The nephrotoxicity of antimicrobial agents (third of three parts).
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Biomedical subjects
Publications and source records attributed to H C Neu.
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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; recovery of them was not prevented by the inclusion of gentamicin in the therapeutic regimen nor did they interfere with clinical improvement. The ticarcillin-resistant 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.
A retrospective and prospective study was made of side effects in 200 patients who received clindamycin over a 15-month period. The incidence of gastrointestinal symptoms in this group of patients was 21.5%; of diarrhea, 13.5%; and of colitis, 2.5%. Factors associated with an increased incidence of diarrhea were older age and parenteral route of administration. Simultaneous use of other antibiotics, particularly aminoglycosides, and increased total dosage of clindamycin did not increase the incidence of diarrhea. The gastrointestinal side effects were usually self-limited if the drug was promptly discontinued and fluid support was provided.
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The antibiotic bacerial inactivity of N-acetylcysteine (NAC) and its interaction with penicillin and aminocyclitol antibiotics was evaluated. NAC inhibited growth of both gram-negative and gram-positive bacteria. Strains of Pseudomonas aeruginosa were more susceptible than other microorgainsms tested. P. aeruginosa strains were inhibited synergistically by NAC and carbenicillin or ticarcillin. However, NAC antagonized the activity of gentamicin and tobramycin. These findings have implications for the combined clinical use of NAC and aerosolized antibiotics and are also important for the processing of sputum specimens in the microbiology laboratory.
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The pharmacokinetics of ticarcillin were determined in patients with abnormal renal function. In individuals with rates of creatinine clearance of greater than 60 ml per min, the half-life (+/- standard deviation) of ticarcillin was 71 +/- 6 min after intravenous administration. In patients with rates of creatinine clearance of 30-60 ml per min, 10-30 ml per min, and less than 10 ml per min, ticarcillin had a half-life of 3.0 +/- 0.6 hr, 8.5 +/- 2.1 hr, and 14.8 +/- 3.7 hr, respectively. Urinary concentrations of ticarcillin after intravenous administration were adequate at all levels of renal function. Ticarcillin was removed by hemodialysis with a reduction in half-life to 3.4 +/- 0.8 hr, but peritoneal dialysis was minimally effective in removing the drug. A program for the use of ticarcillin patients with renal insufficiency was outlined.
Ticarcillin, a semisynthetic penicillin, was evaluated in the treatment of 75 serious gram-negative infections, 50 of which were caused by Pseudomonas aeruginosa. The overall rate of response was 81%. Septicemia and urinary tract infections responded more frequently (93%) than infections of the lower respiratory tract (71%). Response to therapy was comparable to results achieved previously with larger doses of carbenicillin. Response was not correlated with levels of drug in serum. Patients with nonfatal underlying disease were the most likely to respond to treatment. Ticarcillin-resistant organisms were isolated during therapy in 39% of the cases, and superinfection occurred in 12%. Colonization with resistant organisms did nto correlate with success or failure of therapy, severity of underlying disease, or levels of ticarcillin in serum. The clinical response and incidence of colonization were not altered by concurrent use of gentamicin, nor was the development of superinfection affected. Combination of ticarcillin and gentamicin in treatment of 19 patients did not produce toxicity. Eosinophilia, phlebitis, and hypokalemia occurred, as seen with carbenicillin, but major toxicity was not encountered.
Patients who had cystic fibrosis and acute infectious exacerbations of pulmonary disease produced by Pseudomonas aeruginosa were treated with a combination of tobramycin and ticarcillin. P. aeruginosa recovered from patients was inhibited by lower concentrations of both of these drugs than of gentamicin or carbenicillin. Thirteen courses of treatment were administered to 11 patients (mean, 14.4 days). A favorable response was seen in 11 of 12 completed courses of treatment. Improvement was associated with decreases in white blood cell count, temperature, and sedimentation rate. Adverse reactions were uncommon. Although P. aeruginosa was not eradicated from the sputum, the clinical results suggest that the combination of tobramycin and ticarcillin may be particularly useful for treatment of acute exacerbations of pulmonary disease in patients with cystic fibrosis from whom P. aeruginosa is isolated.
In a survey of data on 3,506 patients treated with tobramycin, the 21 cases of drug-related ototoxicity are reported and reviewed. In seven patients the effects were auditory only, in nine vestibular only, and in five both auditory and vestibular. Effects subsided in 14 of the 18 patients who were available for monitoring after therapy. High-frequency audiometric losses persisted in three patients, and a hearing decrease persisted in one. In only one of the three patients did audiometric losses exceed 40 decibels. The patients with drug-related ototoxicity were compared to a group of 49 patients for whom both audiometric testing (before and after therapy) and clinical observation showed that no ototoxic reactions had occurred. Preexisting renal impairment, prior and/or concomitant therapy with other possibly ototoxic drugs, and therapy for 10 days or more with a dose of greater than 3 mg/kg per day were found to be associated with ototoxicity.
The combination of netilmicin (Sch 20569) with carbenicillin, cefazolin, chloramphenicol, and clindamycin was evaluated by in vitro tests against 91 clinical isolates of Pseudomonas, Klebsiella, and Escherichia coli. Combinations were considered to show synergy if there was a fourfold or greater reduction in minimal inhibitory concentration values of both antibiotics when combined. Synergy of netilmicin with carbenicillin could be demonstrated against 21 of 46 Pseudomonas isolates. Comparison of the synergy of carbenicillin with netilmicin or gentamicin showed that netilmicin was less active than gentamicin against Pseudomonas aeruginosa. However, at therapeutic concentrations of the antibiotics, significant differences were not observed. Synergy of netilmicin and cefazolin was demonstrated against only 1 of 21 Klebsiella strains tested, but partial synergy was found for 12 of 20 isolates. Synergy and antagonism were uncommon with the netilmicin-chloramphenicol and netilmicin-clindamycin combinations against E. coli and Pseudomonas.
Netilmicin (Sch 20569) is an ethyl derivative of gentamicin C(1a) that is active against most Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus isolates. Among 342 clinical isolates tested, all staphylococci; 92% of Escherichia coli, 93% of Klebsiella pneumoniae, and 92% of Enterobacter were inhibited by 0.8 mug or less of netilmicin per ml, but only 78% of P. aeruginosa were inhibited by 3.1 mug or less per ml. Most clinical isolates of enterococci, Serratia marcescens, and Providencia were not inhibited by 3.1 mug of netilmicin per ml. Like other aminoglycosides, the netilmicin in vitro activity was markedly influenced by the growth medium used, with activity decreased by sodium, calcium, and magnesium. Netilmicin was more active at alkaline pH. Addition of magnesium to Pseudomonas or Serratia pretreated with netilmicin produced inhibition of killing. Netilmicin was more active than gentamicin, sisomicin, tobramycin, or amikacin against E. coli and K. pneumoniae. Netilmicin inhibited growth of all gentamicin-resistant isolates of Klebsiella and Citrobacter tested, but only 73% of E. coli; Pseudomonas and Providencia were resistant to netilmicin. Most Serratia (95%) and indole-positive Proteus (83%) isolates were resistant to netilmicin but were inhibited by amikacin.