NegGram

NEGGRAM- nalidixic acid tablet
sanofi-aventis U.S. LLC

To reduce the development of drug-resistant bacteria and maintain the effectiveness of NegGram (nalidixic acid, USP) and other antibacterial drugs, NegGram should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

NegGram, brand of nalidixic acid, is a quinolone antibacterial agent for oral administration. Nalidixic acid is 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. It is a pale yellow, crystalline substance and a very weak organic acid.

Nalidixic acid has the following structural formula:

Chemical Structure

Inactive Ingredients — Hydrogenated Vegetable Oil, Methylcellulose, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Yellow Ferric Oxide.

CLINICAL PHARMACOLOGY

Following oral administration, NegGram is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Unchanged nalidixic acid appears in the urine along with an active metabolite, hydroxynalidixic acid, which has antibacterial activity similar to that of nalidixic acid. Other metabolites include glucuronic acid conjugates of nalidixic acid and hydroxy nalidixic acid, and the dicarboxylic acid derivative. The hydroxy metabolite represents 30 percent of the biologically active drug in the blood and 85 percent in the urine. Peak serum levels of active drug average approximately 20 mcg to 40 mcg per mL (90 percent protein bound), one to two hours after administration of a 1 g dose to a fasting normal individual, with a half-life of about 90 minutes. Peak urine levels of active drug average approximately 150 mcg to 200 mcg per mL, three to four hours after administration, with a half-life of about six hours. Approximately four percent of NegGram is excreted in the feces. Traces of nalidixic acid were found in blood and urine of an infant whose mother had received the drug during the last trimester of pregnancy. (See PRECAUTIONS—Drug Interactions.)

Microbiology

NegGram has marked antibacterial activity against gram-negative bacteria including Enterobacter species, Escherichia coli , Morganella Morganii ; Proteus Mirabilis , Proteus vulgaris , and Providencia rettgeri. Pseudomonas species are generally resistant to the drug. NegGram is bactericidal and is effective over the entire urinary pH range. Conventional chromosomal resistance to NegGram taken in full dosage has been reported to emerge in approximately 2 to 14 percent of patients during treatment; however, bacterial resistance to NegGram has not been shown to be transferable via R factor.

Susceptibility Test

Diffusion Techniques

Quantitative methods that require measurement of zone diameters give the most precise estimates of antibacterial susceptibility. One such procedure recommended for use with a disc containing 30 mcg of nalidixic acid is the National Committee for Clinical Laboratory Standards (NCCLS) approved procedure. Only organisms from urinary tract infections should be tested. Results of laboratory tests using 30 mcg nalidixic acid discs should be interpreted using the following criteria:

Zone Diameter (mm) Interpretation
≥ 19 (S) Susceptible
14–18 (I) Intermediate
≤13 (R) Resistant

Dilution Techniques

Broth and agar dilution methods, such as those recommended by the NCCLS, may be used to determine the minimum inhibitory concentration (MIC) of nalidixic acid. MIC test results should be interpreted according to the following criteria:

MIC (mcg/mL) Interpretation
≤16 (S) Susceptible
≥32 (R) Resistant

For any susceptibility test, a report of “susceptible” indicates that the pathogen is likely to respond to nalidixic acid therapy. A report of “resistant” indicates that the pathogen is not likely to respond. A report of “intermediate” generally indicates that the test result is equivocal.

The Quality Control strains should have the following assigned daily ranges for nalidixic acid:

QC Strains
E. Coli
(ATCC 25922)

Disc Zone Diameter
22–28

MIC (mcg/mL)
1.0–4.0

NegGram Indications and Usage

NegGram (nalidixic acid, USP) is indicated for the treatment of urinary tract infections caused by susceptible gram-negative microorganisms, including the majority of E. Coli , Enterobacter species, Klebsiella species, and Proteus species. Disc susceptibility testing with the 30 mcg disc should be performed prior to administration of the drug, and during treatment if clinical response warrants.

To reduce the development of drug-resistant bacteria and maintain effectiveness of NegGram and other antibacterial drugs, NegGram should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered when selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS

NegGram is contraindicated in patients with known hypersensitivity to nalidixic acid or to related compounds, infants less than three months of age, and in patients with porphyria or a history of convulsive disorders. NegGram is contraindicated in patients undergoing concomitant therapy with melphalan or other related cancer chemotherapeutic alkylating agents because of serious gastrointestinal toxicity such as hemorrhagic ulcerative colitis or intestinal necrosis.

WARNINGS

Central Nervous System (CNS) effects including convulsions, increased intracranial pressure, and toxic psychosis have been reported with nalidixic acid therapy. Convulsive seizures have been reported with other drugs in this class. Quinolones may also cause CNS stimulation which may lead to tremor, restlessness, lightheadedness, confusion, and hallucinations. Therefore, nalidixic acid should be used with caution in patients with known or suspected CNS disorders, such as, cerebral arteriosclerosis or epilepsy, or other factors which predispose seizures. (See ADVERSE REACTIONS.) If these reactions occur in patients receiving nalidixic acid, the drug should be discontinued and appropriate measures instituted.

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactoid reactions required immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

Nalidixic acid and other members of the quinolone drug class have been shown to cause arthropathy in juvenile animals. (See PRECAUTIONS and ANIMAL PHARMACOLOGY.)

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NegGram, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

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