Experience with gentamicin and specialty use of gentamicin. Gentamicin: laboratory and clinical experience in Mexico.
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Diarrhea, Infantile↗
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Endotoxin increases the nephrotoxic potential of gentamicin and vancomycin plus gentamicin.
To assess the possible role of endotoxin as an amplification factor for experimental nephrotoxicity due to gentamicin plus vancomycin, rats were given continuous intravenous (iv) endotoxin or saline followed by twice-daily intraperitoneal (ip) saline, vancomycin (20 mg/kg ip), gentamicin (15 mg/kg subcutaneously), or both gentamicin and vancomycin. After 5 or 8 days of treatment, functional and histologic parameters of renal function were evaluated: cortical drug levels, tritiated thymidine incorporation into cellular DNA, creatinine clearance, and appearance by light and electron microscopy. In animals not given endotoxin, only rats that received gentamicin plus vancomycin developed measurable abnormalities. Endotoxin did not cause nephrotoxicity in vancomycin-treated rats. However, in endotoxin-infused rats treated with gentamicin or gentamicin plus vancomycin for 8 days, the increase in blood urea nitrogen, decrease in creatinine clearance, and rise in renal cortical DNA synthesis were more severe than those in non-endotoxin-infused rats (P less than .01). In these studies, endotoxin amplified the nephrotoxic potential of gentamicin alone and gentamicin plus vancomycin.
Animals↗
Antimicrobial gentamicin activity in the presence of exogenous protease inhibitor (Bowman-Birk inhibitor) in gentamicin-induced nephrotoxicity in rats.
In our previous studies, we found increased levels of urinary trypsin inhibitory activity in gentamicin-induced nephrotoxicity in rats. Following administration of the Bowman-Birk trypsin and chymotrypsin inhibitor (BBI), no proteinuria was detected in gentamicin-treated rats, and a decrease in creatinine clearance was noted in only 50% of the injected rats. In the present study, we examined the antimicrobial activity of gentamicin against Escherichia coli in the presence of BBI in gentamicin-induced nephrotoxicity in rats. We found that 50% of rats with E. coli-positive blood cultures died of septicemia. All the rats injected with E. coli plus gentamicin or E. coli plus gentamicin plus BBI survived, the latter showing no proteinuria or deterioration in creatinine clearance. In conclusion, BBI, which is an effective inhibitor of gentamicin-induced nephrotoxicity, does not affect the antimicrobial activity of gentamicin sulfate.
Animals↗
Gentamicin-specific antiserum alters the disposition of gentamicin by the isolated perfused rat kidney.
Previous studies have indicated that antibodies or Fab fragments of antibodies can be used to alter the pharmacologic or toxicologic effects of drugs. The present study was conducted to determine the effect of specific antiserum administration on the renal excretion of a drug with a high nephrotoxic potential (e.g., gentamicin) using the IPK. After a perfusion period during which the renal clearance of gentamicin was determined, either serum or gentamicin-specific antiserum was added to the perfusion medium. Experiments with serum addition served as controls for a comparison of the effects of antiserum addition on gentamicin renal clearance and tissue accumulation. Addition of antiserum decreased the renal clearance and tissue accumulation of gentamicin. Increasing perfusate gentamicin concentrations at the end of the experimental time suggested that these alterations in disposition could be due to the formation of a nonfilterable gentamicin-antiserum complex. The addition of antiserum also rapidly reversed the increasing fractional excretion of potassium ion. Therefore it would appear that a commercially available antiserum is capable of decreasing renal tissue accumulation of gentamicin and that the IPK represents a viable system for studying the effects of antisera on renal drug disposition.
Animals↗
A randomized monocentric trial in febrile neutropenic patients: ceftriaxone and gentamicin vs cefepime and gentamicin.
A prospective, randomized, controlled monocentric trial was performed to evaluate the efficacy and safety of once daily ceftriaxone 2 g plus gentamicin 5 mg/kg in comparison to cefepime 2 g t.i.d. plus gentamicin 5 mg/kg q.d. in the treatment of neutropenic fever. In case of fever (oral temperature > or =38.5 degrees C on one occasion or > or =38.0 degrees C twice within 24 h) and a granulocytopenia (neutrophil count below 500 or below 1000/microl when expected to fall below 500 within 72 h), patients with hematological malignancies or solid tumors were assigned to ceftriaxone or cefepime, each with gentamicin. The primary endpoint was defined as defervescence on day 4-6 followed by at least 7 afebrile days. Secondary endpoints were overall response, defined as defervescence on day 28 and toxicity. Two hundred eleven episodes were included. Fever of unknown origin (FUO) accounted for 124 episodes (58.8%), microbiologically defined infection (MDI) for 39 (18.5%), clinically defined infection (CDI) for 25 (11.8%), and both clinically and microbiologically defined infection (CMDI) for 19 episodes (9%). On an intent-to-treat basis 207 episodes were evaluable for the primary endpoint. Ceftriaxone plus gentamicin and cefepime plus gentamicin were successful in 49.5% and 51%, respectively. Overall response was achieved on study day 28 in 92.5% and 91%, respectively. Diarrhea was more frequent with ceftriaxone/gentamicin (6.5% vs 17%), while nausea/vomiting was less (12.1% vs 5%). Once-daily ceftriaxone plus gentamicin was not inferior to cefepime t.i.d. plus gentamicin q.d. in the empirical treatment of neutropenic fever.
Anti-Bacterial Agents↗
Toxic serum gentamicin levels after the use of gentamicin-loaded sponges in infected total hip arthroplasty.
BACKGROUND: At our clinic, total hip arthroplasties with an acute postoperative infection are treated with surgical debridement and application of several gentamicin-loaded sponges, each with an equivalent of 130 mg gentamicin. We studied the possible systemic effect of this local application of gentamicin. PATIENTS AND METHODS: All 12 patients treated during 1997-2001 were included. 4-6 sponges were used in each case. We measured the serum gentamicin levels daily, from the first postoperative day until gentamicin was no longer measurable. The creatinine levels were monitored daily and the creatinine clearance was calculated according the Cockcroft-Gault formula. RESULTS: In 7 of the 12 patients, we found toxic serum levels of gentamicin (range 2-13 mg/L). In 3 cases there was a significant drop in renal clearance, which persisted. In 3 other cases there was a temporary decrease in renal clearance. INTERPRETATION: We found toxic serum levels after local administration of gentamicin. We even found a persistent decrease in renal clearance in some patients. Because of the alarming results, we have reduced the number of sponges used for this purpose.
Aged↗
Gentamicin sulfate pharmacokinetics: lower levels of gentamicin in blood during fever.
The effect of fever on serum concentrations and urinary excretion of gentamicin sulfate was studied in humans and dogs. Endotoxin-induced fever in dogs resulted in a decrease of approximately 25% in levels of gentamicin in serum 30 and 60 min after intravenous injection of the antibiotic (1.5 mg/kg) when compared with corresponding afebrile values. In six volunteers with etiocholanolone-stimulated fever, serum concentrations of gentamicin was reduced by an average of 40% in all measurements made 1.2, and 3 hr after intramuscular injection (1.5 mg/kg) as compared with afebrile control values in the same subject. Fever was thought to be the principal factor associated with lower levels of gentamicin, although the half-life of gentamicin in serum and renal clearance of the antibiotic were not significantly affected. These findings emphasize the need for frequent measurements of gentamicin in serum as a guide to adjustment of gentamicin treatment in febrile subjects, and perhaps in all patients receiving the antibiotic.
Adult↗
The use of a change in gentamicin clearance as an early predictor of gentamicin-induced nephrotoxicity.
A retrospective review was undertaken in 744 patients who were dose-individualized with gentamicin once daily to evaluate a change in gentamicin clearance as a potential predictor of nephrotoxicity. The definition of nephrotoxicity was chosen to be a change in creatinine clearance greater than 20%. Similarly, a change in gentamicin clearance of greater than 20% was also considered a possible index of nephrotoxicity. Four criteria were developed to assess the usefulness of gentamicin clearance as a predictor of nephrotoxicity. Following the application of the inclusion/exclusion criteria, 132 patients were available for the analysis. The sensitivity, specificity, positive predictive value, and negative predictive value were assessed for each of the criteria. Receiver operating characteristic (ROC) curves were produced to determine if an optimum value in the change of gentamicin clearance could be found to maximize sensitivity and specificity. The overall incidence of nephrotoxicity based on a decrease in creatinine clearance by 20% or more was 3.8%. Women were overrepresented in the nephrotoxic group [71.4% versus 40.1% (P = 0.0025)]. Patients with nephrotoxicity had statistically longer treatment periods, increased cumulative dose, and more dosing predictions (P < 0.05 in each case). The sensitivity of the criteria ranged from 43 to 46%, and specificity ranged from 93 to 99%. The positive and negative predictive values ranged from 63 to 94% and 86 to 89%, respectively. In those patients in whom nephrotoxicity was predicted from a change in gentamicin clearance, this change occurred on average 3 days before the change in creatinine clearance (P < 0.05). A change in gentamicin clearance to predict nephrotoxicity may be a useful addition to current monitoring methods, although it is not the complete answer.
Adolescent↗
Influence of gentamicin dose size on the efficacies of combinations of gentamicin and penicillin in experimental streptomycin-resistant enterococcal endocarditis.
We have evaluated the benefits of low versus high doses of gentamicin combined with procaine penicillin (1.2 X 10(6) U three times daily) in the treatment of streptomycin-resistant experimental enterococcal endocarditis in rabbits. The mean peak serum gentamicin concentration in animals treated with low-dose gentamicin (0.75 mg/kg three times daily) was 3.06 micrograms/ml (range, 2.1 to 4.2 micrograms/ml), and it was 8.05 micrograms/ml (range, 4.5 to 16.1 micrograms/ml) in animals treated with high-dose gentamicin (2 mg/kg three times daily). The mean log10 colony-forming units of enterococci per gram of cardiac valve vegetation in animals treated with procaine penicillin combined with low- or high-dose gentamicin were 2.4 +/- 1.2 and 1.4 +/- 1.3, respectively (P = not significant) after 3 days of treatment and 1.7 +/- 1.2 and 1.7 +/- 1.5, respectively (P = not significant), after 5 days of therapy. The median peak serum bactericidal titer was 1:8 in animals treated with low- or high-dose gentamicin. We detected no significant difference between low- or high-dose gentamicin combined with procaine penicillin in the efficacy of treatment of streptomycin-resistant experimental enterococcal endocarditis.
Animals↗
Vancomycin acts synergistically with gentamicin against penicillin-resistant pneumococci by increasing the intracellular penetration of gentamicin.
Vancomycin and gentamicin act synergistically against penicillin-resistant pneumococci in vitro and in experimental rabbit meningitis. The aim of the present study was to investigate the underlying mechanism of this synergism. The intracellular concentration of gentamicin was measured by using the following experimental setting. Bacterial cultures were incubated with either gentamicin alone or gentamicin plus vancomycin for a short period (15 min). The gentamicin concentration was determined before and after grinding of the cultures by using the COBAS INTEGRA fluorescence polarization system (Roche). The grinding efficacies ranged between 44 and 54%, as determined by viable cell counts. In the combination regimen the intracellular concentration of gentamicin increased to 186% compared to that achieved with gentamicin monotherapy. These data suggest that the synergy observed in vivo and in vitro is based on an increased intracellular penetration of the aminoglycoside, probably due to the effect of vancomycin on the permeability of the cell wall.
Animals↗
Gentamicin-adenylyltransferase activity as a cause of gentamicin resistance in clinical isolates of Pseudomonas aeruginosa.
Gentamicin adenylyltransferase activity was found in extracts of clinical isolates of gentamicin-resistant Pseudomonas aeruginosa. Extracts of one of these isolates, P. aeruginosa POW, inactivated gentamicin in the presence of adenosine 5'-triphosphate. Extracts of strain POW catalyzed the binding of radioactivity from [(14)C]adenine adenosine 5'-triphosphate to gentamicin components, tobramycin, sisomicin, kanamycin A and B and, to a variable degree, streptomycin and spectinomycin. The substrate profile with these agents and other aminocyclitols was similar to that obtained with R factor-mediated gentamicin adenylyltransferase found in Enterobacteriaceae. Adenylylating activity was absent in gentamicin-susceptible mutants of strain POW. Adenylylation may be added to acetylation as an enzymatic mechanism responsible for gentamicin resistance among strains of P. aeruginosa.
Adenosine Triphosphate↗
Gentamicin resistance in clinical-isolates of Pseudomonas aeruginosa associated with diminished gentamicin accumulation and no detectable enzymatic modification.
Three strains of Pseudomonas aeruginosa resistant to gentamicin obtained as representative gentamicin-resistant clinical isolates from the University of Alberta Hospital (UAH) in Edmonton, Canada were characterized to determine their mechanism of resistance. All strains showed wide aminoglycoside resistance (tobramycin, sisomicin, amikacin, streptomycin, kanamycin, SCH 20569) but contained no evidence of gentamicin-acetylating, adenylating or phosphorylating activity. Gentamicin inhibited amino-acid incorporation in cell-free systems equally well with either ribosomes or soluble cell fractions obtained from either resistant or sensitive strains. Plasmid DNA was detected in two strains but resistance could not be transferred by conjugation to either P. aeruginosa or Escherichia coli recipients. The resistant strains showed a marked reduction in energy-dependent accumulation of gentamicin compared to a sensitive strain. These strains which are common at UAH are most likely resistant due to a failure of gentamicin to be transported across the cytoplasmic membrane to ribosomal sites until relatively high external gentamicin concentrations.
Amino Acids↗
Monitoring serum levels of gentamicin to develop a new regimen for gentamicin dosage in newborns.
The newborns studied had gestational ages ranging between 23-44 weeks, weights ranging between 725-4510 g, and were treated with standard doses of gentamicin (5.2 +/- 1.0 mg/kg/day). The gentamicin serum peak and trough levels were unrelated to administered doses, and a large proportion of patients had low (peak less than 4 micrograms/ml in 12%) or potentially toxic concentrations (trough greater than 2 micrograms/ml in 55%). The pharmacokinetic parameters (t1/2e, 8.2 +/- 4.8 h and Vd, 0.64 +/- 0.22 L/kg) varied markedly between patients. The newborn's weight, age, gestational age, and serum creatinine were factors of importance for the variability of gentamicin serum levels. The newborns were divided into four groups: gestational period less or more than 37 weeks and age below or above 7 days. These groups had different gentamicin serum levels and pharmacokinetic parameters. The results suggest that a gentamicin dosage regimen based on the division of newborn patients into subgroups or calculated from individual pharmacokinetic characteristics would decrease the risk of obtaining potentially toxic or subtherapeutic gentamicin concentrations after the use of standard doses.
Analysis of Variance↗
Comparison of 30 microgram and 120 microgram gentamicin disks for the prediction of gentamicin resistance in Enterococcus faecalis.
Single strain regression analysis was performed on PDM II medium for E. faecalis with 10, 30 and 120 micrograms gentamicin disks using E. faecalis, strain ATCC 29212 as the reference. This method permits the calculation of zone diameters corresponding to different MIC values for different disk contents. The lack of discrimination between normal low-level resistant strains and high-level resistance using the 10 micrograms disk was confirmed. However, both the 30 micrograms and 120 micrograms disks seemed to provide a separation of the normal low-level gentamicin-resistant population from strains with increased resistance. Since the 30 micrograms disk is used routinely in some countries, there should be no need for an extra high content disk in these laboratories. This was confirmed when 96 clinical isolates of E. faecalis were analysed and the results of routine disk diffusion tests were compared with the MIC values. Two of the strains showed high-level gentamicin resistance (greater than 2000 mg/l) and produced no zone of inhibition. The other 94 isolates showed gentamicin MIC values between 4-16 mg/l, and 72 of the MIC results were 8 mg/l. The zone diameters for these strains ranged between 15 and 25 mm with a mean of 18.2 and a median value of 18 mm. In order to include statistical considerations of the zone size populations for setting of breakpoints, a study of gentamicin zone size distributions was performed for several bacterial species. Inhibition zone diameter values around the 30 micrograms gentamicin disk for 2079 clinical isolates of E. faecalis, 2268 S. aureus, 3201 E. coli and 547 strains of P. mirabilis from different years were plotted as histograms. Tests for agreement with a Gaussian distribution showed that the histograms were slightly peaked and skewed towards higher zone values. Parametric and non-parametric statistical tests were compared and the results showed that means and medians were very similar and that parametric fractile estimations at the lower end of the histogram populations were conservative and could be used in view of a slightly lower rate of false resistance. The 1% parametric fractile of 12 mm was selected as a suitable breakpoint for the identification of normal, low-level resistant isolates of E. faecalis using the standardized disk test of the Swedish Reference Group for Antibiotics.
Drug Resistance, Microbial↗
[Ionic binding of 3H-gentamicin and short-term bactericidal activity of gentamicin against Pseudomonas aeruginosa isolates differing in lipopolysaccharide structure].
The clinical isolates of Pseudomonas aeruginosa can be roughly classified into long- and short-lipopolysaccharide (LPS) strains and LPS-deficient strains, based on the silver-stained patterns of their LPSs after SDS-PAGE. The ionic binding of 3H-gentamicin, a polycationic antibiotic, to the negatively charged sites on the surface structures of P. aeruginosa strains, often differing in LPS structure, was the highest in the long-LPS strains followed in descending order by the short-LPS strains and LPS-deficient strains. It was presumed that a clinical isolate of P. aeruginosa No. 45 is lacking in the O-polysaccharide chains and some structures of the core-regions consisting of its LPS-structure after SDS-PAGE. On the other hand, the binding of 3H-gentamicin to this strain was quite. high, i.e., similar to that to of the long-LPS strains. To clarify this finding, P. aeruginosa PAC1R and its LPS-deficient mutants were used as reference strains because the chemical structures of their LPSs containing the repeated units of O-polysaccharides and the neutral sugar contents in the core-regions were previously confirmed. The PAC605 strain of the LPS-mutants of the PAC series, was completely lacking in the repeated units of O-polysaccharide and also lacking in some neutral sugar residues of the core-oligosaccharide region. However, this strain was highly bound to 3H-gentamicin, suggesting that the negatively charged sites on the deep core-oligosaccharide region and/or on lipid A participated in the binding of 3H-gentamicin. This manner of binding may be also applied to P. aeruginosa No. 45. When P. aeruginosa PAC1R, PAC605 and No. 45 strains were each exposed to gentamicin (20 micrograms/ml) for 10 minutes, the viable cell counts of PAC1R decreased to about 70% of the initial count, whereas the viable cell counts of PAC605 and No. 45 strains decreased to 3.6 and 11.0% respectively, indicating the vulnerability of both types of the strains to be enhanced by the bactericidal action of gentamicin with short-term incubation.
Anti-Bacterial Agents↗
Renal cortical kinetics of gentamicin after implantation of gentamicin-polymethylmethacrylate beads in rats.
Beads of gentamicin-polymethylmethacrylate (Septopal), each containing 4.5 mg of gentamicin base, were implanted intraperitoneally in rats. Each rat received one bead. Serum levels and urinary excretion of gentamicin were maximal in the first day of treatment (0.6 micrograms/ml in serum 3 h after implantation of the bead and 525 micrograms per 24-h urine sample) and decreased thereafter. Kidney cortical concentrations of gentamicin progressively increased and peaked after 4 days, reaching 117 micrograms/g. Tissue levels decreased thereafter in spite of the persistence of the drug in urine, and this occurred in the absence of cell damage leading to cell death. Release of gentamicin from intact proximal tubular cells, despite continuous uptake, prevented intracellular drug concentrations from reaching a nephrotoxic level. This experimental study provides a rational basis for the previous clinical observation that nephrotoxicity due to treatment with gentamicin-polymethylmethacrylate beads is improbable.
Animals↗
Evidence of nosocomial infection in Japan caused by high-level gentamicin-resistant Enterococcus faecalis and identification of the pheromone-responsive conjugative plasmid encoding gentamicin resistance.
A total of 1,799 Enterococcus faecalis isolates were isolated from inpatients of Gunma University Hospital, Gunma, Japan, between 1992 and 1996. Four hundred thirty-two (22.3%) of the 1,799 isolates had high-level gentamicin resistance. Eighty-one of the 432 isolates were classified and were placed into four groups (group A through group D) with respect to the EcoRI restriction endonuclease profiles of the plasmid DNAs isolated from these strains. The 81 isolates were isolated from 36 patients. For 35 of the 36 patients, the same gentamicin-resistant isolates were isolated from the same or different specimens isolated from the same patient at different times during the hospitalization. For one other patient, two different groups of the isolates were isolated from the same specimen. Groups A, B, C, and D were isolated from 5, 14, 12, and 6 patients, respectively. The strains had multiple-drug resistance. The restriction endonuclease digestion patterns of the E. faecalis chromosomal DNAs isolated from isolates in the same group were also identical. The patients who had been infected with the gentamicin-resistant isolates from each group were geographically clustered on a ward(s). These results suggest that the isolates in each group were derived from a common source and had spread in the ward. The gentamicin-resistant isolates exhibited a clumping response upon exposure to pheromone (E. faecalis FA2-2 culture filtrate). The gentamicin resistance transferred at a high frequency to the recipient E. faecalis isolates by broth mating, and the pheromone-responsive plasmids encoding the gentamicin resistance were identified in these isolates.
Conjugation, Genetic↗
The gentamicin antibiotics. 6. Gentamicin C2b, an aminoglycoside antibiotic produced by Micromonospora purpurea mutant JI-33.
A mutant strain of Micromonospora purpurea, designated var. JI-33, produced an antibiotic complex consisting primarily of gentamicin C1a. A further product of this fermentation was identical to a very minor component isolated from the fermentation of the parent organism and named gentamicin C2b. Physical measurements indicated its structure to be 6'-N-methylgentamicin C1a and this was confirmed by synthesis from gentamicin C1a. The in vitro antibacterial activity of gentamicin C2b was very similar to that of the gentamicin C complex. Antibiotic XK-62-2, produced by Micromonospora sagamiensis, appears to be identical to gentamicin C1b.
Chemical Phenomena↗