Probenecid with cephalosporins

Agents that may interact with cephalosporins include ethanol, aminoglycosides, anticoagulants, polypeptide antibiotics, probenecid, antacids, H2antagonists, iron... 

In those with gout, the serum uric acid level is usually elevated. Sulfinpyrazone increases the excretion of uric acid by the kidneys, which lowers serum uric acid levels and consequently retards the deposit of urate crystals in the joints. Probenecid (Benemid) works in the same manner and may be given alone or with colchicine as combination therapy when there are frequent, recurrent attacks of gout. Probenecid also has been used to prolong the plasma levels of the penicillins and cephalosporins. 

Levofloxacin 500 mg PO daily for 14 days with or without metronidazole 500 mg PO twice daily for 14 days Ceftriaxone 250 mg IM single dose and probenecid 1 g single dose, plus doxycycline 100 mg PO twice daily for 14 days with or without metronidazole, 500 mg PO twice daily for 14 days Third-generation cephalosporin plus doxycycline 100 mg PO twice daily for 14 days with or without metronidazole 500 mg PO twice daily for 14 days... 

Urinary excretion is the major elimination path for most cephalosporins. When prescribing cephalosporins to patients with renal failure, practitioners must consider dose reduction or dose interval extension (Table 45.2). Renal tubular secretion contributes to the elimination of some cephalosporins, and an increase in cephalosporin plasma concentrations may occur when probenecid blocks renal tubular secretion of cephalosporins. Biliary elimination is important for some cephalosporins. Cefmetazole, cefoperazone (Cefobid), cefoxitin, and ceftriaxone achieve biliary concentrations greater than those in plasma. After parenteral administration of cefoperazone, 70% of the dose appears in the bile within 24 hours. Practitioners should decrease the dose of cefoperazone when prescribing for patients with hepatic failure or biliary obstruction. Metabolism is not a major elimination path for most cephalosporins. Cefotaxime is one of the few cephalosporins having an active metabolite, desacetyl cefotaxime. 

Probenecid has been reported to inhibit renal elimination of many drugs acyclovir (325,326), allopurinol (327), bumetanide (328), cephalosporins (329-334), cidofovir (335), ciprofloxacin (336), famotidine (337), fexofenadine (338), furosemide (339), and oseltamivir (Ro 64-0802) (340). Recent studies have elucidated that probenecid is a potent inhibitor of renal organic anion transporters (OAT1 and OAT3) with the Ki values lower than the unbound plasma concentration of probenecid, indicating the interaction with probenecid includes inhibition of the basolateral uptake process mediated by OAT1 and/or OAT3. 

Pharmacokinetics. Usually, cephalosporins are excreted unchanged in the urine, but some, including cefotaxime, form a desacetyl metabolite which possesses some antibacterial activity. Many are actively secreted by the renal tubule, a process which can be blocked with probenecid. As a rule, the dose of cephalosporins should be reduced in... 

Other Beta-lactam Antibiotics - Several newer cephalosporins and cephamy-clns have been tested clinically in gonorrhea. Cefazolln, cefoxitin, cefu-roxime, cefamandole, and others are effective In vitro,10 21 but have given variable results in clinical trials.22-24 Cefuroxlme is the most effective, with cure rates in uncomplicated infection of 98-100% when 1.0-1.5 gm is given IM with probenecid 1.0 gm orally, and is effective against PPNG.25... 

Probenecid, a uricosuric agent (initially 0.25 g t.i.d. for 1 week), is indicated in the treatment of hyperuricemia associated with gout and gouty arthritis. In addition, probenecid is used as an adjunct to therapy with penicillins or cephalosporins, and for elevation and prolongation of plasma levels of these antibiotics. 

A) Oral bioavailability is affected by first-pass hepatic metabolism Only third-generation cephalosporins cross the blood-brain barrier Procaine penicillin G is the most commonly used intravenous form of the antibiotic Renal tubular reabsorption of beta-lactams is inhibited by probenecid Nafcillin and ceftriaxone are eliminated mainly via biliary secretion The mechanism of antibacterial action of cephalosporins involves (A) Inhibition of the synthesis of precursors of peptidoglycans Interference with the synthesis of ergosterol Inhibition of transpeptidation reactions Inhibition of beta-lactamases Binding to cytoplasmic receptor proteins... 

Probenecid inhibits renal tubular reabsorption of water and by this meehanism enhanees the urinary excretion of uric acid. This lowers the level of urate in the serum. It thus serves as a potent uricosuric agent in the treatment of gout. Probenecid also blocks the renal tubular seeretion of penicillins and cephalosporins. It is, therefore, used as an adjuvant therapy with penicillin V or G, ampicillin, cloxacillin, oxacillin, methicillin and naficillin to increase and prolong their plasma levels. Besides it also enhances the plasma levels of anti-inflammatory agents like naproxen and indomethacin, and a host of medicinal compounds such as sulphonamides, sulphonylureas, dapsone, etc. 

Risk of bleeding or hemorrhage is increased with concommitant administration of aspirin, ibuprofen, anticoagulants/thrombolytics, dextran, phenylbutazone, indomethacin, dipyridamole, several penicillins and cephalosporins, valproic acid, divalproex, plicamycin, methimazole, propylthiouracil, probenecid, hydroxychloroquine, chloroquine. Decreased anticoagulation effect with digitalis, tetracyclines, antihistamines, nicotine. 

Cephalosporins Dapsone Methotrexate Penicillins Quinolones Probenecid Serum levels of drug affected raised possibility of toxicity with some drugs... 

The serum levels of many cephalosporins are raised by probenecid. Possible exceptions include ceforanide, ceftazidime, ceftriaxone and latamoxef. The rise in serum levels may possibly increase the risk of nephrotoxicity with some cephalosporins such as cefal-oridine and cefalotin. 

The increased levels and decreased renal excretion of clinafloxacin caused by probenecid are not considered large enough to warrant dosage adjustment," and most of the changes seen with the other quinolones were of a similar magnitude. However, caution has been advised in the presence of other drugs that may also compete for renal excretion (such as some penicillins or cephalosporins). " Grepafloxacin, moxifloxacin, sparfloxacin, and probably ofloxacin, appear not to interact. 

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