Acetohydroxamic acid is an oral agent used as an adjunct in the treatment of chronic urea-splitting urinary tract infections and has been used as last-line adjunct agent for hepatic encephalopathy. Acetohydroxamic acid inhibits the hydrolysis of urea, decreases the production of ammonia, and decreases urinary pH in urine infected with urea-splitting organisms. Acetohydroxamic acid should not be considered an acidifying agent nor does it have any direct antimicrobial effect. Acetohydroxamic acid (Lithostat) was FDA-approved in 1983.
General Administration Information
For store information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer on an empty stomach (i.e., 1 hour before or 2 hours after a meal) with plenty of fluids.
Adverse reactions appear to occur more frequently in patients with preexisting phlebothrombosis, thrombophlebitis, and/or in patients with advanced renal impairment. The risk of developing an adverse reactions appears to be highest during the first year of treatment, and chronic treatment does not increase the risk or severity of adverse reactions.
Headache has been reported in approximately 30% of patients during the initial 48 hours of acetohydroxamic acid treatment. The headaches are mild and have not been associated with vertigo, tinnitus, or any visual or auditory symptoms. These initial headaches respond to oral salicylate analgesics and usually resolve spontaneously. Psychiatric adverse reactions including depression, nervousness (anxiety), and tremulousness (tremor) have been reported in approximately 20% of patients during acetohydroxamic acid therapy. These reactions are typically mild and transitory, but interruption or discontinuation of therapy occurs in about 6% of patients.
Gastrointestinal adverse reactions including anorexia, nausea, vomiting, and associated malaise have been reported in 20-25% of patients during acetohydroxamic acid therapy. These symptoms are typically mild and transient and do not result in interruption or discontinuation of therapy.
Blood dyscrasias have been reported in patients on acetohydroxamic acid. Acetohydroxamic acid inhibits DNA synthesis and chelates metals including iron. Clinical effects noted with acetohydroxamic acid include hemolysis, and a decrease in circulating red blood cells, hemoglobin, and hematocrit, and if significant enough, may produce anemia. Most patients develop mild reticulocytosis (5-6%) during acetohydroxamic acid therapy. Approximately 15% of patients have laboratory findings consistent with Coombs negative hemolytic anemia. Systemic symptoms associated with these findings such as malaise, lethargy, fatigue, nausea, vomiting, and anorexia occasionally occur. Approximately 3% of patients experienced symptoms severe enough to warrant interruption of treatment. These hematological abnormalities are more prevalent in patients with advanced renal failure; the drug is contraindicated in those with serum creatinine > 2.5 mg/dL. Hematologic and laboratory values return to normal with discontinuation of treatment. A CBC, including a reticulocyte count, is recommended following the initial 2 weeks of treatment with acetohydroxamic acid. If the reticulocyte count is >= 6%, a reduction in dose is recommended. A CBC and reticulocyte count are then recommended every 3 months during treatment. Leukopenia and thrombocytopenia have occurred in animals exposed to large doses of acetohydroxamic acid; although such abnormalities have not been reported in man, monitoring is recommended.
A non-pruritic, maculopapular rash on the upper extremities and face has been reported in patients on long-term acetohydroxamic acid therapy. The skin rash, which may be accompanied by a general sensation of warmth, usually occurs during the concomitant use of alcohol (see Drug Interactions) but has occurred in the absence of alcohol. Most patients experiencing this rash have continued treatment, avoided alcohol, or reduced the acetohydroxamic acid dose; however, discontinuation of treatment was necessary in some patients. Alopecia also has been reported in some patients during acetohydroxamic acid therapy.
Superficial phlebitis involving the lower extremities was reported in several patients during Phase II clinical trials of acetohydroxamic acid. Some patients had phlebitic episodes prior to acetohydroxamic acid treatment. Radiographic evidence of pulmonary embolism was seen in 3 patients with phlebitis of the lower extremities. Deep vein thrombosis was reported in one patient. One patient developed phlebothrombosis but also had an associated traumatic injury to the groin; it is unclear if the phlebitis was related to the injury of acetohydroxamic acid therapy. All vascular and embolic abnormalities resolved following discontinuation of acetohydroxamic acid and appropriate medical therapy. Several patients resumed therapy with no further vascular complications. No patient in three Phase III clinical trials developed phlebitis. Palpitations also have been reported with acetohydroxamic acid therapy.
Acetohydroxamic acid is contraindicated in patients whose disease and physical state allow for appropriate antimicrobial therapy and surgical management. Acetohydroxamic acid is contraindicated in patients whose urinary tract infections can be treated with oral antimicrobial agents targeted at culture-specific organisms and in those whose urine is infected by organisms that do not produce urea.
Acetohydroxamic acid is eliminated primarily by the kidneys and the drug accumulates in renal impairment, necessitating dosage adjustment in those with lowered creatinine clearance (CrCl) as evidenced by a serum creatinine > 1.8 mg/dL. The drug is contraindicated in patients with severe renal impairment or renal failure ( with CrCl < 20 mL/min and/or serum creatinine > 2.5 mg/dL). There are insufficient data to determine the optimum dose and/or dosing frequency in patients with moderate renal insufficiency. To avoid excessive drug accumulation, patients with renal impairment should be closely monitored (see Dosage, Patients with Renal Impairment Dosing).
Blood dyscrasias have been reported in patients on acetohydroxamic acid. The drug can chelate dietary iron, resulting in lowered iron absorption (see Drug Interactions); use with caution in patients with anemia. Most patients develop mild reticulocytosis (5-6%) during acetohydroxamic acid therapy, and some develop laboratory findings consistent with Coombs negative hemolytic anemia (see Adverse Reactions). Although leukopenia and thrombocytopenia have not been reported, monitoring is recommended. A CBC, including a reticulocyte count, is recommended 2 weeks after starting therapy and every 3 months thereafter.
Acetohydroxamic acid is classified as FDA pregnancy risk category X and is contraindicated in women who are or may become pregnant. Acetohydroxamic acid may cause fetal harm when administered to pregnant women. Acetohydroxamic acid was found to be teratogenic when given intraperitoneally to rats. Teratogenic effects included retarded and/or clubbed rear legs, exencephaly, and encephalocele. Acetohydroxamic acid is contraindicated in females who are not using appropriate contraception. If a woman becomes pregnant while taking acetohydroxamic acid, the physician and patient should discuss the potential hazard to the fetus.
According to the manufacturer, it is not known whether acetohydroxamic acid is excreted into breast milk. However, due to the potential toxicity of acetohydroxamic acid, breast-feeding is not recommended due to the potential harm to the infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Liver function abnormalities have not been reported with acetohydroxamic acid. However, acetamide, a metabolite of acetohydroxamic acid, has been shown to cause hepatocellular carcinoma in rats at oral doses 1500 times the human dose. Close monitoring of liver function during acetohydroxamic acid therapy is recommended, particularly in those with known hepatic disease.
Although children with chronic, recalcitrant, urea-splitting urinary infections may benefit from treatment with acetohydroxamic acid, studies establishing detailed dosage and dose intervals in children have not been performed. Children have tolerated doses of 10 mg/kg/day in two or three divided doses for up to one year. Close monitoring of children receiving acetohydroxamic acid is recommended. There is no known indication for the use of acetohydroxamic acid in infants or neonates; use in premature neonates would be contraindicated due to the immature renal function.
For use as an adjunct to appropriate anti-infective and surgical therapy in patients with chronic urinary tract infection (UTI) caused by urease-producing bacteria, including patients with struvite nephrolithiasis*:
NOTE: Acetohydroxamic acid should not be used in lieu of curative surgery in patients with nephrolithiasis or in patients whose infections can be controlled with culture-specific therapy.
NOTE: Long-term therapy may be necessary to maintain urease inhibition; however, according to the manufacturer, experience with acetohydroxamic acid does not exceed 7 years.
Oral dosage:
Adults: 250 mg PO 3 or 4 times daily given at 6- or 8-hour intervals on an empty stomach for a total daily dose of 10 to 15 mg/kg/day PO; usual starting dose is 12 mg/kg/day. Do not exceed 1.5 grams/day PO, regardless of body weight.
Adolescents and Children: Detailed studies regarding dosage and dose intervals have not been established. Begin with 10 mg/kg/day PO, administered in two or three divided doses given on an empty stomach every 6 to 8 hours, and titrate as to obtain optimum therapeutic effect and to reduce the risk of side effects. Maximum dose is 15 mg/kg/day, not to exceed 1.5 grams/day PO, regardless of body weight.
Neonates and Infants: Safety and efficacy have not been established; not indicated.
Maximum Dosage Limits:
-Adults
1.5 grams/day PO.
-Geriatric
1.5 grams/day PO.
-Adolescents
15 mg/kg/day PO, not to exceed 1.5 grams/day PO.
-Children
Detailed studies have not established optimum dosage or dose intervals. 15 mg/kg/day PO, not to exceed 1.5 grams/day PO, whichever is less.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
CrCl >= 20 mL/min and serum creatinine > 1.8 mg/dL: No more than 1 gram/day PO administered in 2 divided doses. Further reductions may be required. Adequate data do not exist to determine the optimum dose and/or dose interval in patients with renal impairment.
CrCl < 20 mL/min or serum creatinine > 2.5 mg/dL: Contraindicated.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Acetaminophen; Aspirin: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aluminum Hydroxide: (Major) Antacids may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
Aluminum Hydroxide; Magnesium Carbonate: (Major) Antacids may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) Antacids may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Antacids may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
Aluminum Hydroxide; Magnesium Trisilicate: (Major) Antacids may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
Antacids: (Major) Antacids may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
Aspirin, ASA: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aspirin, ASA; Caffeine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aspirin, ASA; Dipyridamole: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aspirin, ASA; Omeprazole: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aspirin, ASA; Oxycodone: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Bismuth Subsalicylate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Choline Salicylate; Magnesium Salicylate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Ethanol: (Major) Advise patients to avoid alcohol-containing beverages while taking acetohydroxamic acid. Concomitant use of acetohydroxamic acid and alcohol can cause a flushing reaction and a nonpruritic, macular rash on the upper extremities and face. The rash typically occurs within 30 to 45 minutes of alcohol ingestion and disappears 30 to 60 minutes later.
Ferric Maltol: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Food: (Major) Acetohydroxamic acid chelates heavy metals, including dietary iron. Absorption of iron and acetohydroxamic acid from the intestinal lumen may be reduced. Acetohydroxamic acid should be taken without food, on an empty stomach.
Iron Salts: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Iron: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Magnesium Hydroxide: (Major) Antacids may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
Magnesium Salicylate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Magnesium Salts: (Major) Antacids may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
Methadone: (Minor) As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Polysaccharide-Iron Complex: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Salsalate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
Acetohydroxamic acid inhibits the hydrolysis of urea and production of ammonia in urine infected with urea-splitting bacteria. By inhibiting the enzyme, there is a reduction of both urine alkalinity and ammonia concentration. Acetohydroxamic acid does not directly acidify the urine or have any direct antimicrobial effect. The effectiveness of antibacterial medications is enhanced and the formation of urinary calculi, including struvite stones, is reduced.
Acetohydroxamic acid is administered orally. Acetohydroxamic acid is distributed throughout body water. There is no known binding to tissue. A significant portion of the dose (36-65%) is excreted unchanged in the urine. The half-life is approximately 5-10 hours in patients with normal renal function. An increase in the dose of acetohydroxamic acid corresponds to an increase in half-life.
The drug inhibits urease, which results in inhibition of the hydrolysis of urea and production of ammonia in urine infected with urea-splitting organisms (see Mechanism of Action). The therapeutic effect of acetohydroxamic acid is due to excretion of unchanged drug in the urine. The concentration of acetohydroxamic acid in the urine that is needed to inhibit urease is unknown. Therapeutic benefit may be seen from concentrations as low as 8 mcg/mL, but higher concentrations (i.e., 30 mcg/mL) are expected to provide urease inhibition.
-Route-Specific Pharmacokinetics
Oral Route
Acetohydroxamic acid is well absorbed orally. Peak plasma concentrations are reached 0.25-1 hour after oral dosing. Chelation to dietary iron in the gut which may interfere with oral absorption of acetohydroxamic acid and iron (see Drug Interactions).
-Special Populations
Renal Impairment
The plasma half-life of acetohydroxamic acid is prolonged in renal impairment; accumulation may occur. Dosage reductions are recommended (see Dosage, renal impairment). If creatinine clearance is less than 20 mL/min, the drug should not be used.