Biomedical subjects
Publications and source records attributed to D N Gilbert.
The nephrotoxic potentials of netilmicin and tobramycin given in doses of 180 mg/kg per day for up to 14 days were compared in Fischer rats. At this dosage, tobramycin produced mortality and significant changes in renal structure and function; netilmicin evoked minimal nephrotoxicity.
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When amikacin was administered to Fischer rats at a dose of 120 mg/kg/day for up to 14 days, renal proximal tubule cells became vacuolated, but BUN and creatinine remained normal. Renal cortical drug levels rose steadily throughout the treatment period. When, in a second trial of the same duration, the drug dose was tripled, focal proximal tubular necrosis, then regeneration, occurred and the animals became azotemic. Tissue drug concentrations peaked and began to decline during the treatment period, having reached levels more than three times higher than achieved at the lower dose. Ultrastructural changes were similar to those observed with other aminoglycosides. The results indicate that amikacin is less nephrotoxic than gentamicin and more toxin than tobramycin and netilmicin in the Fischer rat.
To examine the possibility that gentamicin binding to renal tubular epithelium is electrostatic, the effect of sodium bicarbonate-induced alkaline diuresis and ammonium chloride administration on the course of gentamicin nephrotoxicity in male Fischer 344 rats was examined. After 14 days of gentamicin, sodium bicarbonate drinking animals did not differ significantly from tap water drinking controls in the degree of nephrotoxicity as determined by serum creatinine, in vitro para-aminohippurate and N-methylnicotinamide uptake, histology and renal cortical gentamicin concentrations. However, 7/10 sodium bicarbonate drinking animals had extensive intratubular renal calcifications as compared to 0/29 tap water drinkers. Ammonium chloride drinking animals had more severe toxicity than tap water drinking controls. We conclude that in our model, sodium bicarbonate administration does not reduce experimental gentamicin toxicity and is associated with intratubular calcification. Ammonium chloride potentiates gentamicin nephrotoxicity.
Peak serum levels of gentamicin were varied in rats by administering a standard nephrotoxic dosage of 40 mg/kg per day in one (QD), two, or three (TID) daily doses. The QD animals had the highest peak serum levels but showed no appreciable increase of serum creatinine concentrations over a 10-day treatment period. The TID rats had the lowest peak serum levels, but, after 10 days of drug administration, the serum creatinine concentration (2.8 +/- 0.2 mg/100 ml, mean +/- SE) was significantly higher than in control rats (0.6 +/- 0.01 mg/100 ml) (P less than 0.001). After two days of gentamicin treatment, the renal concentration of gentamicin was 269 +/- 77 micrograms/g in the QD rats and 820 +/- 29 micrograms/g in the TID rats (P less than 0.001). In this rat model, the frequency of doses was a more important factor in the development of nephrotoxicity than the peak serum concentration of gentamicin. The results suggest that dose frequency should be considered when data from different laboratories are compared.
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A fatal case of human herpes simplex type 1 hepatitis is presented and compared with cases previously reported. The patient presented with fulminant hepatic necrosis, coagulopathy, leukopenia, thrombocytopenia, and absence of typical herpetic mucocutaneous lesions. Liver biopsy helped to establish a presumptive diagnosis in this patient and in one previously reported case. Theoretically, early diagnosis might enable application of specific antiviral therapy in future cases of this usually fatal infection.
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This report describes the effect of a combined education and monitoring program on the use of gentamicin in a community hospital. The use of gentamicin was evaluated in 82 patients prior to an education program and in 80 patients after the education program. The results indicate that the attention focused on gentamicin by the study significantly improved the valid indications for treatment from 75% to 87% (p less than .05), increased the pretreatment use of bacteriologic cultures from 85% to 97% (p less than .05), increased the use of alternative less toxic antibiotics from 36% to 75% (p less than .05), and increased the frequency with which serum gentamicin concentrations were requested during therapy from 28% to 56% (p less than .001). Thus, the data support the tenet that the ways antibiotics are employed in community hospitals can be altered.
A rat model was utilized to compare the nephrotoxic potential of gentamicin and tobramycin. Gentamicin, 40 mg/kg per day, predictably produced renal failure and morphological evidence of proximal tubular necrosis over 14 days of treatment. An identical dosage of tobramycin was associated with only minimal morphological changes and normal concentrations of serum creatinine and blood urea nitrogen. Similar results were obtained even after the tobramycin dosage was tripled to 120 mg/kg per day. A decrease in urine osmolality, mechanism unknown, was observed in all aminoglycoside-treated rats, but the lowest osmolalities were found in the gentamicin-treated rats. According to both histological criteria and renal function measurements, gentamicin was more nephrotoxic than tobramycin in this animal model.
Prophylactic antibiotics are prescribed frequently for patients requiring permanent transvenous cardiac pacemakers, despite a paucity of data indicating effectiveness. A 10 year retrospective analysis was performed of 298 pacemaker insertion procedures involving 204 patients. On the basis of prestudy criteria relating to timing and dosage of antibiotics, the use of prophylactic antibiotics was judged as adequate or inadequate. There were no postoperative infections in the 108 battery pack replacement procedures despite no or inadequate use of antibiotics in 49 procedures. There were nine infections in the 190 battery pack plus pacing wire procedures for an infection rate of 5 percent. There was no significant difference in infection rate between the group given prophylactic antibiotics and the group given no or inadequate prophylactic antibiotics. Of the 190 battery pack plus pacing wire procedures, no infections occurred in the 50 procedures in which surgical drains were not used (p less than 0.003). In the 140 procedures in which drains were used, there was no correlation between wound infection and absent or inadequate coverage with prophylactic antibiotics. Two severe bacteremic Staphylococcus aureus infections occurred in two patients not given prophylactic antibiotics. The other seven infections were clinically indolent. These results suggest the following: (1) There is no need for prophylactic antibiotics in battery pack replacement procedures; (2) prophylactic antibiotics may decrease the severity of infection in battery pack plus pacing wire procedures; (3) surgical drains should be avoided in battery pack plus pacing wire procedures. A prospective controlled study is necessary to confirm these results.
It is customary to treat patients with infective endocarditis or osteomyelitis for a prolonged period in hospital with parenteral antibiotics. It was felt that it might be feasible to allow parenteral administration of antibiotics by the patients themselves at home. Results in 13 patients who administered antibiotics parenterally themselves (experimental group) were compared with those in 7 patients (control group) treated entirely within the hospital. Antibiotic-related complications were similar in both groups. There was no instance of infection of the intravenous cannula in either group. The average daily cost of antibiotic therapy decreased from $243.22 for inpatients to $69.35 for outpatients. The average cost of illness was $6,357.22 in the experimental group and $10,022.23 in the control group. If patients are carefully selected and well educated, the outpatient self-administration of antibiotics parenterally is both economical and safe.
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Seven young to middle-aged patients with Haemophilus parainfluenzae endocarditis are reported. Three patients had underlying heart disease and three patients had recent events predisposing for endocarditis. The clinical presentation was subacute or acute and new pathologic murmurs were uncommon. Diagnosis was prolonged because of difficulties in isolating the organism. Routine subculturing of blood cultures to chocolate agar with incubation in CO2 is recommended. A prominent complication, occurring in six patients, was major arterial occlusion secondary to emboli. Antibiotic control of infection was difficult and best achieved by the concomitant administration of ampicillin and gentamicin. Killing curves proved useful in assessing antibiotic efficacy. There were two medical failures and one death in the series. It appears H. parainfluenzae endocarditis is characterized by distinctive clinical features, difficult in vitro isolation of the organism, and the necessity for combination antibiotic therapy.
The toxicity of amphotericin B (AmB) for neutrophils and the protective effect of serum cholesterol were investigated. Neutrophils were exposed in vitro to varying concentrations of AmB. As judged by trypan blue exclusion, neutrophil viability decreased by 40% (P < 0.001) within 30 min of incubation in sterol-free buffer containing 5 mug of AmB per ml. In the presence of 4 mg of cholesterol per 100 ml in buffer, the AmB concentration could be increased to 50 mug/ml before significant (P < 0.01) neutrophil toxicity occurred. Hexose monophosphate shunt activity of neutrophils incubated in serum or cholesterol-containing buffer with 10 mug of AmB per ml was normal. These results suggest that serum contains a protective factor, probably cholesterol, which protects neutrophils in vitro from the toxic effects of AmB.
Interstitial nephritis is a recognized complication of methicillin therapy. Hemorrhagic cystitis due to methicillin has not been emphasized. Evidence of hemorrhagic cystitis developed in six patients receiving methicillin therapy and was confirmed by cystoscopy in three of them.