Cisplatin with aminoglycosides

Infections are a frequent cause of morbidity in the immunocompromised cancer patients and often necessitate antibiotic therapy. The use of certain bread-spectrum antibiotics, which are potentially nephrotoxic by themselves, may add to the renal toxicity of the anticancer agents. Clinically, the incidence of nephrotoxicity has heen recognized to be greater in patients receiving cisplatin in combination with aminoglycosides than in patients receiving cisplatin alone [46]. 

Hypomagnesemia is usually associated with disorders of the intestinal tract or kidneys. Drugs (e.g., aminoglycosides, amphotericin B, cyclosporine, diuretics, digitalis, cisplatin) or conditions that interfere with intestinal absorption or increase renal excretion of magnesium can cause hypomagnesemia. 

Examples of drugs that can give permanent damage to the inner ear or acoustic nerve are antibiotics (aminoglycosides) and chemotherapy (cisplatin). Other more commonly used drugs can give reversible ototoxity with vertigo. 

Chatteijee et al., 1984 Sens et al., 1988), and cyclosporine (TrifiUis et al., 1984). Studies reported by Tay et al. (1988) in rabbit proximal tubule cultures with cisplatin revealed biochemical effects upon DNA synthetic activty that correlated with in vivo histochemical effects of this antitumor agent in animals. With respect to studies involving mercuric chloride and aminoglycoside antibiotics in primary renal cultures, light and electron microscopy revealed similar patterns of cellular pathology in vitro as compared to in vivo exposure in animals (Chatteijee et al., 1984 Aleo et al., 1987). 

Drugs that may interact with zalcitabine include antacids, chloramphenicol, cisplatin, dapsone, didanosine, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, vincristine, cimetidine, metoclopramide, amphotericin, aminoglycosides, foscarnet, antiretroviral nucleoside analogs, pentamidine, and probenecid. 

The severity of aminoglycoside nephrotoxicity is additive with that of vancomycin, polymixin, gallium, furosemide, enflurane, cisplatin, and cephalosporins. Aminoglycoside nephrotoxicity is synergistic with that of amphotericin B and cyclosporine. 

Increased risk of nephrotoxicity with cidofovir, aminoglycosides, carbopla-tin, cisplatin, clofarabine, efavirenz/emtricitabine/tenofovir, tacrolimus... 

Increased nephrotoxicity with cidofovir, aminoglycosides, carboplatin, cisplatin, clofarahine, efavirenz/emtricitahine/tenofovir, gallium, tenofovir... 

Based on its considerable nephrotoxic potential, cisplatin should be given after, rather than before, other anticancer drugs and other drugs with a low therapeutic index (for example aminoglycoside antibiotics or bleomycin) that are primarily excreted in the urine in unchanged form. Concomitant use of potentially nephrotoxic agents (for example conventional amphotericin, tacrohmus) with cis-platin should be avoided (279,280). 

Beta-lactam induced renal toxicity can results from their use in monotherapy or when used in combination with other nephrotoxic drugs such as aminoglycosides, amphotericin B, cisplatin, cyclosporine, furosemide, ifosfamide, vancomycin and nephrotoxic p-lactams. While the risk of nephrotoxic injury from monotherapy with p-lactams is relatively low, this risk is substantially increased when multiple drug combinations are required. 

Major risk factors for renal toxicity in cancer patients include nephrotoxic chemotherapy drugs, age, nutritional status, concurrent use of other nephrotoxic drugs (e.g., aminoglycoside antibiotics), and preexisting renal dysfunction. Drugs with a high risk for renal toxicity include cisplatin, ifosfamide,... 

Clinically important, potentially hazardous interactions with altretamine, amikacin, aminoglycosides, antineoplastics, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, corticosteroids, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, estramustine, etoposide, fludarabine, fluorouracil, gemcitabine, gentamicin, hydroxyurea, idarubicin, ifosfamide, indomethacin, kanamycin, levamisole, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, neomycin, pentostatin, plicamycin, procarbazine, streptomycin, streptozocin, thioguanine, thiotepa, tobramycin, tretinoin, uracil, vinblastine, vincristine, vinorelbine... 

Clinically important, potentially hazardous interactions with acitretin, aldesleukin, aminoglycosides, amiodarone, amoxicillin, ampicillin, aspirin, bacampicillin, bismuth, carbenicillin, chloroquine, cisplatin, cloxacillin, co-trimoxazole, dapsone, demeclocycline, dexamethasone, diclofenac, dicloxacillin, etodolac, etoricoxib, etretinate, fenoprofen, flurbiprofen, folic acid antagonists, haloperidol, hydrocortisone, ibuprofen, indomethacin, influenza vaccines, ketoprofen, ketorolac, lithium, magnesium trisalicylate, meclofenamate, mefenamic acid, methicillin, mezlocillin, minocycline, nabumetone, nafcillin, naproxen, NSAIDs, omeprazole, oxacillin, oxaprozin, oxytetracycline, paromomycin, penicillin G, penicillin V, penicillins, phenylbutazone, piperacillin, piroxicam, polypeptide antibiotics, prednisolone, prednisone, probenecid, procarbazine, rofecoxib, salicylates, salsalate, sapropterin, sulfadiazine, sulfamethoxazole, sulfapyridine, sulfasalazine, sulfisoxazole, sulindac, tazobactum, tenoxicam, tetracycline, ticarcillin, tolmetin, trimethoprim, vaccines... 

Clinically important, potentially hazardous interactions with ACE inhibitors, amikacin, aminoglycosides, aminophylline, anti-diabetics, antihypertensives, cephalosporinss, cisplatin, gentamicin, indomethacin, kanamycin, neomycin, probenecid, salicylates, streptomycin, tobramycin... 

Biomarkers of exposure to xenobiotics causing nephrotoxicity may take one of several forms. The measurement of blood or tissue levels of drugs known to have adverse effects on the kidney, such as cyclosporine, aminoglycoside antibiotics, or lithium, is a standard practice. The awareness of the total amount of drug administered is frequently important when considering amphotericin and cisplatin nephrotoxicity. More difficulty is encountered with the determination of the body burden of a toxicant, although under certain circumstances such a value is necessary to determine the health effects of exposure to heavy metals such as cadmium and lead, and some analgesics [2]. 

This continued use of the aminoglycosides warrants a discussion of the toxicities associated with their use. Surprisingly, many of the toxicities of the aminoglycosides are similar to those ascribed to cisplatin, that being nephrotoxicity, neurotoxicity, and hearing loss. Why these two disparate classes of drugs cause similar toxicities is unknown. 

Carboplatin and cyclophosphamide are indicated in the treatment of advanced ovarian carcinoma. Cisplatin and carboplatin produce predominantly interstrand DNA crosslinks rather than DNA-protein cross-links, and the effect is cell-cycle nonspecific. Carboplatin is not bound to plasma proteins, whereas platinum from carboplatin becomes bound to plasma protein and is eliminated slowly with a half-life of 5 days. The major route of elimination of carboplatin is the kidneys, and its doses should be reduced in renal impairment. Furthermore, the coadministration of aminoglycosides increases the chance of nephrotoxicity. Carboplatin causes anemia, neutropenia, leukopenia, and thrombocytopenia requiring transfusions. Cisplatin and, to a lesser extent, carboplatin cause emesis, which requires treatment with antiemetic agents. Alopecia, pain, and asthenia do occur (see also Figure 15). 

Hypomagnesemia has been associated with more than 50 drugs, especially those that are nephrotoxic, including cisplatin, aminoglycoside antibiotics, cyclosporine, and amphotericin B. Secondary hypocalcemia and hypokalemia may result with myasthenia and tetany (Swaminathan 2003). 

Vancomycin is both potentially nephrotoxic and ototoxic, and its manufacturers therefore suggest that it should be used with particular care, or avoided in patients with renal impairment or deafiiess. They also advise the avoidance of other drugs that have nephrotoxic potential, because the effects could be additive. They list amphotericin B, aminoglycosides, bacitracin, colistin, poymyxin B, viomycin and cisplatin. They also list etacrynic acid and furosemide as potentially aggravating ototoxicity. 

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