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New trends in the chemotherapy of staphylococcal infections.

The authors evaluated the susceptibility of some antibiotics against several Staphylococci subdivided in lyogroups and different resistance patterns: methicillin-susceptible/penicillin-susceptible (MS/PS), methicillin-susceptible/penicillin-resistant (MS/PR), methicillin-resistant/penicillin-resistant (MR/PR) and methicillin-resistant/penicillin-susceptible (MR/PS). The antimicrobial agents used were: methicillin, penicillin, rifampin, tetracycline, lincomycin, erythromycin, gentamicin and netilmicin. Netilmicin showed better activity against all Staphylococcus strains tested, particularly against coagulase-negative.

Anti-Bacterial Agents↗

Chemical assay, involving liquid chromatography, for aminoglycoside antibiotics in serum.

We describe a chemical assay involving "high-pressure" liquid chromatography for the quantitative determination of three aminoglycosides: netilmicin, tobramycin, and gentamicin. The drugs are separated from serum by means of precipitation of the serum proteins with acetonitrile after dilution with a buffer. The aminoglycosides are quantitatively extracted into the supernate, which is further purified by a two-step partition procedure involving derivatization of the drugs with o-phthalaldehyde. The drug derivatives are separated by reversed-phase chromatography and detected by on-line fluorometry. Sensitivity is 1 mg/L for tobramycin and 0.5 mg/L for netilmicin and gentamicin. Intra- and interassay variation was below 8%. Analytical recovery of each of the three drugs was 92 to 100%. Correlation with microbiological and radioimmunological assay methods was good. The assay is rapid (about 30 min), precise, and specific, and seems suitable for use in a routine clinical laboratory.

Anti-Bacterial Agents↗

[Salmonella meningitis].

A four - month old boy with Salmonella Typhimurium meningitis is presented. This patient was admitted to the hospital with a diagnosis of staphylococcal pneumonia, pyo-pneumothorax, cardiac failure and anemia. He has been treated for 18 days and he was discharged in good condition. Two days after discharge patient was readmitted with a fever, vomiting and feeding problem. In physical examination, stiff neck and bulging of the fontanel were remarkable. Examination of cerebrospinal fluid (CSF) has revealed meningitis and cultures of blood and CSF specimens were positive for S. typhimurium. It was sensitive only to trimethoprim sulphamethoxazole and netilmicin. Trimethoprim sulphamethoxazole (IM) and netilmicin (IV) were given. At the fifth day of this treatment patient expired. Postmortem examination has revealed the same agent in both meninges tissue and CSF cultures.

Autopsy↗

Evaluation of a new aminoglycoside antibiotic in the treatment of infections in neonates, infants, and children.

A total of 804 pediatric patients (572 neonates and 232 infants and children) with suspected or documented serious infections were enrolled in a multicenter open study of netilmicin, a new semisynthetic aminoglycoside. All patients were evaluable for safety; 161 (20%) had bacteriologically documented infections and were thus evaluable for efficacy. Clinical success was seen in 94.4% (169/179) and bacteriological success in 91.1% (163/179) of sites; clinical success was seen in 94% (205/218) and bacteriological success was seen in 90.3% (196/217) of organisms. No significant adverse renal function changes were seen, and only one instance of an eighth nerve problem, probably related to netilmicin therapy, was encountered.

Adolescent↗

Comparative nephrotoxicity of four aminoglycosides: biochemical and ultrastructural modifications of lysosomes.

In 1982, aminoglycosides still are widely prescribed and considered indispensable for the treatment of severe gram-negative infections. All the aminoglycosides are nephrotoxic, but both experimental works and clinical investigations indicate that they do not all have the same nephrotoxic potential. Within the renal tubular cell in several animal species and in man, the initial and the most extensive changes are those that occur in the lysosomes. We compared the effects of gentamicin, tobramycin, netilmicin and, amikacin on (a) lysosomal structural latency, (b) the activity of several enzymes, either lysosomal or those contained in the proximal tubular cell brush border, and (c) the accumulation of myeloid bodies in the lysosomes. From our results, it appears that gentamicin is the aminoglycoside that induces the greatest number of lysosomal changes whereas amikacin induces the least, with the effects of netilmicin and tobramycin quite close to those of amikacin. Other works comparing the nephrotoxicity of aminoglycosides reveal the same high nephrotoxic potential of gentamicin.

Amikacin↗

A laboratory assessment of the activities of four aminoglycosides.

An in vitro comparison of the activities of gentamicin, tobramycin, amikacin and netilmicin against selected clinical isolates showed differences in the susceptibility of individual strains to the four drugs, as well as substantial differences in sensitivity patterns between genera. Sensitive strains of Klebsiella and Enterobacter were most susceptible to netilmicin, but amikacin was more active against resistant strains. Tobramycin was most active against sensitive strains of Pseudomonas aeruginosa, but resistant strains were more susceptible to amikacin. In serious infections caused by these Gram-negative bacilli knowledge of the organism's identity and susceptibility may help in the selection of the most suitable aminoglycoside.

Amikacin↗

Aminoglycoside nephrotoxicity in dogs: dependence on drug, dose and regimen.

In female mongrel dogs nephrotoxicity of three aminoglycosides (gentamicin, tobramycin and netilmicin) was compared with relation to the cortical aminoglycoside concentration. A standard regimen of 45 mg/kg/day with constant intravenous infusion and once daily dosing of each aminoglycoside was used, and in subsequent dogs netilmicin daily dose was increased to an average of 73 mg/kg/day.

Animals↗

The effect of aminoglycosides on glomerular endothelium: a comparative study.

In addition to being tubular nephrotoxins, the aminoglycosides are known to injure the glomerular endothelium by decreasing the diameter and density of endothelial fenestrae. To determine whether or not these changes correlate with the rank order of toxicity we compared in rats the effects of netilmicin, tobramycin, and amikacin on renal function, tubular and glomerular ultrastructure, at 10 and 25 times the recommended human dose. According to measurements of glomerular filtration rate their rank order of toxicity, in increasing severity was: netilmicin, tobramycin, and amikacin. The same order of effect was observed on glomerular ultrastructure. Thus glomerular structural changes correspond to glomerular functional changes in this model.

Amikacin↗

[Evaluation of hearing loss by means of inner ear acoustic emission in neonates treated with aminoglycoside].

Despite their ototoxic and other side effects, aminoglycosides are still widely used in the treatment of neonatal infections. A novel method for evaluation of hearing loss is distortion product otoacoustic emission (DPOAE). Physiologic acoustic energy-emission produced by sound stimulus in the inner ear is detected by DPOAE. Existing acoustic emission indicates the functional integrity of the inner ear. DPOAE was performed in 19 newborns treated with netilmicin for different infections. Serum netilmicin levels did not exceed 12 mg/l; renal functions were normal. Existence of emission was detected in 15 newborns. There was no emission found in 4 newborns unilaterally, which was fully restored in 2 months. In conclusion, aminoglycosides have no considerable ototoxic side effects. DPOAE is thought to be an objective, fast, and non-invasive method for hearing screening in the newborn period.

Anti-Bacterial Agents↗

[Dosing aminoglycosides once a day].

In the past few decades aminoglycosides have usually been administered as multiple daily dosing regimens. However, animal experiments have shown that nephrotoxicity can be reduced if, with the same total daily dose, the dosing interval is spread out. Further, several in-vitro and in-vivo studies suggest that once-daily dosing may be more effective. In 24 randomized, clinical trials, once- vs. multiple daily dosing regimens of amikacin, netilmicin and gentamicin have been compared in a total of 3181 patients. An analysis of these studies revealed significant advantages in favour of once-daily dosing for both clinical efficacy (89.5% vs. 84.7%, p < 0.001) and bacteriological efficacy (88.6% vs. 83.4%, p < 0.01). In addition, improved but not statistically significant results were obtained with once-daily dosing with regard to nephrotoxicity (4.5% for once-daily vs. 5.5% for multiple daily dosing) and ototoxicity (4.2% vs. 5.8%). Furthermore, once-daily dosing is cheaper, as less infusions are required and the expense of monitoring serum levels can be reduced. In conclusion, amikacin, netilmicin and gentamicin can be administered once a day.

Amikacin↗

The influence of postantibiotic effects and postantibiotic effects of sub-inhibitory concentrations of quinolones and aminoglycosides on phospholipase C of Pseudomonas aeruginosa.

We have studied the postantibiotic effect (PAE) and postantibiotic sub-MICs effect (PA SME) of ciprofloxacin, pefloxacin, netilmicin and tobramycin on the production of phospholipase C (PLC) in a Pseudomonas aeruginosa strain isolated from clinical material. All antibiotics tested (postantibiotic phase evoked by 2.MIC) reduced the production of PLC, particularly pefloxacin to 13.2%. The PA phase evoked by 4.MIC of quinolones did not cause regrowth of P. aeruginosa and aminoglycosides inhibited PLC, in particular with tobramycin to 16.9%. The effect of PA SME (2.MIC) of netilmicin and tobramycin inhibited PLC more expressively (< 20%) than ciprofloxacin; pefloxacin did not allow regrowth. PA SMEs of the antibiotics tested reduced the production of PLC more effectively than PAE.

Anti-Bacterial Agents↗

Changes in serum sensitivity and hydrophobicity in a clinical isolate of Klebsiella pneumoniae treated with subinhibitory concentrations of aminoglycosides.

The effects of subinhibitory concentrations (sub-MICs) of gentamicin, netilmicin and amikacin on the serum sensitivity and the cell surface hydrophobicity of Klebsiella pneumoniae were investigated. At concentrations 1/16 or 1/8 of the MICs, in all antibiotics significantly enhanced the sensitivity of K. pneumoniae to human serum as compared to nontreated bacteria. The higher concentration of the antibiotics tested was more efficient. Survival of bacteria under these conditions ranged from 24.1% to 36.7% after incubation with 10% serum for 180 min when compared with the viability of the control bacteria. Bacteria grown with the test antibiotics at sub-MICs (1/8 or 1/4 of the MICs) manifested an effective decrease of the surface hydrophobicity. The aminoglycosides which were more effective at a concentration of 1/4 of the MICs reduced bacterial hydrophobicity to 28.5% (gentamicin), 14.8% (netilmicin) and 12.7% (amikacin) of the nontreated bacteria.

Amikacin↗

Aminoglycoside antibiotics--two decades of their HPLC bioanalysis.

Several reviews have been published on high-performance liquid chromatographic (HPLC) methods for the determination of aminoglycoside antibiotics (aminoglycosides) in biological fluids [e.g. Nilsson-Ehle, I. (1983). J. Liq. Chromat. 6: 251]. Of these, the paper by Maitra et al. [(1979a). Clin. Chem. 25: 1361.] briefly summarizes the early 2-3 years of experience on HPLC assaying of amikacin, gentamicin, netilmicin and tobramycin in body fluids. The reviews by Nilsson-Ehle, I. [(1983). J. Liq. Chromat. 6: 251] and by Miner, D. J. [(1985). Antibiotics. In Therapeutic Drug Monitoring and Toxicology by Liquid Chromatography, (Wong S. H. Y., ed.), ch. 10, p. 269. Marcel Dekker, New York and Basel.] devoted to the monitoring of antibiotics, also evaluated the first 6-8 years of the application of HPLC assays for the aminoglycosides amikacin, gentamicin, netilmicin, sisomicin and tobramycin. This report presents a great majority of the HPLC assay methods published during the last two decades for determining practically a dozen different aminoglycoside antibiotics in body fluids, particularly in the serum or plasma, and in urine.

Aminoglycosides↗

Epidemiologic study of Staphylococcus strains isolated from clinical material in 24 Italian hospitals.

A nationwide epidemiologic study of clinical Staphylococcus isolates was performed in Italy by 24 operative units distributed throughout the country. A total of 7,017 Staphylococcus strains were examined according to a standard protocol. Three species of acknowledged importance in human infections (namely S. aureus, S. epidermidis, and S. saprophyticus) were identified singly, whereas the other staphylococci were considered as a whole and designated Staphylococcus spp. S. aureus totalled 55% of total isolates and was reported by most operative units as the predominant species among isolates both from various inpatient departments and from outpatients. S. saprophyticus was twofold more frequent among isolates from out- than from inpatients. Susceptibility to methicillin varied considerably from hospital to hospital, but a general tendency toward an increasing spread of resistance was noted. The overall incidence of methicillin resistance (29%) resulted from a wide range of values generally higher in isolates from inpatients (35%) than from outpatients (21%). Particularly high percentages of resistance (45%) were recorded in isolates from intensive care departments. Susceptibility testing to four additional beta-lactams (cefoxitin, cefuroxime, cefotaxime, and piperacillin) and to four aminoglycosides (gentamicin, tobramycin, amikacin, and netilmicin) indicated that antibiotic resistance was widespread and in all species more frequent among methicillin-resistant than among methicillin-sensitive staphylococci. Netilmicin proved more active than the other antibiotics tested; its greater activity was most evident against methicillin-resistant strains. Coagulase-negative staphylococci were more resistant than S. aureus to methicillin and most of the other antibiotics, suggesting their increasing involvement in human infections.

Anti-Bacterial Agents↗

Once-daily dosing of aminoglycosides.

Since their introduction one or more decades ago, aminoglycosides have generally been administered in multiple daily (i.e. twice- or thrice-daily) dosing regimens. However, nephrotoxicity can be reduced in animal models by administering the same total daily dose as one large dose instead of as multiple small doses. In addition, in vitro and in vivo studies that considered the impact of dosing regimens on efficacy suggest that once-daily dosing is equally or more effective compared to multiple daily dosing. Once-daily versus multiple daily dosing regimens have been compared for amikacin, netilmicin, and gentamicin in 24 randomized, clinical trials including a total of 3,181 patients. An analysis of these studies revealed superior results for once-daily regimens with respect to clinical efficacy (89.5% vs. 84.7%, p < 0.001) as well as bacteriological efficacy (88.6% vs. 83.4%, p < 0.01). No statistically significant differences were noted for toxicity. Nevertheless, both nephrotoxicity and ototoxicity occurred less frequently during once-daily dosing (4.5% vs. 5.5% and 4.2% vs. 5.8%, respectively). Finally, once-daily dosing is more economical, since less nursing time and infusion material are required and the efforts for drug monitoring can be reduced. In conclusion, amikacin, netilmicin, and gentamicin can be administered once a day.

Aminoglycosides↗

In vitro susceptibility of gentamicin and/or tobramycin resistant gram-negative bacilli to seven aminoglycosides.

The in vitro activity of gentamicin, tobramycin, sisomicin, netilmicin, amikacin, kanamycin and streptomycin was tested simultaneously by the agar dilution method against 584 clinical isolates of gram-negative bacilli that were resistant to gentamicin and/or tobramycin. About half of the gentamicin-resistant Pseudomonas were susceptible to tobramycin but cross-resistance was virtually complete between gentamicin and tobramycin for Enterobacteriaceae. Sisomicin was much more active than gentamicin against Klebsiella, Escherichia and Citrobacter species. Only 18.9%, 27.4% and 27.9% of Klebsiella, Enterobacter and Serratia respectively were resistant to netilmicin. Amikacin was the most effective aminoglycoside with an overall resistance of 15.6%. Kanamycin was effective against 40% of Proteus and Providencia species. Surprisingly, more than half of Klebsiella and Enterobacter species and 85.3% of Serratia species were susceptible to streptomycin.

Aminoglycosides↗

In vitro comparison of aminoglycoside activities and their synergistic action with piperacillin.

The antimicrobial activity of six aminoglycosides against 927 clinical isolates was compared. Gentamicin and netilmicin were most active against Enterobacteriaceae, followed by tobramycin greater than dibekacin greater than amikacin greater than kanamycin. Tobramycin was most active against Pseudomonas aeruginosa, both mucoid and non-mucoid strains, followed by dibekacin greater than gentamicin greater than netilmicin greater than amikacin greater than kanamycin. Piperacillin-aminoglycoside combinations acted (partially) synergistically against 33-40% of the Enterobacteriaceae, 34-58% of non-mucoid strains of P. aeruginosa and 63-84% of the mucoid strains of P. aeruginosa (p less than 0.01). Piperacillin + gentamicin was the most synergistic combination against Enterobacteriaceae and non-mucoid strains of P. aeruginosa (p less than 0.05). The action against Staphylococcus aureus and Streptococcus faecalis was mostly indifferent. Antagonism was not observed. In treating gram-negative infections where tissue concentrations are less important, every aminoglycoside combination may be effective; for Pseudomonas lung infections in cystic fibrosis, piperacillin + gentamicin or tobramycin will remain the drugs of first choice.

Aminoglycosides↗

Diversity of aminoglycoside resistance in Enterobacter cloacae in Greece.

Ninety Enterobacter cloacae strains isolated from 12 Greek hospitals were examined in terms of epidemiological types and resistance mechanisms. Using O serotyping 69% of the strains were assigned to a specific serotype and overall 16 different serotypes were identified. The combination of serotyping, phagetyping and biotyping efficiently discriminated most of the strains, indicating that single epidemic strains were not prevalent, although serotypes 3, 7, and group II predominated. Eight representative strains, all resistant to gentamicin, tobramycin, amikacin and netilmicin, were further examined for transferability and mechanisms of resistance. Aminoglycoside resistance was found to be transferable in most strains, and 13 R plasmids of 40-120 MDa molecular weight were detected. The enzymes detected consisted of three enzymes active against gentamicin [ANT(2h'), AAC(3)-I and AAC(3)-V]; three active against tobramycin [ANT(2"), AAC(3)-V and AAC(6')-I]; two active against netilmicin [AAC(3)-V and AAC(6')-I]; and one active against amikacin [AAC(6')-I]. APH(3') and ANT (3"), which modify neomycin and streptomycin plus spectinomycin respectively, were also found. Overall up to five aminoglycoside modifying enzymes were detected on the same R plasmid, AAC(6')-I plus ANT(2") being the most prevalent. The high incidence of multiresistance in Enterobacter cloacae and the fact that resistance is due to enzymatic inactivation of the antibiotics, indicate that in Greece this species might act as a gene pool for the spread of resistance to other bacteria of clinical relevance.

Aminoglycosides↗