Aminoglycosides tolerances

Sundin DP, Meyer C, Dahl R, Geerdes A, Sandoval R, Molitoris BA, Cellular mechanism of aminoglycoside tolerance in long-term gentamicin treatment. Am J Physiol, 1997, 272 Cl 309-18. 

Paromomycin sulfate is an aminoglycoside antibiotic that until recently was used in parasitology only for oral therapy of intestinal parasitic infections (see previous text). It has recently been developed for the treatment of visceral leishmaniasis. A phase 3 trial in India showed excellent efficacy for this disease, with a daily intramuscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and noninferiority compared with amphotericin. The drug was registered for the treatment of visceral leishmaniasis in India in 2006. In initial studies, paromomycin was well tolerated, with common mild injection pain, uncommon ototoxicity and reversible liver enzyme elevations, and no nephrotoxicity. Paromomycin is much less expensive than liposomal amphotericin or miltefosine, the other promising new therapies for visceral leishmaniasis. 

Speich R, Imhof E, Vogt M, Grossenbacher M, Zimmerli W. Efficacy, safety, and tolerance of piperacil-lirr/tazobactam compared to co-amoxiclav plus an aminoglycoside in the treatment of severe pneumonia. Eur J Clin Microbiol Infect Dis 1998 17(5) 313-17. 

Aztreonam, a monobactam, is a useful alternative for patients with aerobic gram-negative infections who are allergic to penicillins, but has no activity against anaerobes. Aztreonam appears to be the only p-lactam antibiotic that can be safely administered to penicillin-allergic patients [58]. Aztreonam has a spectrum of activity that is comparable to the aminoglycosides but it is less nephrotoxic in patients [59] and it appears to be well tolerated in infants and children [60]. 

The clinician should have an understanding of in vivo antimicrobial agent disposition in order to select the most appropriate therapy for a given infection and to help monitor for clinical or bacteri-ologic efficacy. Serum concentration monitoring is the most common method used to attempt to maximize efficacy and minimize toxicity of antimicrobials. Since most antimicrobials are well tolerated at their usual doses, only a select few agents (e.g., aminoglycosides, chloramphenicol, and vancomycin) are monitored routinely in the current clinical environment. There are a number of direct and indirect methods that are used to quantify the concentration of antimicrobial in an experimental sample. 

Transient azotemia occurs in 80% of patients who receive C-AMB for deep mycoses. Toxicity is dose-dependent and increased by concurrent therapy with other nephrotoxic agents (e.g., aminoglycosides, cyclosporine). Permanent impairment is uncommon in adults with normal renal function unless the cumulative dose is >3-4 g. Renal tubular acidosis and wasting of K and Mg also may occur during and for several weeks after therapy, often requiring repletiort Administration of 1 L of normal saline intravenously prior to C-AMB administration is recommended for adults who can tolerate the Na load. Azotemia occurs less frequently with lipid preparations of amphotericin, and saline loading is not needed. 

Probenecid but not cidofovir alters zidovudine pharmacokinetics such that zidovudine doses should be reduced when probenecid is present, as should the doses of drugs similarly affected by probenecid fe.g., /i-lactam antibiotics, nonsteroidal anti-inflammatory drugs [NSAIDs], acyclovir, lorazepam, furosemide, methotrexate, theophylline, and rifampin). Concurrent nephrotoxic agents are contraindicated, and an interval of 1 week before beginning cidofovir treatment is recommended after prior exposure to aminoglycosides, intravenous pentamidine, amphotericin foscamet, NSAIDs, or contrast dye. Cidofovir and oral ganciclovir in combination are poorly tolerated at full doses. 

The quantification and confirmation of aminoglycoside antibiotics (Eig. 7.8) at trace residue concentrations in animal tissues has long been a challenge because of the high polarity of the analytes and lack of a suitable chromophore for detection. MRLs are often relatively high for example, for neomycin, MRLs range from 500 to 10000 p-g/kg in Australia in line with the revised MRLs established by CAC, from 500 to 5000 pg/kg in the EU and from 150 to 7200 pg/kg as tolerances in the United States of America. ... 

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