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PubMed1990

Role of N-acetylneuraminic acid in rat renal brush-border membrane vesicle aggregation by aminoglycosides.

Interaction between aminoglycosides (AGs) and rat renal brush-border membrane (BBM) vesicles was investigated by the aggregation technique. The order of aggregation was gentamicin greater than dibekacin not equal to netilmicin greater than amikacin, and this order corresponds to the strength of the nephrotoxicity of the aminoglycosides in vivo rather than the number of amino groups in the aminoglycosides. BBM vesicles were aggregated through ionic interaction, as evident from the finding that aggregation ceased to occur at alkaline pH. By addition of N-acetylneuraminic acid (NANA) to the incubation medium, the vesicle aggregation induced by gentamicin was significantly inhibited. To affect the liberation of the NANA residue from BBM vesicles, the vesicles were treated with neuraminidase, resulting in an about 60% release with a significant decrease in the uptake of gentamicin into the vesicles. The decrease in the degree of vesicle aggregation was in proportion to the amount of NANA liberated. It follows from the findings that the NANA residue may in some way be responsible for the accumulation of aminoglycosides in renal proximal tubular cells.

Aminoglycosides↗
PubMed1988

Inhibition of renal ornithine decarboxylase by aminoglycoside antibiotics in vitro.

The inhibition of renal ornithine decarboxylase (ODC) by aminoglycoside antibiotics was characterized in the postmitochondrial fraction of a kidney homogenate from adult pigmented guinea pigs. Enzymatic activity was defined as the rate of decarboxylation of [14C]ornithine sensitive to a specific ODC inhibitor, alpha-difluoromethylornithine (DFMO). The Km for ornithine was 61 +/- 32 microM. There were two forms of the enzyme with respect to their affinity for pyridoxal phosphate (PLP): (I) Km = 2.1 +/- 1.8 microM; (II) Km = 36.2 +/- 12.7 microM. Putrescine, a known ODC inhibitor, acted competitively on the renal enzyme with Ki = 1.7 +/- 1.4 mM. Aminoglycoside antibiotics inhibited ODC by an uncompetitive mechanism with inhibitor constants of comparable magnitude: neomycin, Ki = 1.3 +/- 0.1 mM; gentamicin, Ki = 1.6 +/- 0.1 mM; kanamycin, Ki = 1.9 +/- 0.2 mM; and netilmicin, Ki = 1.7 +/- 0.2 mM. Neomycin inhibited both forms of the enzyme (low and high affinity for PLP) uncompetitively with similar inhibitor constants (1.5 +/- 0.3 and 1.8 +/- 0.4 mM respectively), suggesting a single mechanism of action. Inhibition of ODC suggests that aminoglycoside-polyamine interactions may be an important component of the sequence of biochemical events associated with aminoglycoside toxicity.

Aminoglycosides↗
PubMed1991

Colonic fermentation to short-chain fatty acids is decreased in antibiotic-associated diarrhea.

To elucidate the pathogenesis of antibiotic-associated diarrhea, colonic carbohydrate fermentation was investigated in three groups of subjects--a group of controls, a group of patients with antibiotic-associated diarrhea, and a group of patients receiving antibiotic therapy without diarrhea. Compared with controls, the colonic fermentation was markedly impaired in patients with antibiotic-associated diarrhea reflected by both very low concentrations (22.1 vs. 59.5 mmol/L; P less than 0.01) and production rates of short-chain fatty acids. In the group of patients without diarrhea, the effect on the colonic fermentation was dependent on the antibiotic administered. Penicillin and pivampicillin PO did not reduce the concentrations (69.9 and 66.7 mmol/L, respectively) or production rates. Dicloxacillin, erythromycin, and combined IV treatment with ampicillin, netilmicin, and metronidazole reduced both concentrations (27.1, 38.2, and 18.8 mmol/L; P less than 0.01) and production rates of short-chain fatty acids to levels seen in patients with diarrhea. L-Lactate and D-lactate concentrations were normal in all patients (less than 5 mmol/L), but lactate production was reduced in the patients who had reduced production of short-chain fatty acids, including patients with diarrhea. Thus, antibiotic-associated diarrhea was always related to reduced fecal concentrations and production rates of short-chain fatty acids and production rates of lactate. These results suggest that the antibiotic-associated diarrhea might be secondary to impaired colonic fermentation in otherwise disposed subjects, resulting in accumulation of luminal carbohydrate and/or decreased short-chain fatty acid-stimulated sodium and water absorption.

Adult↗
PubMed1983

Effects of aminoglycosides on glomerular permeability, tubular reabsorption, and intracellular catabolism of the cationic low-molecular-weight protein lysozyme.

Gentamicin and other aminoglycoside antibiotics in high doses may produce proteinuria and other signs of nephrotoxicity. Proteinuria may result from general renal damage or may reflect alterations in specific steps in the renal handling of proteins. To distinguish between these two possibilities, experiments were designed to quantify the effects of nephrotoxic doses of several aminoglycosides on the renal handling of proteins in the isolated perfused rat kidney with the cationic low-molecular-weight protein lysozyme as a representative protein. Each aminoglycoside was administered ip to male Wistar rats (30 mg/kg/day) for 7 days. Lysozyme and 125I-lysozyme were added to the perfusate to achieve a lysozyme perfusate concentration of about 100 mg/liter. Clearances of inulin and lysozyme, release of tyrosine and trichloroacetic acid-soluble radioactive metabolites into the perfusate, and the glomerular sieving coefficient of lysozyme were determined. Scanning and transmission electron microscopy indicated that gentamicin and tobramycin decreased the number and diameter of the endothelial fenestrae of the glomerular capillaries. Concurrently, gentamicin and tobramycin decreased the glomerular sieving coefficient of lysozyme from 0.8 to 0.6 and 0.5, respectively. Netilmicin did not affect the percentage reabsorption of lysozyme whereas gentamicin and tobramycin decreased lysozyme reabsorption from 71.7 to 35.4 and 34.4% of the filtered load, respectively. Lysozyme degradation, estimated by the release of tyrosine into the perfusate during a 150-min perfusion period, was decreased from a control value of 12 mumol/liter to 4.43 and 4.65 mumol/liter in kidneys from rats treated with gentamicin and tobramycin, respectively. This study demonstrates that polycationic aminoglycosides may affect several processes involved in renal handling of lysozyme including glomerular permeability, tubular reabsorption, and intracellular proteolytic degradation.

Absorption↗
PubMed1986

Microbiologic studies of coagulase-negative staphylococci isolated from patients with nosocomial bacteraemias.

We studied 50 strains of coagulase-negative staphylococci (CNS) isolated from 50 patients with hospital-acquired bacteraemia, identified by prospective surveillance at the University of Virginia Hospital between March 1981 and September 1982. Using the Staph-Ident System for speciation, we found that 37 strains (74%) were Staphylococcus epidermidis, 7 (14%) Staph. hominis, 3 (6%) Staph. haemolyticus and 3 (6%) Staph. warneri. 33 (66%) of the strains produced slime and a higher proportion of the Staph. epidermidis group (75%) than the non-epidermidis group (46%), did so. Minimal inhibitory concentrations (MIC) were determined by a microdilution technique with 20 different antibiotics. There was no difference in geometric mean MICs between slime producers and non-slime producers within either the epidermidis or non-epidermidis group. The most potent antibiotics against Staph. epidermidis (MIC90 mg l-1) were rifampin (0.05), netilmicin (0.05), amikacin (2.9), thienamycin (0.75), teichomycin (0.85), vancomycin (1.0) and nafcillin (0.39). On the other hand strains were resistant to tobramycin (15), moxalactam (50), fosfomycin (greater than 64), and clindamycin (greater than 64). Overall, eight (16%) of the CNS strains were resistant to methicillin, three of which were Staph. haemolyticus. The non-epidermidis strains were more resistant than the Staph. epidermidis strains to most beta-lactam antibiotics. Differences in antibiograms indicate that speciation of CNS may prove useful for clinical and epidemiologic purposes.

Anti-Bacterial Agents↗
PubMed1988

Staphylococcal infections in hospital: the Greek experience.

Resistance rates of various species to many antimicrobials are very high in Greece. Mean resistance rates of Staphylococcus aureus isolated in 12 Athens hospitals in the second half of 1986 were 80% for penicillin, 32% for methicillin, 22% for gentamicin, 27% for erythromycin, 17% for lincomycin and 16% for co-trimoxazole. In a prospective study in the General Hospital of Athens from May to July 1987, 40 coagulase-positive staphylococcal strains were isolated from various materials from inpatients. Of these 78% were resistant to penicillin, 50% to methicillin at 37 degrees C, 62% to methicillin at 30 degrees C, 38% to erythromycin, 32% to tobramycin, 15% to clindamycin, 15% to fusidic acid, 9% to amikacin, 5% to netilmicin and 0% to vancomycin. Ten of these strains (seven methicillin-resistant) were responsible for severe infections and three of the affected patients died (two nosocomial pneumonias, one infected burn, all due to methicillin-resistant strains). Another 11 strains (eight methicillin-resistant) were responsible for mild infections. From 41 coagulase-negative staphylococci isolated from inpatients, seven (five methicillin-resistant) were held responsible for mild infections. Of the 20 patients with infections due to methicillin-resistant strains, nine had previously received a beta- lactam antibiotic. Staphylococci are not responsible, however, for a large proportion of infections in our hospital at the moment. High resistance rates in Greece are due to overuse of antibiotics, a phenomenon attributed to a consumer's society behaviour of doctors and patients.

Anti-Bacterial Agents↗
PubMed1990

A study of the relationships between antibiotic resistance phenotypes, phage-typing and biotyping of 117 clinical isolates of Acinetobacter spp.

Two typing systems were used to conduct an epidemiological study of Acinetobacter and to establish their relationship to antibiotic resistance phenotypes. Biotyping was performed with biochemical tests according to the new definition of Acinetobacter baumannii (18 biotypes). Phage typing included two complementary systems: 125 phage-types and 25 subtypes. Resistance phenotype analysis included 11 antibiotics. The results of the study showed that: (1) nine phage-types or subtypes (67%) and two groups of atypical phage-types (5%) or of untypable strains (28%), could be defined; (2) all strains that were resistant to carboxy/ureido-penicillins and cephalosporins (62%) belonged to biotypes 6 or 9; among them 70% belonged to phage-types 17 or 124; (3) imipenem resistance was observed in five isolates of biotype 9 and one of biotype 6; (4) a phenotype including resistance to third generation cephalosporins (but not carboxypenicillins) and to amikacin (but not tobramycin) represented 8.5% of the isolates; 90% of them belonged to biotype 1 and were not phage-typable; (5) 15% of the isolates were not identified as A. baumannii; among them five Acinetobacter haemolyticus strains all had the same resistance phenotype: amikacin-tobramycin-kanamycin-netilmicin resistant; they were however, susceptible to beta-lactams and to gentamicin. There was a clear relationship between biotypes 6 and 9 and phage-types 17 and 124 which were the strains most resistant to beta-lactams and aminoglycosides and were predominant in the survey. The three typing systems were complementary but it seems that antibiotic resistance phenotypes and one of the two other typing systems would be required in parallel to provide suitable information for epidemiological purposes.

Acinetobacter↗
PubMed1992

Pseudobacteraemia with multiply-resistant Klebsiella pneumoniae resulting from contamination from the blood gas machine on a neonatal unit.

Klebsiella pneumoniae with an unusual antibiotic susceptibility pattern was isolated from blood cultures of seven unwell premature babies on the Special Care Baby Unit. Although the organism was sensitive to cefuroxime it was resistant to ceftazidime. It was also resistant to gentamicin, tobramycin, netilmicin, piperacillin and aztreonam but sensitive to ciprofloxacin, imipenem and amikacin. On extensive investigation to trace the source, a K. pneumoniae with the same susceptibility pattern as that obtained from blood cultures was isolated from the probe and probe cover on the blood gas machine but not from any other environmental samples or clinical specimens. Where clinically indicated, antibiotics were used to treat these babies, with success. The difficulty, however, of differentiating between true septicaemia and pseudobacteraemia could be enormous as withholding treatment will have disastrous consequences in genuine cases of bacteraemia.

Bacteremia↗
PubMed1980

Comparative toxicity of aminoglycoside antibiotics towards the lysosomes in a cell culture model.

Cultured rat fibroblasts were used to compare the cellular toxicity of 4 aminoglycosides: accumulation of the antibiotic in the lysosomes, its adverse effect on phospholipases and consequently the intralysosomal accumulation of phospholipids. Gentamicin and Tobramycin are more noxious than Netilmicin and Amikacin. These data, when corrected for the lesser capture of Tobramycin by the kidney proximal tubules, closely match the toxicological evaluation of these aminoglycosides on the basis of animal and clinical studies.

Aminoglycosides↗
PubMed1990

Aminoglycoside-induced ototoxicity.

One of the major side effects of aminoglycoside antibiotics (AG) is ototoxicity. The authors review the literature revealing many controversies on every aspect of this side-effect. Although epidemiological studies have to face the problem of reliable evaluation techniques, the incidence of cochleo- and vestibulotoxic side-effects has been estimated at 7.5% for each. Netilmicin appears to be less ototoxic. No definite risk factors can be proposed, although age, length of therapy, bacteremia, fever, liver and renal dysfunction are probably very important parameters. Most pathological changes at the cochlear level follow a clear spatial sequence, showing unspecific, degenerative lesions, involving every structure of the cochlea. This makes it impossible to draw etiopathological conclusions. Recent pharmacokinetic studies have rejected the 'accumulation theory' of AGs in perilymph, while also in endolymph no accumulation can be found. Only a few data are available on inner ear tissue levels. Among the different pharmacodynamic hypotheses on the action of AGs, binding of the drug to acidic glycosaminoglycans in the stria vascularis, and interference by the drug with phosphoinositide metabolism in the hair cells seem to be of major importance.

Aminoglycosides↗
PubMed1989

Determination of aminoglycosides in pharmaceutical formulations--II. High-performance liquid chromatography.

A post-column derivatization procedure using OPA and fluorescence detection has been used for the determination of seven aminoglycosides (dibekacin, framycetin, kanamycin, netilmicin, sisomicin, tobramycin and gentamicin) in commercial pharmaceutical formulations. The linearity, precision and detection limits were satisfactory. Recoveries from eye drops, ointments, injections and capsules were comparable (P = 0.05) to those obtained with TLC or microbiological assays. A ruggedness test showed that the method was not sensitive to minor variations in the mobile phase composition, post-column derivatization system or detection wavelength.

Aminoglycosides↗
PubMed1995

Conductimetric titrimetry for assay of selected antibiotics in non-aqueous media.

In this study, a conductimetric titration method is proposed for the determination of some commonly used antibiotics. The conductimetric titration of three antibiotics, namely ampicillin, amoxycillin trihydrate and rifampin, was carried out in acetic acid using perchloric acid as titrant. Ciproflaxacin hydrochloride, however, was titrated after being dissolved in acetic acid containing an excess of mercury(II) acetate. For the titration of netilmicin sulphate, barium acetate prepared in acetic acid was used as titrant. The method was found to be highly accurate and precise, having a relative standard deviation of less than 1.0% for all antibiotics studied. It was also shown that the conductimetric titrimetry could be successfully applied to the assay of commercial preparations containing the above-mentioned antibiotics. The validity of the method was tested by the recovery studies of standard addition to pharmaceuticals and the results were found to be satisfactory.

Acetates↗
PubMed1987

Mechanism of aminoglycoside resistance among beta-lactam-resistant Escherichia coli in the United States.

We examined aminoglycoside (AG) resistance in ampicillin-resistant Escherichia coli obtained from nine hospitals participating in the National Nosocomial Infections Study. The isolates were tested to 25 antimicrobials using broth microdilution methods. If the organism was intermediate or resistant to gentamicin, tobramycin, netilmicin, or amikacin, we determined the class of aminoglycoside-modifying enzyme (AME) using the phosphocellulose paper binding assay. Of 423 E. coli, 21 (5%) were intermediate or resistant to one or more of the AGs. All but two of these E. coli isolates had at least one AME. Twelve isolates had phosphotransferase (APH) enzymes; seven had adenyltransferase (ANT) enzymes (all ANT[2"]); and four had acetyltransferase (AAC) enzymes. The seven ANT[2"]-producing isolates were more likely to be acquired in the community than in the hospital (4/7 ANT[2"]-producing E. coli versus one of 14 of the other AG-resistant E. coli, p = 0.03, Fisher's exact test). These findings suggest that for E. coli resistant to both ampicillin and an AG, APH enzymes are the predominant AME class. Additionally, isolates with certain AMEs may be acquired both in the community and in the hospital.

Aminoglycosides↗
PubMedDate not supplied

A review of chemoprophylaxis and therapy of bacterial infections in neutropenic patients.

Gram-negative infections in neutropenic patients frequently originate from the intestinal flora. Attempts to decrease the incidence of these infections include several regimens for gastrointestinal decontamination, some of which have proved to be clinically useful. The orally administered nonabsorbable antibiotics such as aminoglycosides and polymyxins can decrease the incidence of Gram-negative sepsis during neutropenia. However, tolerance of these agents, with the possible exception of netilmicin, is very poor, and patient compliance is low. Cotrimoxazole (trimethoprim/sulfamethoxazole) has been widely used for prophylaxis of infections in neutropenic patients with variable clinical results. Its efficacy is clearly related to epidemiologic patterns of resistance to cotrimoxazole from potential pathogens in the population under study. More recently, the quinolones, which are well tolerated and inhibit most Enterobacteriaceae, have been associated with the virtual eradication of Gram-negative infections in neutropenic patients. These results are paralleled by an increase in the frequency of Gram-positive infections, for which the mortality rate is fortunately much lower than that seen in Gram-negative sepsis. In addition, quinolone antibiotics are absorbed systematically and this might help to explain their efficacy as chemoprophylaxis during neutropenia. Synergy, as demonstrated in vitro, and adequate bactericidal activity in the serum both correlate with improved clinical effectiveness in severe infections that occur during granulocytopenia. Whereas empiric antimicrobial therapy in febrile granulocytopenic cancer patients has become accepted medical practice, controversy still remains as to the optimal therapeutic regimen that should be used.

Agranulocytosis↗
PubMed1996

[Neonatal cholestatic lithiasis associated with E. coli infection].

BACKGROUND: Cholestasis associated with gallbladder lithiasis is quite uncommon in the neonate. We report such a case possibly due to a bacterial infection. CASE REPORT: A 25 day-old neonate was admitted because he suffered from cholestatic jaundice associated with biological findings of inflammation. Hepatic cellular function and transaminases were normal. Ultrasonography showed hepatomegaly and a 10 mm diameter gallstone with sludge into the gallbladder. The patient was given cefotaxime plus netilmicine. Soluble antigenes for E coli were positive in the urine. Jaundice and inflammatory findings returned to normal within 10 days and ultrasonography was normal at the age of 20 months. CONCLUSION: Neonatal E coli infection could be responsible for gallstone formation since E coli endotoxin may induce biliary stasis and favours lithogenous action of bacterial glycoproteins.

Cholelithiasis↗
PubMed2005

Antibiotic resistance in exopolysaccharide-forming Staphylococcus epidermidis clinical isolates from orthopaedic implant infections.

The opportunistic pathogen Staphylococcus epidermidis is able to produce biofilm and to frequently cause implant infections. In recent years, it has also exhibited an increasing antimicrobial drug resistance. Here, the resistance to a panel of 16 different antibiotics in 342 clinical strains of S. epidermidis from orthopaedic implant infections has been investigated. The isolates were pheno- and genotyped for extracellular polysaccharide production, relevant to staphylococcal biofilm formation, in order to ascertain possible associations with antibiotic resistance. Approximately 10% of the isolates were found to be sensitive to all screened antibiotics. In all, 37-38% were resistant to beta-lactams such as oxacillin and imipenem, while the resistance to penicillin, ampicillin, cefazolin, cefamandole, was consistently observed in over 80% of the strains. Erythromycin- and clindamycin- resistant strains were approximately 41% and 16%, respectively. Of the isolates, 10% was resistant to chloramphenicol, 23% to sulfamethoxazole and 26% to ciprofloxacin. Resistance to vancomycin was never observed. Interestingly, exopolysaccharide-producing strains exhibited a significantly higher prevalence in the resistance to the four aminoglycosides (gentamicin, amikacin, netilmicin, tobramycin), to sulfamethoxazole and to ciprofloxacin with respect to non-producing isolates. Moreover, multiple resistance to antibiotics was more frequent among exopolysaccharide-forming strains.

Agar↗
PubMed2004

Aerobic bacterial isolates from burn wound infections and their antibiograms--a five-year study.

A retrospective study of major aerobic bacterial isolates from pus/wound swabs taken from patients admitted to the burn unit at Govt. Medical College Hospital, Chandigarh, India, over a period of 5 years (June 1997-May 2002) was undertaken. The study was carried out to determine the bacterial profile and antimicrobial susceptibility of the isolates and to describe the change in trends over the study period. The pus/wound swabs yielded very high culture positivity (96%) for 665 total isolates. Pseudomonas aeruginosa was found to be most common isolate (59%) followed by Staphylococcus aureus (17.9%), Acinetobacter spp. (7.2%), Klebsiella spp. (3.9%), Enterobacter spp. (3.9%), Proteus spp. (3.3%) and others (4.8%). Although P. aeruginosa continued to remain the predominant isolate over the five years, a constant and significant increase in the incidence of Acinetobacter spp. was found. Amikacin was found to be the most effective drug against gram negative bacteria, however, resistance to it was significantly increased over 5 years. For S. aureus and P. aeruginosa netilmicin and piperacillin were found to be the most effective drugs. Most of the isolates showed high level resistance to antimicrobial agents.

Bacteria, Aerobic↗