Effect Of Amikacin Research Articles

Amikacin: A Novel Modulator of Vesical and Prostate Efferences. An in vitro Experimental Study

The autonomic efferent neurotransmission to the bladder and prostate smooth muscle is a potential target for drug therapy of specific low urinary tract disfunction (LUTD). Since amikacin and other amynoglicosides were reported to affect neurotransmission by a pre-junctional mechanism, we investigated the effect of amikacin on isolated rat and human detrusor smooth muscle contraction and on isolated rat and human prostate contraction, to further evaluate its potential relaxant properties. Materials and Methods Samples of detrusor smooth muscle and prostate tissue, obtained from 97 rats and 16 patients undergoing surgery, were studied through the measurement of isometric contraction induced by electrical field stimulation (EFS) and other pharmacological stimuli in the presence or absence of 1mM amikacin in a low-Ca medium. Results Amikacin 1 mM significantly reduced contraction of isolated rat and human detrusor muscle and prostate, achieved with pre-junctional stimulation, while no significant effect was observed on contraction induced by pharmacological post-junctional stimulators. EFS contraction inhibited by amikacin was restored after addition of calcium chloride. The amikacin effect was comparable to the effect of magnesium ions, which are known to exert a pre-junctional inhibition of neurotransmitter release. Conclusions Amikacin significantly inhibited rat and human detrusor and prostate contraction evoked by pre-junctional stimulation in vitro, suggesting a depressant effect on autonomic efferent neurotransmission. Further pharmacokinetics studies and researches on related compounds may hold potential for future development in the treatment of specific low urinary tract disfunction (LUTD).

The effect of amikacin and imipenem alone and in combination against an extended-spectrum β-lactamase–producing Klebsiella pneumoniae strain

In vitro and in vivo activities of amikacin and imipenem alone, and in combination, were studied against an extended-spectrum β-lactamase–producing Klebsiella pneumoniae strain. The strain was in vitro susceptible to both antimicrobials at 10 5 and 10 7 CFU/mL. In time–kill studies amikacin, imipenem, and amikacin plus imipenem decreased the bacterial counts; difference between the bactericidal effects was not observed. Chequerboard technique showed no interaction between the tested drugs. Mice infected with 10 7 CFU/g of the K. pneumoniae were treated by amikacin (15 mg/kg every 8 h), imipenem (40 mg/kg every 4 h), or amikacin plus imipenem for 24 h. Blood bacterial counts in the group treated with amikacin plus imipenem did not differ significantly from the groups treated with amikacin or imipenem alone. Combination of amikacin and imipenem did not demonstrate any advantage over imipenem alone either in vitro or in vivo.

Amikacin: a novel modulator of vesical and prostate efferences. An in vitro experimental study

The autonomic efferent neurotransmission to the bladder and prostate smooth muscle is a potential target for drug therapy of specific low urinary tract disfunction (LUTD). Since amikacin and other amynoglicosides were reported to affect neurotransmission by a pre-junctional mechanism, we investigated the effect of amikacin on isolated rat and human detrusor smooth muscle contraction and on isolated rat and human prostate contraction, to further evaluate its potential relaxant properties. MATERIALS AND METHODS. Samples of detrusor smooth muscle and prostate tissue, obtained from 97 rats and 16 patients undergoing surgery, were studied through the measurement of isometric contraction induced by electrical field stimulation (EFS) and other pharmacological stimuli in the presence or absence of 1mM amikacin in a low-Ca medium. RESULTS. Amikacin 1 mM significantly reduced contraction of isolated rat and human detrusor muscle and prostate, achieved with pre-junctional stimulation, while no significant effect was observed on contraction induced by pharmacological post-junctional stimulators. EFS contraction inhibited by amikacin was restored after addition of calcium chloride. The amikacin effect was comparable to the effect of magnesium ions, which are known to exert a pre-junctional inhibition of neurotransmitter release. CONCLUSIONS. Amikacin significantly inhibited rat and human detrusor and prostate contraction evoked by pre-junctional stimulation in vitro, suggesting a depressant effect on autonomic efferent neurotransmission. Further pharmacokinetics studies and researches on related compounds may hold potential for future development in the treatment of specific low urinary tract disfunction (LUTD).

P134: The Effects of Amikacin on Purinergic Receptors in the OHC

P134: The Effects of Amikacin on Purinergic Receptors in the OHC

Effect of amikacin, cephalothin, clindamycin and vancomycin on in vitro fibroblast growth

The effect of four antibiotics (amikacin, clindamycin, cephalothin and vancomycin) was investigated considering that bacterial infection in fibroblasts cultures is a very frequent event. The investigation included the effect of the antibiotics on fibroblast growth and on the activity of the enzyme glucocerebrosidase. The antibiotics were added to the fibroblast cultures and cell growth was evaluated by counting the number of cells and their viability. After cell harvesting, the enzyme activity and content of protein were measured. The results allowed us to conclude that none of the antibiotics affected the cellular number nor the cellular viability. The content of protein decreased when cephalothin and clindamycin were added to the cultures, and glucocerebrosidase was affected in the presence of amikacin. Vancomycin did not interfere with any of the parameters analyzed, so it was chosen to be used in cell cultures to prevent the contamination by gram positive bacteria.

Potentiation of noise-induced hearing loss by amikacin in guinea pigs

Noise and aminoglycosides initially attack cochlear outer hair cells (OHCs). Distortion product otoacoustic emissions (DPOAEs) are used for the early diagnosis of damage to OHCs. The effects of sub-damaging doses of amikacin, an aminoglycoside antibiotic agent, on noise-induced hearing loss (NIHL) were examined in guinea pigs. Animals were grouped by gender and exposed to broadband noise at 105 dB SPL for 12 h and/or injected i.m. with either amikacin (100 mg/kg/day) or saline for 10 days. Auditory brainstem response (ABR) thresholds, along with DPOAE amplitudes, were measured serially before and after noise exposure. DPOAE amplitudes decreased and ABR thresholds elevated immediately after noise exposure and then gradually recovered. At all frequencies, the emission amplitudes recovered completely to pre-exposure baseline values by 4 days after noise exposure. There was no effect of amikacin on either the ABR threshold or DPOAE amplitudes, in animals treated with amikacin only. However, amikacin significantly prolonged the effect of noise exposure on DPOAE amplitude but not on the noise-induced temporary threshold shift (TTS) of the ABR. In animals treated with a combination of noise and amikacin, significant changes in DPOAE amplitudes were still observed at 4 weeks after cessation of noise exposure. No gender difference in the responses to noise and/or amikacin could be demonstrated. The present findings indicate that even sub-damaging dosages of amikacin might impair recovery from NIHL in guinea pigs.

Effect of amikacin on cytotoxic activity and hydrophobicity of Acinetobacter baumannii

Effect of amikacin at suprainhibitory (2 or 4 x MIC) or supra-subinhibitory concentrations (2 or 4 x MIC + 0.2 x MIC) on bacterial growth, cytotoxicity and cell surface hydrophobicity of three Acinetobacter baumannii strains was studied. Amikacin at suprainhibitory concentrations induced postantibiotic effects (PAEs; suppression of bacterial growth after short time exposure of bacteria to the antibiotic) against all A. baumannii strains. PAEs ranged from 1.2 to 2.9 h (2 x MIC) and 3.5 to 6.3 h (4 x MIC). Supra-subinhibitory concentrations of amikacin (2 x MIC + 0.2 x MIC) manifested a more significant delay of bacterial regrowth (PA SMEs) for two strains (6.6 or 7.5 h) in comparison with PAEs. One strain under these conditions as well as all strains treated with amikacin at 4 x MIC + 0.2 x MIC did not show any regrowth. Amikacin at all concentrations tested significantly reduced cytotoxic activity of A. baumannii evaluated on alveolar epithelial type II cells. Survival of type II cells after application of antibiotic-treated A. baumannii was in the range of 88 to 101% of the control cells. Cell surface hydrophobicity of amikacin-treated bacteria was practically unchanged varying between 94 and 100.9% as compared to the controls.

Adhesion of Pseudomonas aeruginosa to collagen biomaterials: effect of amikacin and ciprofloxacin on the colonization and survival of the adherent organisms.

The adherence of P. aeruginosa to collagen membrane, sponge, and to a new anti-infective COLL dressing and the susceptibility of the organisms attached to the biomaterials to amikacin were investigated in vitro. After 17 h of attachment, the bacteria demonstrated an increased resistance to amikacin compared with their free-floating counterparts. Amikacin, even at a concentration exceeding 150 times the minimal bactericidal concentration (MBC) for the strain tested, did not eradicate the attached bacteria from the surface of collagen membrane. However, when the drug at a high concentration (over 16 times the minimal inhibitory concentration, MIC) was present in the incubation medium before it had been inoculated with P. aeruginosa, a reduction of 2 log10 units in the organisms adherent to the surface of collagen membrane was observed. We conclude that slow release of the antibiotic from the COLL dressing could control the bacterial colonization on the surface. In fact, the released amikacin at the final concentration of 32 times the MBC reduced the number of adherent bacteria by 6 log10 units. In contrast, ciprofloxacin at the same final bactericidal concentration completely eradicated the bacteria from the surface of COLL dressing. However, as ciprofloxacin is not recommended for use as a topical antimicrobial agent, a further search is needed to find an agent with a similar anticolonization activity.

Co-ordination of copper(II) by amikacin. Complexation equilibria in solution and oxygen activation by the resulting complexes †

Protonation and copper(II) co-ordination properties of amikacin (A) were studied in solution by potentiometry, and NMR, UV/VIS, CD and EPR spectroscopies. Mononuclear, tetragonal and five-co-ordinate complexes of stoichiometries ranging from Cu(H3A) to CuH–2A were found. The effects of amikacin on copper(II) binding by physiological copper(II) carriers, histidine and albumin, and facilitation of oxidation of 2′-deoxyguanosine by copper(II)–amikacin complexes were also investigated. The results indicate that complexation of CuII by amikacin should not be expected to affect copper(II) homeostasis in blood, but may contribute to the intracellular activity of the drug.

Does vancomycine increase aminoglycoside nephrotoxicity?

Vancomycine and amikacin combined is an effective antibiotic combination used in the treatment of serious Gram-positive bacteremia in childhood. However, both drugs may have a potential nephrotoxic effect when used individually. The present study investigates whether the nephrotoxicity of these drugs that display a nephrotoxic effect when used separately increases when used in a combined manner. Ten 2-month-old rats were subjected to intraperitoneal injections of vancomycine (100 mg/kg) and amikacin (80 mg/kg) and ten other 2-month-old rats were administered amikacin (80 mg/kg) for a period of 15 days. The control group of animals consisting of five 2-month old rats were untreated. The renal tissues obtained by laparotomy were processed for both light and electron microscopy. Paraffin sections and ultrathin sections were evaluated in order to determine the renal structure of the control and the experimental groups. In addition, serum creatinine and blood, urea and nitrogen (BUN) levels were measured in blood samples obtained from the rats. In the amikacin and combined amikacin-vancomycine treatment groups, renal morphological changes were observed at the glomerular and tubular levels when compared to the control group, and the serum creatinine and BUN levels were also higher in these groups. Although both experimental groups were different from the control group, they had similar morphological and biochemical features. It was concluded that vancomycine did not influence the nephrotoxic effect of amikacin and both drugs could be used in a combined manner.

Effects of amikacin on the rat's tectorial membrane

Effects of amikacin on the rat's tectorial membrane

Effects of amikacin on the rat's tectorial membrane

Resumen de la comunicacion presentada en 35th European Congress of Toxicology, Alicante, September 22-25, 1996.

Preparation, properties and the effects of amikacin, netilmicin and tobramycin in free and liposomal formulations on Gram-negative and Gram-positive bacteria

The most common problems limiting the medical use of aminoglycosides have been the nephro- and oto-toxicities and the increasing bacterial resistance. It has been shown that encapsulation of drugs into liposomes enhances their efficacy while reducing their toxicities. The present in vitro study was designed to evaluate the antimicrobial activities of free and liposomal amikacin, netilmicin and tobramycin. We, therefore, encapsulated these drugs into liposomes prepared by sonication. The drug contained in liposomes was measured by enzyme multiplied immunoassay technique (EMIT) after lysis of the vesicles by 0.2% Triton X-100. The comparative encapsulation efficiency of the three antibiotic preparations was assessed. Aminoglycosides kinetic release from liposomes in presence of normal human sera was also studied in vitro over a 48 h period at 37°C under 5% CO 2. The MICs of these encapsulated drugs to Pseudomonas aeruginosa, Xanthomonas maltophilia, Escherichia coli, Streptococcus faecalis and Staphylococcus aureus were determined and compared to those of respective free drugs using an agar dilution method. The amikacin and tobramycin encapsulation efficiencies were significantly ( P ≤ 0.05) higher (5.36% ± 0.17 and 5.06% ± 0.10) than those of netilmicin (3% ± 0.18). However, in presence of sera, liposomal retention of netilmicin was significantly ( P ≤ 0.05) lower (61.88 ± 0.14%) than that of amikacin (81.45 ± 0.64%) and tobramycin (94.07 ± 0.18%) after 1 h of incubation and then remained nearly constant over an 48 h period of the study. The MICs of liposomal netilmicin against all bacterial strains tested were reduced, compared to those of free netilmicin. However, liposomal amikacin and tobramycin MICs were nearly similar to those of free respective drugs. Overall, liposomal netilmicin appears to be a promising approach in the management of Gram-positive and Gram-negative bacterial infections and should be further evaluated in in vivo experiments.

Age-related differences in the glomerular and renal tubular effects of amikacin in the rat.

Several biological responses to drugs are dependent on the age of the individual. Renal excretion of amikacin occurs mainly through glomerular filtration and this function is diminished in the young animal. We evaluated the renal response to amikacin in the unanesthetized infant rat (21-day-old) and we compared it with that of the adult rat. Either amikacin (7.5 and 75.0 mg/kg body weight, i.m.) or vehicle were administered to infant rats and the effects on sodium, potassium and water balance were assessed. Creatinine clearance (Ccr) was calculated. Amikacin induced an increment in sodium absolute excretion, whereas the Ccr decreased. In the infant rat the effects were more marked. Changes in FENa were more marked than those in Ccr, suggesting a direct effect of amikacin on the tubular reabsorption of electrolytes in addition to deleterious effects on glomerular dynamics. Our results suggest that amikacin induces more changes in renal function in the infant than in the adult rat and therefore it might be convenient to carefully evaluate the renal condition in the patients that receive this drug.

Time-dependent change in the toxic effects of amikacin on renal functions

The present study was undertaken to examine whether there was a time-dependent change in the toxic effects of amikacin, an aminoglycoside, on renal functions. Male Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Amikacin (1.2 g/kg) was injected intraperitoneally to animals at 4 am, 10 am, 4 pm or 10 pm. Glomerular function estimated by creatinine clearance (Clcr) and tubular function estimated by urinary excretion of a loop diuretic, furosemide, which was excreted in urine mainly by tubular secretion, were determined before and 24 hours after amikacin injection. The values of these parameters were reduced by amikacin at each observation point. The magnitude of these decrements was greatest at 4 pm both for Clcr and urinary furosemide excretion. These results suggest that the toxic effects of amikacin on renal glomerular and tubular functions vary with its time of administration.

Synergic post-antibiotic effect of amikacin in combination with β-lactam antibiotics on Gram-negative bacteria

The post-antibiotic effect (PAE) of amikacin alone and in combination with ceftazidime, ceftriaxone and piperacillin was studied for two strains each of Pseudomonas aeruginosa and Serratia marcescens using a bioluminescent assay of bacterial ATP. Two models were used for combining beta-lactam antibiotics and amikacin: in one model the cultures were incubated with 32 mg/L of ceftazidime, 128 mg/L of ceftriaxone or 32 mg/L of piperacillin for 1 h. Different concentrations of amikacin (0.5-64 mg/L) were then added. Incubation of the combinations continued for one more hour. The antibiotics were eliminated by dilution. In the second model tested, one strain of S. marcescens was simultaneously exposed to amikacin and a beta-lactam antibiotic for 2 h. The PAEs produced by the drugs in combination were longer than the sum of the individual effects of the drugs when they were used alone. Results were equally good with both models. A synergic PAE was also found with amikacin concentrations close to the MIC in combination with low concentrations of ceftazidime, ceftriaxone and piperacillin.

Effect of netilmicin and amikacin on urinary phospholipids excretion in humans.

Lysosomal phospholipidosis of proximal tubular cells is an early index of aminoglycoside-induced nephrotoxicity and has been documented both biochemically and morphometrically in animals and humans treated with therapeutic doses of these antibiotics (see Laurent and Tulkens 1987, for review). The various aminoglycosides differ in their capacity to induce this alteration (Laurent et al 1982; De Broe et al 1984) and amikacin, in particular, induces considerably less changes than netilmicin (Tulkens et al 1983; De Broe et al 1983). In animals, aminoglycoside administration is also associated with a marked increase of phospholipiduria (Ibrahim and Tulkens 1986; Josepovitz et al 1986). The purpose of present study was to examine phospholipiduria in humans and to compare the effect of amikacin and netilmicin in this respect.

Activities of amikacin, roxithromycin, and azithromycin alone or in combination with tumor necrosis factor against Mycobacterium avium complex.

The effect of amikacin and two new macrolides (roxithromycin and azithromycin) used either alone or in combination with recombinant tumor necrosis factor (TNF) to inhibit or kill Mycobacterium avium complex in human macrophages was examined in vitro. Macrophage monolayers infected with M. avium complex (strain 101, serotype 1) were treated with antibiotics or TNF by using three different protocols: (i) antibiotics or TNF was added to the monolayers immediately after infection and washed out after 24 h, (ii) antibiotics or TNF was replenished daily for 4 dys, or (iii) infected macrophage monolayers were treated with antibiotics plus TNF for 4 consecutive days. The number of viable intracellular bacteria was determined after 2 and 4 days of treatment by lysing cultured macrophages. Treatment for 24 h resulted in an inhibition of growth, as determined by macrophage lysis at day 4, for all three antimicrobial drugs and killing of 22% of intracellular bacteria after treatment with TNF. After treating the monolayers with amikacin, roxithromycin, or azithromycin for 4 consecutive days and replenishing the drug concentration daily, we observed 18 +/- 6, 20 +/- 4, and 22 +/- 1% killing, respectively. TNF (100 U/ml) was added daily to the monolayers, which resulted in 54 +/- 5% killing after 4 days. Combinations of antibiotics with TNF were associated with 62 +/- 3% killing with TNF-azithromycin, 73 +/- 6% killing with TNF-roxithromycin, and 56 +/- 4% killing of intracellular M. avium complex with TNF-amikacin after 4 days. The mycobactericidal effect was enhanced (91 +/- 4% killing by roxithromycinamikacin). Combinations of antimicrobial agents with immunomodulators like TNF may be useful for treatment of M. avium complex infection.

An overview of amikacin.

Amikacin, a semisynthetic analog of kanamycin, is very active against most gram-negative bacteria including gentamicin- and tobramycin-resistant strains. The effectiveness of amikacin in the treatment of serious gram-negative bacillary infections is well documented. Due to its resistance to inactivating enzymes, it is the aminoglycoside of choice for the treatment of known or suspected serious gram-negative infections caused by organisms resistant to gentamicin or tobramycin. Amikacin should be part of an empiric antibiotic regimen for the therapy of suspected sepsis in febrile, leukopenic immunocompromised hosts since it exhibits enhanced activity against the organisms most frequently encountered in this patient population. High response rates have been reported with the use of amikacin combined with beta-lactam antibiotics in immunocompromised or granulocytopenic patients. It exhibits impressive in vitro synergy against aminoglycoside-sensitive and -resistant organisms when used in combination with the new acylureidopenicillins and third-generation cephalosporins. Amikacin has the advantage of being the aminoglycoside least inactivated by the semisynthetic penicillins. Amikacin achieves high and predictable serum concentrations and has a favorable therapeutic index. Its potential for nephrotoxicity and ototoxicity is not significantly different than that encountered with gentamicin or tobramycin. Amikacin appears to be the preferred aminoglycoside for use at the present time because of its activity against gentamicin- and tobramycin-resistant organisms, its low resistance potential, its relative low degree of inactivation by the semisynthetic penicillins, and its superior pharmacokinetic profile.

Neuromuscular blocking property of amikacin in man.

The effect of amikacin on the neuromuscular junction was studied in man during anesthesia and surgery. Amikacin alone did not show any neuromuscular blocking action in normal man in therapeutic doses (100-200 mg). However, during recovery from either d-tubocurarine block or phase II block with succinylcholine, the intravenous administration of 200 mg of amikacin caused a decrease in twitch tension. This neuromuscular block aggravated by amikacin was antagonized by edrophonium (10 mg) or calcium chloride (400 mg). Data obtained from the peroneal nerve-anterior tibial muscle preparation of rabbits suggested that the neuromuscular blocking potency of amikacin was one-twelfth of that of kanamycin in therapeutic doses. Although amikacin is thus less potent than kanamycin, caution should be taken in its use for patients with myasthenic state.