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At least 19 recordsLinked to original sources
PubMed1999

Aminoglycoside resistance mediated by the bifunctional enzyme 6'-N-aminoglycoside acetyltransferase-2"-O-aminoglycoside phosphotransferase.

The expression of the bifunctional aminoglycoside inactivating enzyme 6'-N-aminoglycoside acetyltransferase-2"-O-aminoglycoside phosphotransferase is the most important mechanism of high-level aminoglycoside resistance in Staphylococcus and Enterococcus. The enzyme is unique because it presents two different aminoglycoside-modifying activities located in different regions of the molecule. The gene aac(6')-aph(2") which encodes the synthesis of the enzyme is present in Tn4100-like transposons which are inserted both in R plasmids and the chromosomes of aminoglycoside-resistant isolates. The genetic structure of aac(6')-aph(2")-containing isolates indicates that their origin is not clonal, but plasmid conjugation together with multiple insertion events are in the basis of the rapid spread of aminoglycoside resistance among Gram-positive bacteria. There is not any prevalent genetic linkage of aac(6')-aph(2") with other antibiotic-resistance determinant. However, most methicillin resistant Staphylococcus strains present also high-level aminoglycoside resistance as the consequence of constant antibiotic pressure. This situation could change in the next future with the reported reemergence of gentamicin-susceptible MRSA isolates. Recent data show that inhibitors of eukaryotic protein kinases inhibit as well the aminoglycoside phosphotransferase activity. This effect indicates a common structure for these two families of proteins and opens the possibility for a meaningful survey of inhibitors of 6'-N-aminoglycoside acetyltransferase-2"-O-aminoglycoside phosphotransferase useful in clinical practice.

Acetyltransferases↗
PubMedDate not supplied

[Streptomyces rimosus aminoglycoside-3'-phosphotransferase VIII: comparisons with aminoglycoside-3'-phosphotransferases of aminoglycoside-producing strains with eukaryotic protein kinases].

The nucleotide sequence was established for the aphVIII aminoglycoside phosphotransferase gene of an oxytetracycline-producing Streptomyces rimosus strain. The gene is 804 bp in size and possibly codes for APHVIII of 267 residues. Heterologous expression of aphVIII was studied in Escherichia coli and Chlamydomonas reinhardtii. The deduced APHVIII sequence was compared with known sequences of aminoglycoside phosphotransferases of aminoglycoside-producing actinomycete strains and of eukaryotic protein kinases. A local homology of 38 residues was found between APHVIII and actinomycete serine-threonine protein kinases in the conserved region possibly involved in ATP binding. APHVIII differed from aminoglycoside 3'-phosphotransferases of aminoglycoside-producing actinomycete strains and of clinical isolates, and can be classed to a separate group.

Amino Acid Sequence↗
PubMed1995

The changing nature of aminoglycoside resistance mechanisms and the role of isepamicin--a new broad-spectrum aminoglycoside. The Aminoglycoside Resistance Study Groups.

Aminoglycoside resistance mechanisms from recent studies were compared with those found in earlier studies in the USA and Europe for three pathogen groups. Among Citrobacter-Enterobacter-Klebsiella, four single mechanisms (AAc(3)-II, AAC(3)-I, ANT(2")-I and AAC(6')-I were found in all studies, but the most recent studies showed a significant increase in combinations of AAC(6')-I with the other common mechanisms. Since AAC(6')-I confers resistance to tobramycin, netilmicin and amikacin, combinations of it with the other gentamicin modifying enzymes conferred broad-spectrum resistance to all clinically available aminoglycosides except isepamicin. Similar changes occurred in Escherichia-Morganella-Proteus-Salmonella-Shigella except that the frequency of combinations was much lower and two additional single mechanisms - AAC(3)-IV and permeability - were also found frequently. Among aminoglycoside-resistant Pseudomonas, three mechanisms, AAC(6')-II, ANT(2")-I and permeability, were always common and remained common. However, combinations of the three mechanisms with each other and with other mechanisms were more common in the recent surveys. Different genes which produce different proteins with the same aminoglycoside-modifying activity are now known. The results of hybridisation studies with two aac(3)-I, 2 aac(6')-II and 4 aac(6')-I gene probes are presented. The most commonly occurring genes were: aac(3)-Ia, aac(3)-IIa, aac(6')-IIa, aac(6')-Ib and, in Serratia, aac(6')-Ic. The activity of isepamicin against amikacin resistant strain which produce AAC(6')-I can be related to differences in the structure of these two similar aminoglycosides at Position 3". Amikacin may form a stable complex with AAC(6')-I enzymes via binding interaction at Position 3 and 3". Isepamicin, which has a secondary amino group at Position 3", may only be able to interact at Position 3 and enzyme-isepamicin complexes are likely to be less stable.

Acetyltransferases↗
PubMed1994

In-vitro synergy between aminoglycosides deployed against Staphylococcus spp. harbouring a 6'-aminoglycoside acetyltransferase, 2"-aminoglycoside phosphotransferase enzyme.

In-vitro synergistic effects between commercial aminoglycosides are described for gentamicin resistant Staphylococcus strains harbouring 6'-aminoglycoside acetyltransferase activity. Seventy eight strains were studied using the double-disc test and synergy was observed with combinations in which at least one of the components has a garosamine-like 6'-aminosugar. These results were confirmed in chequerboard titrations (sigma FIC < or = 0.5) carried out on Staphylococcus epidermidis strains RYC13036 and RYC4904. Additionally, a clear reduction in tobramycin acetylating activity was observed in the presence of gentamicin or netilmicin in crude extracts of these strains. These experiments suggest that the observed synergy is due to inhibition of the aminoglycoside-modifying enzyme by aminoglycosides with a garosamine like 6'-aminosugar component.

Acetyltransferases↗
PubMed1997

The most frequent aminoglycoside resistance mechanisms--changes with time and geographic area: a reflection of aminoglycoside usage patterns? Aminoglycoside Resistance Study Groups.

The aminoglycoside resistance mechanisms revealed by two surveys in Europe and other countries have been compared to those revealed in earlier studies. Mechanisms have become more complex in all bacterial groups. In Providencia, Serratia, Pseudomonas, Acinetobacter, and Staphylococcus species isolates, genus-specific mechanisms were very common, and it was not possible to see differences between different geographic areas. In other Enterobacteriaceae, the increasing complexity of mechanisms was most often caused by combinations of gentamicin-modifying enzymes with AAC(6')-I, which acetylates amikacin but not gentamicin. The occurrence of these combinations varied by geographical region and among hospitals. The frequency of these combinations correlated with aminoglycoside usage in either the geographical regions or in individual hospitals. These broad-spectrum combinations occurred most frequently in Citrobacter, Enterobacter, and Klebsiella species but also occurred in Escherichia, Morganella, Proteus, Salmonella, and Shigella species. Often the only clinically available aminoglycoside that retained its normal activity was isepamicin.

Acinetobacter↗
PubMed1999

Role of aminoglycoside 6'-acetyltransferase in a novel multiple aminoglycoside resistance of an actinomycete strain #8: inactivation of aminoglycosides with 6'-amino group except arbekacin and neomycin.

From a rare actinomycete strain #8 isolated from soil as arbekacin (ABK) resistant, we cloned a gene segment (0.9 kb) conferring multiple resistance to aminoglycoside (AG) antibiotics with 6'-NH2 including semisynthetic ones except ABK and neomycin (NM). Enzymatic modification using cell free extracts from Streptomyces lividans TK21/pANT-S2 carrying the cloned gene revealed that the gene coded for an AG 6'-acetyltransferase [AAC(6')] capable of acetylating all of the tested AGs with 6'-NH2 including semisynthetic ones and astromicin. The substrate specificity of the enzyme was thus similar to that of AAC(6')-Ie of Enterococcus faecalis. Antibiotic assay revealed a weak but clear antibiotic activity of 6'-N-acetylABK (8% of ABK activity) in contrast with substantial inactivation by the AAC(6') of the other AGs including amikacin and isepamicin. The NM acetylation by the AAC(6') also did not result in NM inactivation. It seems thus likely that AAC(6')-dependent resistance to ABK and NM, if it emerges, will remain at low level.

Acetylation↗
PubMed2004

Thermodynamics of aminoglycoside binding to aminoglycoside-3'-phosphotransferase IIIa studied by isothermal titration calorimetry.

The aminoglycoside-3'-phosphotransferase IIIa [APH(3')-IIIa] phosphorylates aminoglycoside antibiotics and renders them ineffective against bacteria. APH(3')-IIIa is the most promiscuous aminoglycoside phosphotransferase enzyme, and it modifies more than 10 different aminoglycoside antibiotics. A wealth of information exists about the enzyme; however, thermodynamic properties of enzyme-aminoglycoside complexes are still not known. This study describes the determination of the thermodynamic parameters of the binary enzyme-aminoglycoside and the ternary enzyme-metal-ATP-aminoglycoside complexes of structurally related aminoglycosides using isothermal titration calorimetry. Formation of the binary enzyme-aminoglycoside complexes is enthalpically driven and exhibits a strongly disfavored entropic contribution. Formation of the ternary enzyme-metal-ATP-aminoglycoside complexes yields much smaller negative DeltaH values and more favorable entropic contributions. The presence of metal-ATP generally increases the affinity of aminoglycosides to the enzyme. This is consistent with the kinetic mechanism of the enzyme in which ordered binding of substrates occurs. However, the observed DeltaH values neither correlate with kinetic parameters k(cat), K(m), and k(cat)/K(m) nor correlate with the molecular size of the substrates. Comparison of the thermodynamic properties of the complexes formed by structurally similar aminoglycosides indicated that the 2'- and the 6'-amino groups of the substrates are involved in binding to the enzyme. Thermodynamic properties of the complexes formed by aminoglycosides differing only at the 3'-hydroxyl group suggested that the absence of this group does not alter the thermodynamic parameters of the ternary APH(3')-IIIa-metal-ATP-aminoglycoside complex. Our results also indicate that protonation of ligand and protein ionizable groups is coupled to the complex formation between aminoglycosides and APH(3')-IIIa. Comparison of DeltaH values for different aminoglycoside-enzyme complexes indicates that enzyme and substrates undergo significant conformational changes in complex formation.

Adenosine Triphosphate↗
PubMed1991

Serum aminoglycoside clearance is predicted as poorly by renal aminoglycoside clearance as by creatinine clearance in critically ill patients.

OBJECTIVE: To determine the relationships among serum aminoglycoside clearance, renal aminoglycoside clearance, measured creatinine clearance, and estimated creatinine clearance derived from a standard formula in critically ill patients. SETTING: A ten-bed general ICU in a university hospital. PATIENTS: Eighteen critically ill patients who were being treated with gentamicin or tobramycin for severe infections, and were hemodynamically stable. INTERVENTIONS: The various clearances were measured simultaneously after the administration of a dose of aminoglycoside by assaying serial blood samples for aminoglycoside and creatinine concentration, and by measuring the content of these substances in urine collected over the same time period. OUTCOME MEASURES: The slopes, intercepts and coefficients of determination (r2) of the various regressions were determined, along with the 95% confidence intervals for the prediction of serum aminoglycoside clearance from each other variable. RESULTS: Renal aminoglycoside clearance, creatinine clearance, and estimated creatinine clearance accounted for only 58%, 59%, and 62%, respectively, of the variance in serum aminoglycoside clearance. Only 64% of the variance in renal aminoglycoside clearance was explained by creatinine clearance. Substantial and variable nonrenal aminoglycoside clearance was evident. CONCLUSIONS: The 95% confidence intervals for the prediction of serum aminoglycoside clearance from each index of renal function indicated that none of these indices provided acceptable accuracy for the prediction of serum aminoglycoside clearance and dosage requirements in critically ill patients. Renal aminoglycoside clearance was not better than creatinine clearance in this respect, and thus no other index of renal function is likely to be more accurate. This finding implies that the only accurate method of determining the dose requirements to achieve target serum concentrations in such patients will be individualized pharmacokinetic dosing.

Aminoglycosides↗
PubMed2006

[Molecular mechanisms underlying renal accumulation of aminoglycoside antibiotics and mechanism-based approach for developing nonnephrotoxic aminoglycoside therapy].

Aminoglycoside antibiotics, such as gentamicin and amikacin, are a class of clinically important antibiotics used worldwide in the treatment of infections caused by Gram-positive and Gram-negative bacteria. However, nephrotoxicity and ototoxicity are serious problems in the use of aminoglycosides and are the major dose-limiting side effects. Most of the intravenously administered dose is excreted into the urine, whereas some of the aminoglycoside injected (about 10% of the dose) is selectively accumulated in the renal cortex, leading to renal injury. Aminoglycosides are taken up into the epithelial cells of the renal proximal tubules by an endocytic pathway. Acidic phospholipids, broadly distributed in the plasma membranes in various tissues, were considered to be the binding site of aminoglycosides. Recently, megalin, a giant endocytic receptor abundantly expressed in renal proximal tubules, has been reported to bind aminoglycosides. Therefore we first examined whether megalin plays an important role in the renal accumulation of aminoglycosides under in vivo and in vitro conditions. We then attempted to develop new strategies for preventing the nephrotoxicity of aminoglycosides based on the molecular mechanisms of aminoglycoside accumulation in the kidney. This review summarizes our recent findings ol the role of megalin in the renal accumulation of aminoglycosides and our approach to develop nonnephrotoxic aminoglycoside therapy.

Aminoglycosides↗
PubMed1986

Susceptibility of aerobic gram-negative bacilli to aminoglycosides. Effects of 45 months of amikacin as first-line aminoglycoside therapy.

Amikacin was instituted as the primary empiric aminoglycoside at the San Juan Veterans Administration Medical Center in January 1982; at that time, 16 percent of the strains at the hospital were gentamicin-resistant. A prospective surveillance study was designed to correlate detection of bacterial resistance with aminoglycoside use. In the current report, the baseline period, during which gentamicin was the first-line aminoglycoside, accounting for 61 percent of overall aminoglycoside use, is compared with the period from January 1982 to September 1985, during which the first-line aminoglycoside was amikacin, accounting for 85 percent of overall use. This study is ongoing. During the two periods, the patient population did not differ with regard to aminoglycoside therapy, indications, or overall aminoglycoside use (541 versus 680 patient days per month). Among the gram-negative bacilli isolated, the percent of strains resistant to amikacin was as follows: pre-baseline period/baseline period, 0.8/0.2 percent; amikacin-usage period, 3.6 percent. Resistance to gentamicin and tobramycin during the period of amikacin use decreased from 16 to 11 percent for gentamicin and from 17 to 11 percent for tobramycin. The decrease in resistance of the gram-negative bacilli to gentamicin varied among strains: the resistance of Escherichia coli decreased from 8 to 4 percent; that of Proteus mirabilis, from 12 to 5 percent; that of indole-positive Proteus, from 19 to 12 percent; that of Acinetobacter, from 57 to 23 percent; that of Citrobacter, from 15 to 7 percent; and that of Pseudomonas aeruginosa, from 24 to 16 percent. During the amikacin-usage period, amikacin resistance was unchanged for most strains, with the exception of P. aeruginosa, the resistance of which increased from 4.5 to 7.8 percent. Of the 4,795 strains isolated, 174 were resistant to amikacin; of these, 29 Pseudomonas strains were studied for all mechanisms of resistance. Changes in permeability were exhibited by 11 of the 29 strains; 14 strains exhibited the AAC(6')-I enzyme, 10 strains exhibited the APH(3')-II enzyme, and two strains exhibited ANT(2") in addition to some other unidentified mechanism. Multiple enzyme production was found in 15 of the strains. The use of amikacin as a first-line aminoglycoside is associated with a decrease in resistance to other aminoglycosides and a slight increase in overall resistance to amikacin among aerobic gram-negative bacilli. The usefulness of amikacin has not been affected at our institution.

Acetyltransferases↗
PubMed1997

Specific binding of aminoglycosides to a human rRNA construct based on a DNA polymorphism which causes aminoglycoside-induced deafness.

RNA constructs prepared from wild-type and mutant (1555(G)) human mitochondrial 12S RNA were studied with respect to their abilities to specifically bind aminoglycoside antibiotics. The 1555(G) point mutation had previously been found to be associated with hereditary deafness induced by aminoglycosides. It is shown here that the 1555(G) RNA analog stoichiometrically binds aminoglycosides with high affinities, while the wild-type construct does not bind aminoglycosides at all. Analogous mutations in a 16S bacterial rRNA construct show the opposite behavior. Bacterial 16S rRNA constitutes the functional target for aminoglycoside antibiotics. While the wild-type 16S rRNA decoding region construct binds aminoglycosides stoichiometrically with binding affinities in the micromolar range, the mutant is unable to specifically bind aminoglycosides. These results demonstrate the importance of a specific GC base pair in aminoglycoside binding in both the human and the bacterial rRNA constructs. These studies also provide quantitative evidence in support of the hypothesis that the 1555(G) point mutation in human mitochondrial 12S RNA causes aminoglycoside induced deafness.

Aminoglycosides↗
PubMed2002

Thermodynamics of aminoglycoside-rRNA recognition: the binding of neomycin-class aminoglycosides to the A site of 16S rRNA.

We use spectroscopic and calorimetric techniques to characterize the binding of the aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin to a RNA oligonucleotide that models the A-site of Escherichia coli 16S rRNA. Our results reveal the following significant features: (i) Aminoglycoside binding enhances the thermal stability of the A-site RNA duplex, with the extent of this thermal enhancement decreasing with increasing pH and/or Na(+) concentration. (ii) The RNA binding enthalpies of the aminoglycosides become more exothermic (favorable) with increasing pH, an observation consistent with binding-linked protonation of one or more drug amino groups. (iii) Isothermal titration calorimetry (ITC) studies conducted as a function of buffer reveal that aminoglycoside binding to the host RNA is linked to the uptake of protons, with the number of linked protons being dependent on pH. Specifically, increasing the pH results in a corresponding increase in the number of linked protons. (iv) ITC studies conducted at 25 and 37 degrees C reveal that aminoglycoside-RNA complexation is associated with a negative heat capacity change (Delta C(p)), the magnitude of which becomes greater with increasing pH. (v) The observed RNA binding affinities of the aminoglycosides decrease with increasing pH and/or Na(+) concentration. In addition, the thermodynamic forces underlying these RNA binding affinities also change as a function of pH. Specifically, with increasing pH, the enthalpic contribution to the observed RNA binding affinity increases, while the corresponding entropic contribution to binding decreases. (vi) The affinities of the aminoglycosides for the host RNA follow the hierarchy neomycin > paromomycin > ribostamycin. The enhanced affinity of neomycin relative to either paromomycin or ribostamycin is primarily, if not entirely, enthalpic in origin. (vii) The salt dependencies of the RNA binding affinities of neomycin and paromomycin are consistent with at least three drug NH(3)(+) groups participating in electrostatic interactions with the host RNA. In the aggregate, our results reveal the impact of specific alterations in aminoglycoside structure on the thermodynamics of binding to an A-site model RNA oligonucleotide. Such systematic comparative studies are critical first steps toward establishing the thermodynamic database required for enhancing our understanding of the molecular forces that dictate and control aminoglycoside recognition of RNA.

Anti-Bacterial Agents↗
PubMed2002

Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropaenia.

BACKGROUND: Chemotherapy treated cancer patients are prone to neutropaenia and life-threatening infections. Early, empirical antibiotic treatment is therefore administered routinely to febrile neutropaenic patients. Currently, either beta-lactam-aminoglycoside combination treatment or beta-lactam monotherapy are recommended. OBJECTIVES: We compared beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutroepaenia. SEARCH STRATEGY: Cochrane Library (Issue 4,2001), the Cochrane Cancer Network Register of trials (July 2000), EMBASE (January 1980-2000), MEDLINE (1966-8/2001), and ICAAC conference proceedings (1995 onwards). We scanned references of all included studies, pertinent reviews, and contacted the first author of each included trial and the pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing any beta-lactam antibiotic monotherapy to any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial, empirical treatment of febrile neutropaenic cancer patients. DATA COLLECTION AND ANALYSIS: Data concerning mortality, treatment failure (including treatment modifications), superinfections, adverse effects and study quality measures were extracted independently by two reviewers. Relative risks with their 95% confidence intervals (CI) were estimated. Outcomes were extracted by intention-to-treat analysis whenever possible. MAIN RESULTS: Forty-six trials and 7642 patients were included. All cause mortality was the primary outcome assessed. For all mortality comparisons, no significant difference between monotherapy and combination therapy was seen, relative risk 0.85 (95% CI 0.72-1.02) for all studies combined. Treatment failure was the outcome reported in all included trials. No significant difference between study groups was shown for studies comparing the same beta-lactam, relative risk 1.12 (95% CI 0.96-1.29). A significant advantage to monotherapy was observed for studies comparing different beta-lactams, relative risk 0.86 (95% CI 0.80-0.93). Bacterial and fungal superinfections developed with similar frequencies in the monotherapy and combination treatment groups. Adverse events were significantly more common in the combination treatment group, relative risk 0.83, (95% CI 0.72-0.97). These included events associated with significant morbidity, primarily renal toxicity. Results were consistent for subgroup and sensitivity analyses. REVIEWER'S CONCLUSIONS: We have shown an advantage to broad-spectrum beta-lactam monotherapy over beta-lactam-aminoglycoside combination therapy for febrile neutropaenia. This advantage comprises of 1) a similar, if not better, survival, 2) a significantly lower treatment failure rate, 3) comparable probability for secondary infections and, 4) most importantly, a lower rate of adverse events associated with significant morbidity. Monotherapy can be regarded, therefore, as the standard of care for febrile neutropaenic patients.

Aminoglycosides↗
PubMed2006

Molecular determinants of affinity for aminoglycoside binding to the aminoglycoside nucleotidyltransferase(2'')-Ia.

One of the most commonly occurring aminoglycoside resistance enzymes is aminoglycoside 2''-O-nucleotidyltransferase [ANT(2'')]. In the present study molecular determinants of affinity and specificity for aminoglycoside binding to this enzyme are investigated using isothermal titration calorimetry (ITC). Binding of aminoglycosides is enthalpically driven accompanied by negative entropy changes. The presence of metal-nucleotide increases the affinity for all but one of the aminoglycosides studied but has no effect on specificity. The substituents at positions 1, 2', and 6' are important determinants of substrate specificity. An amino group at these positions leads to greater affinity. No correlation is observed between the change in affinity and enthalpy. At the 2' position greater affinity results from a more negative enthalpy for an aminoglycoside containing an amino rather than a hydroxyl at that position. At the 6' position the greater affinity for an aminoglycoside containing an amino substituent results from a less disfavorable entropic contribution. The thermodynamic basis for the change in affinity at position 1 could not be determined because of the weak binding of one of the aminoglycoside substrates, amikacin. The effect of increasing osmotic stress on affinity was used to determine that a net release of approximately four water molecules occurs when tobramycin binds to ANT(2''). No measurable net change in the number of bound water molecules is observed when neomycin binds the enzyme. Data acquired in this work provide the rationale for the ability of ANT(2'') to confer resistance against kanamycins but not neomycins.

Aminoglycosides↗
PubMed1993

Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes.

The three classes of enzymes which inactivate aminoglycosides and lead to bacterial resistance are reviewed. DNA hybridization studies have shown that different genes can encode aminoglycoside-modifying enzymes with identical resistance profiles. Comparisons of the amino acid sequences of 49 aminoglycoside-modifying enzymes have revealed new insights into the evolution and relatedness of these proteins. A preliminary assessment of the amino acids which may be important in binding aminoglycosides was obtained from these data and from the results of mutational analysis of several of the genes encoding aminoglycoside-modifying enzymes. Recent studies have demonstrated that aminoglycoside resistance can emerge as a result of alterations in the regulation of normally quiescent cellular genes or as a result of acquiring genes which may have originated from aminoglycoside-producing organisms or from other resistant organisms. Dissemination of these genes is aided by a variety of genetic elements including integrons, transposons, and broad-host-range plasmids. As knowledge of the molecular structure of these enzymes increases, progress can be made in our understanding of how resistance to new aminoglycosides emerges.

Acetyltransferases↗
PubMed1977

Aminoglycoside nephrotoxicity. I. Effects of aminoglycoside antibiotics on iodohippurate accumulation in rabbit renal cortical slices.

The effects of aminoglycoside antibiotics on the accumulation of O-125I-hippurate (OIH) in rabbit renal cortical slices were assessed in an attempt to establish an in vitro model for aminoglycoside nephrotoxicity. Accumulation of OIH was measured after incubation of cortex slices in media containing aminoglycosides in different concentrations. All aminoglycosides depressed OIH accumulation in the following minimum concentrations: Dihydrostreptomycin and kanamycin, 2,000 microgram/ml (P less than 0.01); streptomycin and neomycin, 1,000 microgram/ml (P less than 0.05 and P less than 0.01); amikacin and tobramycin, 300 microgram/ml (P less than 0.05); gentamicin, 100 microgram/ml (P less than 0.05). A concentration of 2,000 microgram/ml caused the following reduction in OIH accumulation: Dihydrostreptomycin, 19.3%; streptomycin, 28.9%; kanamycin, 23.8%; neomycin, 62.5%; gentamicin, 68.0%; amikacin and tobramycin, 100%. Changes in pH of the incubation media after addition of aminoglycosides were only partially responsible for the observed depression of OIH accumulation and there was no evidence of substrate competition between aminoglycosides and OIH. The in vitro model described here appears to be inadequate as a sole predictor of aminoglycoside nephrotoxicity, but may provide a supplementary tool in the investigation of aminoglycoside proximal tubular cell toxicity.

Aminoglycosides↗
PubMed1996

Aminoglycoside resistance mechanisms in Enterobacteriaceae and Pseudomonas spp. from two Danish hospitals: correlation with type of aminoglycoside used.

Sixty-two aminoglycoside-resistant Gram-negative enteric bacteria were isolated over a 3-year period from two hospitals (Bispebjerg and Esbjerg) among a total of almost 270,000 isolates. These hospitals were selected because of their different aminoglycoside policies during the years investigated. At Bispebjerg Hospital the principal aminoglycoside used was tobramycin, while gentamicin was the first choice at Esbjerg Hospital. Escherichia coli was the most frequently found aminoglycoside-resistant species. Among the 61 aminoglycoside-resistant strains studied, resistance was due to aminoglycoside-modifying enzymes in all except two Xanthomonas maltophilia strains. The ANT(2") enzyme occurred significantly more often at Esbjerg Hospital (p = 0.001), while enzymes of the AAC(3) or AAC(6') moieties were more common, but not significantly so, at Bispebjerg Hospital. The phenotypic pattern of aminoglycoside resistance, as determined by disc diffusion, correlated 100% with the ANT(2") and AAC(3)-V (the two most common enzymes among the isolates) genotype of the organisms as established using DNA probes. Median minimum inhibitory concentrations (MICs) (mg/l) for clinically utilized aminoglycosides were: amikacin (1.6), gentamicin (25.0), kanamycin (50.0), netilmicin (1.6-25.0) and tobramycin (12.5-50.0). Isolates from Bispebjerg Hospital revealed significantly higher MICs for netilmicin and tobramycin (p < 0.01) as compared to isolates from Esbjerg Hospital.

Aminoglycosides↗
PubMed1988

High-content aminoglycoside disks for determining aminoglycoside-penicillin synergy against Enterococcus faecalis.

We investigated the use of high-content aminoglycoside disks for determining Enterococcus faecalis susceptibility to aminoglycoside-penicillin synergy. The susceptibility of the organisms to synergy was established by 24-h time-kill studies performed with streptomycin, kanamycin, amikacin, gentamicin, and tobramycin, alone and in combination with penicillin. A total of 20 isolates that were susceptible to all drug combinations and 20 strains that were resistant to each aminoglycoside-penicillin combination were selected for testing against high-content disks. Disk-agar diffusion was performed on Mueller-Hinton agar, with and without 5% sheep blood, by using disks that contained either 300 or 2,000 micrograms of streptomycin and either 120 or 2,000 micrograms of kanamycin, amikacin, tobramycin, or gentamicin. Zone size results obtained for each aminoglycoside, except amikacin, could be used to differentiate between synergy-susceptible and -resistant isolates. No overlap occurred between the zone sizes of susceptible and resistant strains. Susceptibility to amikacin-penicillin synergy could reliably be tested with kanamycin, but not amikacin, disks. When the disks containing 120 micrograms were tested, a narrow zone size range of 6 to 7 mm could be used to identify all resistant strains. In contrast, when the disks containing 2,000 micrograms were used, the zone size ranges for resistant isolates varied widely with the aminoglycoside being tested. The presence of blood in the medium did not appreciably affect the disk test results. To detect resistance to every aminoglycoside-penicillin combination that may be considered for therapy, E. faecalis isolates need to be tested against a maximum of three different high-content disks (i.e., streptomycin, gentamicin, kanamycin). The disk-agar diffusion test performed with high-content aminoglycoside disks can provide laboratories with a convenient and reliable method for detecting E. faecalis isolates that are resistant to aminoglycoside-penicillin synergy.

Amikacin↗