Pathophysiologic mechanisms of selected types of nephrotoxicity. These agents are freely filtered by the glomeruli and quickly taken up by the proximal tubular epithelial cells, where they are incorporated into lysosomes after first interacting with phospholipids on the brush border membranes. The relative affinity of an aminoglycoside for the ptc plasma membrane correlates with the nephrotoxicity observed in clinical practice 4,1517. Nephrotoxic effects of aminoglycosides on the developing kidney samira samieezafarghandy1. Experimental studies in healthy human volunteers indicate aminoglycosides cause proximal tubular damage in most patients, but rarely, if ever, cause glomerular or tubular dysfunction. Pdf aminoglycoside nephrotoxicity revisited researchgate. An increase in proximal intratubular freeflow pressure of single nephrons, most. Aminoglycoside nephrotoxicity typically is associated with nonoliguric acute renal failure, that is, azotemia in the presence. They are broadly categorized as patientspecific, kidneyrelated, and drugrelated factors. Definition, structure these are group of natural and semisynthetic antibiotics having polybasic amino groups linked glycosidically to two or more animosugar 3. Nephrotoxicity and ototoxicity in particular, hearing loss are the major adverse events when aminoglycoside antibiotics are used.
Nevertheless, by multivariate discriminant analysis they found that age was a significant discriminant factor, and that it was the most important factor identified before aminoglycoside treatment was initiated. While most of these are clinically insignificant, some drugs. Druginduced impairment of renal function george sunny pazhayattil, anushree c shirali section of nephrology, yale university school of medicine, new haven, ct, usa abstract. The most potent side effect associated with aminoglycosides is its toxic affect on the kidney. Nephrotoxicity risk is significantly decreased with extendedinterval dosing. The model is a powerful tool to represent and describe the influence of the dosage regimen on aminoglycoside nephrotoxicity. The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside dosing and monitoring guidelines for adult. Renal vulnerability to drug toxicity american society of.
Traditionally, aminoglycoside nephrotoxicity has been considered to result mainly from tubular damage. Aminoglycoside definition of aminoglycoside by medical. Despite nephrotoxicity and ototoxicity, these drugs are still being used in clinical practice because of the antibacterial effect, low cost, and limited bacterial resistance 8. Vancomycininduced nephrotoxicity 1ahmad bilal 1,2, omar aburomeh 1,2, talla a. The kidney is a major organ of drug excretion and, thus, is exposed to high concentrations of potentially toxic medications. The use of aminoglycoside ag antibiotics has declined over the past 15 years primarily due to comparable potency of other antimicrobials and the nephrotoxicity potential of ag drugs. Risk factors for nephrotoxicity in patients treated with. Nephrotoxicity induced by aminoglycosides manifests clini.
The epidemiology of aminoglycoside induced nephrotoxicity is not fully understood. Druginduced nephrotoxicity is a common and potentially serious complication of medication administration that occurs in both inpatient and outpatient settings. Observational studies suggest that the morbidity from side effects of. Renal excretory failure with near cessation of effective glomerular filtration rate is but the final manifestation of this clinical disorder.
The manifestations of and risk factors for aminoglycoside nephrotoxicity are discussed separately. The relative insensitivity of immature rats to aminoglycoside induced nephrotoxicity in vivo and the comparative nephrotoxicity of the various aminoglycosides suggest that renal membranebinding. The onset of nephrotoxicity is delayed in the oda group p 0. New insights into the mechanism of aminoglycoside nephrotoxicity. Aminoglycoside antibiotics, in particular gentamicin and tobramycin, are still commonly used in paediatric clinical practice. One, two, or all three of the factor categories can act to promote various forms of renal injury. Aminoglycoside antibiotics display bactericidal activity against gram.
Commercial gentamicin is a mixture of various congeners and their enantiomers. They contain an inositol moiety substituted with two amino or guanidino groups and with one or more sugars or aminosugars. Extendedinterval aminoglycoside dosing eiad generally consists of administering the total daily dose as one dose, usually every 24 hours. Although usually reversible, aminoglycosideinduced renal injury prolongs. The age distribution of patients who developed nephrotoxicity was the same as the age distribution of those who did not p 0. Acute tubular necrosis due to ischemia or other insults and the pathogenesis and potential therapy of aminoglycoside nephrotoxicity are discussed separately. These substances can include molds and fungi, cancer therapeutics such as cisplatin, antibiotics such as aminoglycosides, metals such as mercury, arsenic and lead, and drugs of. Risk factors for nephrotoxicity in patients treated with aminoglycosides were determined from the case records of 214 patients in two prospective, randomized clinical trials of gentamicin and tobramycin. Cin toxicity include a combination of direct cytotoxicity with postischemic reperfusion injury resulting in oxygen free radical production leading to endothelial damage. Pdf aminoglycosides have long been one of the commonest causes of. Rousan 2 and kai lau 1,2,3 1section of nephrology 2department of medicine.
Druginduced kidney disease occurs primarily in patients with underlying risk factors. A number of factors enhance the vulnerability of the kidney to the nephrotoxic effects of drugs and toxins. Aminoglycosides have long been one of the commonest causes of druginduced nephrotoxicity. Full text druginduced impairment of renal function ijnrd. Methods search strategy we searched embase and pubmed from january 1966 to september 2003 using the following key words. All aminoglycosides reduce ach release from motor nerve ending, they have curare like action and cause neuromuscular blockade that can cause paralysis and fatal respiratory arrest. Nephrotoxicity can be defined as the adverse effect of substances on renal function perazella, 2009.
Aminoglycoside antibiotics are a central component of the treatment of pulmonary exacerbations of cystic fibrosis cf and slow the decline in lung function which ultimately causes the death of most patients. Manifestations of and risk factors for aminoglycoside. Extendedinterval aminoglycoside administration for. Aminoglycoside nephrotoxicity aminoglycosides preferentially affect the proximal tubular cells.
Clinical application of this model might make it possible to adjust aminoglycoside dosage regimens by taking into account both the efficacies and toxicities of the drugs. Aminoglycosideinduced nephrotoxicity in children pdf. Nephrotoxicity, defined as a 50% or greater fall in calculated creatinine clearance, developed in 30 patients 14. The central element of this aminoglycosidic nephrotoxcity is tubular cytotoxicity. Pharmaceutical agents provide diagnostic and therapeutic utility that are central to patient care. Studies of risk factors for aminoglycoside nephrotoxicity. Aminoglycoside nephrotoxicity kidney international. Urine output is, therefore, an unreliable marker for the development of amino. Aminoglycoside ag nephrotoxicity is a wellknown occurrence. A prospective comparative study of gentamicin and amikacin. Pharmacokinetic training packet for pharmacists revised 109, 612 original document compiled by. These drugs cause nephrotoxicity, which particularly affects the proximal tubule epithelial cells due to selective endocytosis and accumulation of aminoglycosides via the multiligand receptor megalin. Mechanisms of antimicrobialinduced nephrotoxicity in. Protective effects of cilastatin against vancomycin.
The aim of this study was to compare the nephrotoxic potential of amikacin ak and gentamicin gm in patients with normal baseline renal function. Patients at highest risk of druginduced nephrotoxicity are those with one or more of the following. Reasons that favor combination of an aminoglycoside with a betalactam antibiotic. Incidence of nephrotoxicity due to aminoglycosides has risen from 23% in 1969 to 20% in the past decade. The prognosis of cf has improved, and thus side effects of treatments have become increasingly important.
Nephrotoxicity is the side effect that most limits the dose of van, particularly in patients receiving high doses or combinations with other antibiotics, such as aminoglycosides 7. Aminoglycoside nephrotoxicity and age annals of internal. Pathophysiologic mechanisms of selected types of nephrotoxicity 31214, 10. To date, no model has completely described the pharmacodynamic behavior of ag nephrotoxicity, even though the mechanism of this toxicity has been widely studied 4, 7, 15, 27. See pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity.
However, resurgence in the use of ag antimicrobials is occurring due to multidrugresistant gramnegative nosocomial infections. The lowest level of nephrotoxicity was observed when aminoglycosides were administered at 1. They may cause apnea on iv injection,the blockade if severe can be effectively treated by neostigmine. Aminoglycosides streptomycin 1944 actinomycetes streptomyces griseus bactericidal antibiotics interfere with protein synthesis used to treat aerobic gram ve bacteria resemble each other in moa, pharmacokinetic therapeutic and toxic properties relatively low margin of safety exhibit ototoxicity and nephrotoxicity. Stanford health care aminoglycoside dosing guideline. Aminoglycoside nephrotoxicity is characterized by a variety of renal functional alterations.
Gentamicin is the most potent nephrotoxic aminoglycoside upon which most studies on aminoglycoside nephrotoxicity are based. Aminoglycoside antibiotics are widely used for the treatment of gram negative sepsis. Aminoglycoside dosing in adult patients extended interval dosing of aminoglycosides eida eida is the preferred method for dosing aminoglycosides for gramnegative infections as it offers the potential of reducing nephrotoxicity while maximizing concentrationdependent killing. Pdf prostaglandlns and aminoglycoside nephrotoxicity. Aminoglycoside is a medicinal and bacteriologic category of traditional gramnegative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an aminomodified glycoside. As the use of aminoglycosides became more widespread, the toxic effects of these agents, most notably ototoxicity and nephrotoxicity, became more apparent. Aminoglycosides are concentrationdependent, bactericidal agents that undergo active transport into the cell where they inhibit protein synthesis on the 30s subunit of the bacterial ribosome. The main concerns with the use of aminoglycoside antibiotics are nephrotoxicity and ototoxicity. However, all agents also carry adverse drug effect profiles. It is well known that they can cause dose related renal toxicity and ototoxicity, which occur in almost everyone who receives a sufficiently toxic dose. Clinical trials of aminoglycosides in seriously ill patients indicate that the relative risk for developing acute renal failure. Aminoglycosides pharmacology video lecturio online. Aminoglycoside induced nephrotoxicity article pdf available in journal of pharmacy practice 276 september 2014 with 1,253 reads how we measure reads. To continue reading this article, you must log in with your personal, hospital, or group practice subscription.
Nephrotoxic effects of aminoglycosides on the developing. A combination of broadspectrum antibiotics including aminoglycosides is frequently administered as initial antimicrobial treatment. Aminoglycosideinduced nephrotoxicity a focus on monitoring. Aminoglycoside dosing and monitoring guidelines for adult patients at stony brook university hospital algorithm for initial aminoglycoside dosing egfr is normalized to bsa 1. Although a clear recognition of the patient and treatmentrelated risk factors, combined with the onceaday schedule and effective monitoring procedures, have definitely improved the situation over what prevailed in the early 1980s, we are still short of having brought the safety of. Acute kidney injury and renal recovery with the use of. Extendedinterval aminoglycoside dosing in pediatrics. Aminoglycoside nephrotoxicity sage journals sage publications.