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
||Zone diameter (mm)
| ≤ 16
|| ≥ 32
|| ≥ 19
|| ≤ 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
||MIC range (μg/mL)
||Zone Diameter (mm)
|Escherichia coli ATCC 25922
NegGram (nalidixic acid) and related drugs have been shown to cause arthropathy
in juvenile animals of most species tested. (See WARNINGS)
Long-term administration of nalidixic acid to rats resulted in retinal degeneration
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
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.