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.

Experimental infection with Streptococcus pneumoniae in mice: correlation of in vitro activity and pharmacokinetic parameters with in vivo effect for 14 cephalosporins.

A mouse model using intraperitoneal inoculation of Streptococcus pneumoniae type 3 was used to compare in vitro and in vivo effects of 14 cephalosporins, selected to encompass a wide range of minimal inhibitory concentrations (MICs) against the organism. Antibiotics were subcutaneously administered as single doses 1 hr after inoculation of pneumococci, and the effect was measured as the 50% effective dose (ED50). The correlation between log ED50 and log MIC was highly significant (r = .87, P less than .001). Pharmacokinetic properties of the cephalosporins were estimated after a fixed dose of 5 mg per mouse (167 mg/kg) for all drugs. The only correlation that was significant was between log ED50 and the time the serum concentration remained above the MIC for each drug (r = -.90, P less than .001). Ceftriaxone was the most-effective cephalosporin in vivo because of a combination of high in vitro activity and prolonged serum elimination half-life.

The susceptibility of Plasmodium falciparum to sulfadoxine and pyrimethamine: correlation of in vivo and in vitro results.

In 1982, 2 of 14 Plasmodium falciparum infections acquired in East Africa and diagnosed in Copenhagen were resistant to treatment with sulfadoxine plus pyrimethamine (Fansidar), while in 1983, 6 of 18 were so. The in vivo tests were supplemented by determinations of drug concentrations in serum, and 4 isolates from in vivo-sensitive cases and 6 from in vivo-resistant cases were selected for in vivo tests. These were performed in ordinary RPMI 1640 medium and in a medium with physiological p-aminobenzoic acid and folic acid concentrations. Pharmacokinetic aberrations were found to be of possible importance in only 2 of the in vivo-resistant cases. In vitro susceptibility to sulfadoxine was found to be uniformly low in all isolates. Testing with a combination of sulfadoxine and pyrimethamine in the medium with physiological concentrations of cofactors probably reflects the in vivo situation most accurately, but in all but 1 of the isolates studied in vitro the in vivo susceptibility to Fansidar would be predicted by in vitro susceptibility to pyrimethamine in either medium. The concentration of p-aminobenzoic acid in serum, quantitated by high performance liquid chromatography, was found to be subject to wide variation, and this may have implications for in vitro testing.

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.

Frequency, phage types and antibiotic resistance of Staphylococcus aureus isolated from blood cultures in Denmark 1975-1981.

In the period 1975-1981, 4060 cases of Staphylococcus aureus bacteremia were recorded in Denmark, and the corresponding strains were examined. The percentage of strains, resistant to penicillin only, rose to 82, and the percentage of multiply-resistant strains fell to five. Newer phage types (94, 96 and 95) increased from 10% to 27% of the material. These strains were usually resistant only to penicillin, but produced large amounts of penicillinase. The ample penicillinase production has also been characteristic for previous epidemic strains, and it is furthermore correlated to mortality. The overall mortality of 34.6% was lower than that of the preceding period. Mortality rates were highest in elderly patients, nosocomial cases, patients with serious primary diseases and endocarditis cases.