Nephrotoxicity with gentamicin or tobramycin.
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Biomedical subjects
Publications and source records attributed to M E Plaut.
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We assessed the value of quantitative cast excretion as an early marker of renal tubular damage in 154 seriously ill patients. One hundred twenty-four of these received aminoglycoside antibiotics, and 30 of the 124 experienced a rise in serum creatinine of 0.5 mg/dl or more during therapy. The remaining 30 of the 154 patients were treated with other antibiotics and served as controls. Casts were quantitated in random urines collected before morning diuretic doses. Cast counts in control patients averaged 44 +/- 51 casts during the intensive care unit admission. Patients given aminoglycosides without a significant rise in serum creatinine of 0.5 mg/dl or more excreted 153 +/- 196 casts, significantly more than controls. In comparison to both the control and nontoxic patients, the 30 nephrotoxic patients excreted significantly more casts (625 +/- 364) and were significantly higher as early as 9 days before serum creatinine first rose. Daily urinary cast counts are a rapid and inexpensive means of identifying early renal tubular damage in critically ill patients given aminoglycosides.
In a prospective trial to determine the incidence of nephrotoxicity with each of three aminoglycoside antibiotics, adults in intensive care units with presumed or proven bacterial infections were treated with intravenous gentamicin, tobramycin, or amikacin. Treatment groups were similar with respect to age, other medical disorders, type of infection, duration of aminoglycoside therapy, additional antibiotics used, other drugs prescribed (notably diuretics and corticosteroids), and rate of superinfection. Nephrotoxicity occurred with gentamicin during 44/121 (36.3%) treatment courses, with tobramycin during 21/92 (22.8%) courses, and with amikacin during 4/16 (25.0%) courses. Although frequent, nephrotoxicity reversed after treatment stopped. Tobramycin nephrotoxicity occurred significantly less often than did gentamicin nephrotoxicity (p less than 0.05). The relative safety of tobramycin may result from lower tissue accumulation during therapy.
In 64 adults treated with gentamicin sulfate, peak and trough serum concentrations rose gradually and declined in two phases after the final dose. Seventeen patients experienced renal damage. The 17 patients had greater amounts of gentamicin in tissues even after the first dose and before any renal effects were noted. This pharmacokinetics analysis provided evidence that patients who experience gentamicin-related nephrotoxic effects while receiving recommended doses of gentamicin could be distinguished from patients with no toxic effects because they experienced abnormal tissue accumulation before detectable changes in renal function occurred.
The efficacy and safety of cefamandole nafate and penicillin G procaine suspension were compared in the treatment of pneumococcal pneumonia in hospitalized adults. One hundred thirteen patients with clinical and radiographic evidence of pneumococcal pneumonia were randomly assigned to receive 600,000 units of procaine penicillin intramuscularly every 12 hr or 500 mg of cefamandole intramuscularly every 6 hr. The two groups were comparable with regard to patient type and extent and severity of pneumonia. Alcohol abuse was a host factor in 31% of all patients in the trial. All strains of Streptococcus pneumoniae isolated were inhibited by less than or equal to 1.6 microgram of cefamandole/ml. Of 58 patients treated with cefamandole, 50 had a satisfactory response, as did 46 of the 55 patients treated with penicillin. Results of tests of liver function were abnormal (primarily, elevated levels of transaminase or alkaline phosphatase) in 38% of the entire group of patients and occurred with equal frequency in patients receiving cefamandole or penicillin. Side effects during therapy, including superinfection, occurred equally with either drug. In a random trial, cefamandole was as effective and safe as penicillin in the treatment of pneumococcal pneumonia in adults.
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Tobramycin pharmacokinetics is usually described by a one-compartment model, but this model fails to account for both the incomplete urinary recovery and prolonged post-treatment persistence noted with this drug. We examined the multiple-dose behavior of tobramycin in 35 treated patients with stable renal function, using peak and trough serum concentrations, urine recovery, and postmortem tissue analysis. Serum concentrations rose slowly throughout treatment and declined in two phases after the drug was stopped. The first-phase half-life correlated well with renal function, but the second averaged 146 h and was poorly related to creatinine clearance. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of drug in the tissue compartment at all times during and after treatment. Predicted tissue amounts rose continually throughout treatment in all study patients. In 5 patients, the total amount of tobramycin in the body after the final dose was recovered in the urine, but urine had to be collected for 10 to 20 days to achieve complete recovery of the drug. In four patients, the predicted tissue amount was recovered from postmortem tissues. Regardless of the dose, tobramycin accumulated in the tissues of all patients receiving this antibiotic. The two-compartment pharmacokinetic model explains both the rising peak and trough concentrations during treatment and the detection of the drug in serum and urine long after the last dose.
The gynecologic literature was reviewed and yielded 11 well-designed and well-conducted studies since 1960 involving the use of systemic prophylactic antibiotics. Five had significant results that support using prophylactic antibiotics in vaginal hysterectomy while three supported prophylaxis in cesarean sections. A cephalosporin agent is effective as a prophylactic agent and should be administered 2 hours before surgery by the intravenous route and discontinued 24-72 hours after surgery. A change in the bacteriologic flora of the cervical cuff occurs after surgery with an increase in E. coli and enterococci and a decrease in coagulose negative staphylococci and steptococci. Future studies should be randomized, prospective, and performed in a double-blind manner with antibiotics begun preoperatively. Special attention should be given to bacteriologic techniques, especially the search for anaerobic pathogens.
We used a radioimmunoassay to evaluate the changes in the urinary excretion of beta2-microglobulin (beta2M) in 21 patients receiving aminoglycosides for treatment of infection. Excretion of this protein rose to a peak at least 5 times the baseline value in the urine, and declined rapidly to control values after drug administration ceased. In six patients who developed aminoglycoside nephrotoxicity, urinary beta2M excretion rose 5 days or more before serum creatinine rose, and 5 of 6 nephrotoxic patients excreted more than 50 mg/day (normal, less than 0.1 mg/day). Urinary beta2M is a non-specific indication of renal tubular damage, but heralds aminoglycoside-induced damage before standard tests of kidney function change.
A two-compartment pharmcokinetic model was used to caracterize serum concentrations and to predict tissue accumulation of gentamicin in 47 treated patients. Postmortem tissues were obtained in six cases; in each instance, tissues yielded the predicted amount of drug. Slow release of tissue-bound gentamicin accounts for its prolonged retention in the body. The two-compartment model adequately predicts gentamicin accumulation from serum concentrations and explains why this antibiotic persists in serum and urine.
We reviewed the English-language literature over a 16-year period (1960 through 1976) on the subject of prophylaxis with systemic antibiotics in surgery. Trials in genitourinary and cardiovascular surgery were not reviewed. Our definition of prophylaxis is antibiotic administration of the absence of infection or contamination. Of 131 articles reporting clinical trials using systemic antibiotics for prophylaxis, only 24 met the criterion on an appropriately designed study that generated evaluable data. In these, systemic antibiotics were shown to be of value in reducing wound infections after abdominal and vaginal hysterectomy, cesarean section, biliary surgery, total hip replacement, and microneurosurgical craniotomy. Antibiotic prophylaxis was of no value in laparotomy and groin hernia repair. Patients undergoing any of 21 different operations did not benefit from prophylactic antibiotic administration, though study groups were too small or infection rates too low to allow for firm conclusions. In certain patients at high risk of infection, systemic prophylaxis is warranted. Future clinical studies must be designed as randomized, blinded, prospective trials, with antibiotics administered by a parenteral route beginning preoperatively.
Of 5,954 adult inpatients consecutively discharged from a university hospital during a three-month period, only 8.4% had serologic tests for syphilis performed during hospitalization. The testing rate was 20.1% on patients admitted to a medical teaching service and 1.4% on a surgical teaching service. In patients tested, a positive rapid plasma reagin test result was obtained in 6.2% and the diagnosis was confirmed by further testing, but effective therapy was not always given. On 9 of 30 patient records listed syphilis as a diagnosis on discharge. We conclude that serologic testing for syphilis is routinely omitted in the evaluation of hospitalized patients; even when tests are positive, the results are often ignored.
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The rate of carriage and infections due to strains of Staphylococcus aureus were evaluated in adults with acute leukemia in isolators characterized by laminar air flow and barrier isolation. Patients were randomly given antimicrobial prophylaxis with oral nonabsorbed antibiotics and a nasal antibiotic ointment. In four years S aureus was isolated from the nostrils or other sites in 36 patients. Persistent isolation was noted in 24 patients. Suppression of gut flora was associated with a higher carriage rate of S aureus. Five episodes of bacteremia due to S aureus occurred at the nadir of leukopenia induced by chemotherapy. Death occurred within five days in the three patients whose peripheral white blood cell count did not rise. Patient isolation and suppression of gut flora helped reduce infections due to Pseudomonas sp and fungi, but S aureus emerged as a life-threatening pathogen.