by multiply resistant organisms.

Efficacy of oral fluoroquinolones versus conventional intravenous antipseudomonal chemotherapy in treatment of cystic fibrosis.

The clinical efficacy of the conventional aminoglycoside plus beta-lactam treatment was compared to that of monotherapy with oral quinolones in 26 adult cystic fibrosis patients in an open prospective clinical trial in which six two-week courses of antipseudomonas treatment were administered with an interval of approximately three months between treatments. In each patient two courses of conventional treatment were followed by two courses of quinolone treatment and then by another two courses of conventional treatment. The observed improvements in pulmonary function were somewhat higher when the patients received conventional treatments, and in the most seriously affected patients conventional treatment was significantly better than quinolone treatment. On the basis of these findings it is suggested that quinolone monotherapy cannot replace conventional antipseudomonal chemotherapy in patients with severe pulmonary involvement.

The efficacy and safety of ciprofloxacin and ofloxacin in chronic Pseudomonas aeruginosa infection in cystic fibrosis.

The clinical efficacy and safety of ciprofloxacin and ofloxacin were compared in a prospective, randomized double blind, placebo combined cross-over study in 26 adult cystic fibrosis patients with chronic broncho-pulmonary Pseudomonas aeruginosa infection. Active treatment consisted of ciprofloxacin 750 mg orally twice daily or ofloxacin 400 mg orally twice daily; both treatments were given for 14 days, with three months between treatment periods; 21 patients completed both treatment periods. Treatment with both ciprofloxacin and ofloxacin was associated with a good clinical response as judged by clinical score, lung function tests and inflammatory parameters; no difference between ciprofloxacin and ofloxacin was found. Adverse reactions were seen in nine of 24 patients who received ciprofloxacin and in six of 23 who received ofloxacin. The majority were dyspeptic reactions or photosensitivity. No serious adverse reactions occurred. Three cases of treatment failure were found, one of which was associated with development of resistant P. aeruginosa during ofloxacin treatment. The mean MIC of both drugs increased during treatment but returned to pretreatment values within three months. Ciprofloxacin and ofloxacin seem to be valuable agents for intermittent treatment of chronic P. aeruginosa lung infection in adult cystic fibrosis patients.

Combined imipenem/cilastatin and tobramycin therapy of multiresistant Pseudomonas aeruginosa in cystic fibrosis.

Ten patients with cystic fibrosis (CF) and chronic broncho-pulmonary Pseudomonas aeruginosa infection were given imipenem/cilastatin (100 mg/kg/day) in combination with tobramycin (15 mg/kg/day). Forced vital capacity and forced expiratory volume in the first second improved significantly in nine out of ten patients, and most of the patients improved clinically. P. aeruginosa was not eradicated in any patient and resistance against imipenem developed in all patients during treatment. A concomitant increase in MIC of piperacillin and ceftazidime occurred during treatment. In-vitro bactericidal synergy of imipenem and tobramycin was noted in 57% of pretreatment isolates. Seven patients complained of adverse reactions, mainly gastrointestinal, and treatment of three patients was discontinued after 5, 8, and 12 days of therapy, because of rash or nausea and vomiting. The side effects were considered to be due to imipenem/cilastatin. Because of the rapid development of imipenem resistance despite combination therapy, the high proportion of side effects, and the risk of induction of beta-lactam resistance, imipenem/cilastatin cannot be recommended for routine treatment of CF-patients with P. aeruginosa infection.

Imipenem/cilastatin treatment of multiresistant Pseudomonas aeruginosa lung infection in cystic fibrosis.

Ten patients with cystic fibrosis and chronic broncho-pulmonary Pseudomonas aeruginosa infection received 45 mg imipenem/cilastatin per kg body weight/day, intravenously for two weeks. The treatment was safe with only minor side effects and clinical parameters improved considerably during therapy. In all patients resistance of Ps. aeruginosa to imipenem developed in the second week of treatment; in seven patients the therapy selected for a resistant strain and in three resistance developed in the original strain. The resistance persisted after cessation of treatment and thus the clinical usefulness of imipenem/cilastatin as monotherapy in CF-patients with Ps. aeruginosa seems to be limited.