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)
Mechanism of Action
Nalidixic acid blocks DNA replication in susceptible bacteria by inhibiting a subunit of DNA gyrase.
Conventional chromosomal resistance to nalidixic acid 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.
Activity in vitro and in vivo
Nalidixic acid 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. Nalidixic acid is bactericidal and is effective over the entire urinary pH range.
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 Clinical and Laboratory Standards Institute (CLSI) approved procedure.1 Only organisms from urinary tract infections should be tested. Results of laboratory tests using 30 mcg nalidixic acid discs should be interpreted according to the criteria outlined in Table 1.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure.2 Broth and agar dilution methods, such as those recommended by the CLSI, may be used to determine the minimum inhibitory concentration (MIC) of nalidixic acid. MIC test results should be interpreted according to the criteria outlined in Table 1.
Table 1: Susceptibility Interpretive Criteria for nalidixic
|MIC (μg/mL)||Zone diameter (mm)|
|≤ 16||-||≥ 32||≥ 19||14-18||≤ 13|
|S=Susceptible, I=Intermediate, and R=Resistant|
A report of ”Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard nalidixic acid powder should provide the MIC values provided in Table 2. For diffusion technique, the 30-μg nalidixic acid disk should provide the zone diameters outlines in Table 2.
Table 2: Quality Control for Susceptibility Testing
|Strains||MIC range (μg/mL)||Zone Diameter (mm)|
|Escherichia coli ATCC 25922||1-4||22-28|
Long-term administration of nalidixic acid to rats resulted in retinal degeneration and cataracts.
Hydroxynalidixic acid, the principal metabolite of NegGram, did not produce any oculotoxic effects at any dosage level in seven species of animals including three primate species. However, oral administration of this metabolite in high doses has been shown to have oculotoxic potential, namely in dogs and cats where it produced retinal degeneration upon prolonged administration leading, in some cases, to blindness.
In experiments with NegGram itself, little if any such activity could be elicited in either dogs or cats. Sensitivity to CNS side effects in these species limited the doses of NegGram that could be used; this factor, together with a low conversion rate to the hydroxy metabolite in these species, may explain the absence of these effects.
1. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Villanova, PA, 2009.
2. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, NCCLS, Villanova, PA, 2009.
Last reviewed on RxList: 6/10/2011
This monograph has been modified to include the generic and brand name in many instances.
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