Macrodantin Nitrofurantion Crystals

MACRODANTIN NITROFURANTION CRYSTALS- nitrofurantoin capsule
Almatica Pharma Inc.

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Rx Only

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

DESCRIPTION

Macrodantin (nitrofurantoin macrocrystals) is a synthetic chemical of controlled crystal size. It is a stable, yellow, crystalline compound. Macrodantin is an antibacterial agent for specific urinary tract infections. It is available in 25 mg, 50 mg, and 100 mg capsules for oral administration.

structure

1-[[(5-nitro-2-furanyl)methylene] amino]-2,4-imidazolidinedione

Inactive Ingredients: Each capsule contains edible black ink, gelatin, lactose, starch, talc, titanium dioxide, and may contain FD&C Yellow No. 6 and D&C Yellow No. 10.

CLINICAL PHARMACOLOGY

Macrodantin is a larger crystal form of Furadantin® (nitrofurantoin). The absorption of Macrodantin is slower and its excretion somewhat less when compared to Furadantin. Blood concentrations at therapeutic dosage are usually low. It is highly soluble in urine, to which it may impart a brown color.

Following a dose regimen of 100 mg q.i.d. for 7 days, average urinary drug recoveries (0-24 hours) on day 1 and day 7 were 37.9% and 35.0%.

Unlike many drugs, the presence of food or agents delaying gastric emptying can increase the bioavailability of Macrodantin, presumably by allowing better dissolution in gastric juices.

MICROBIOLOGY

Nitrofurantoin is a nitrofuran antimicrobial agent with activity against certain Gram-positive and Gram-negative bacteria.

Mechanism of Action

The mechanism of the antimicrobial action of nitrofurantoin is unusual among antibacterials.

Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates which inactivate or alter bacterial ribosomal proteins and other acromolecules. As a result of such inactivations, the vital biochemical processes of protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis are inhibited. Nitrofurantoin is bactericidal in urine at therapeutic doses. The broad-based nature of this mode of action may explain the lack of acquired bacterial resistance to nitrofurantoin, as the necessary multiple and simultaneous mutations of the target macromolecules would likely be lethal to the bacteria.

Interactions with Other Antibiotics

Antagonism has been demonstrated in vitro between nitrofurantoin and quinolone antimicrobials. The clinical significance of this finding is unknown.

Development of Resistance

Development of resistance to nitrofurantoin has not been a significant problem since its introduction in 1953. Cross-resistance with antibiotics and sulfonamides has not been observed, and transferable resistance is, at most, a very rare phenomenon.

Nitrofurantoin has been shown to be active against most strains of the following bacteria both in vitro and in clinical infections [see Indications and Usage):

Aerobic and facultative Gram-positive microorganisms:

Staphylococcus aureus

Enterococci (e.g. Enterococcus faecalis)

Aerobic and facultative Gram-negative microorganisms:

Escherichia coli

NOTE: While nitrofurantoin has excellent activity against Enterococcus faecalis , the majority of Enterococcus faecium isolates are not susceptible to nitorfurantoin.

At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for nitrofurantoin. However, the efficacy of nitrofurantoin in treating clinical infections due to these

microorganisms has not been established in adequate and well-controlled trials.

Aerobic and facultative Gram-positive microorganisms:

Coagulase-negative staphylococci (including Staphylococcus epidermidis and Staphylococcus saprophyticus)

Streptococcus agalactiae

Group D streptococci

Viridans group streptococci

Aerobic and facultative Gram-negative microorganisms:

Citrobacter amalonaticus

Citrobacter diversus

Citrobacter freundii

Klebsiella oxytoca

Klebsiella ozaenae

NOTE: Some strains of Enterobacter species and Klebsiella species are resistant to nitrofurantoin.

Susceptibility Test Methods:

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution techniques: 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. Standardized procedures are based on a dilution method (broth or agar) (1) or equivalent with standardized inoculum concentrations and standardized concentrations of nitrofurantoin powder. The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion technique: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure (2) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 300 Ilg of nitrofurantoin to test the susceptibility of microorganisms to nitrofurantoin. The disk diffusion interpretive

criteria are provided in Table 1.

Table 1. Susceptibility Interpretive Criteria for Nitrofurantoin
Pathogen Susceptibility Interpretive Criteria
Minimum Inhibitory
Concentrations
(µg/mL)
Disk Diffusion
(zone diameter in mm)
S I R S I R
Enterobacteriaceae ≤32 64 ≥128 ≥17 15-16 ≤14
Staphylococcus spp. ≤32 64 ≥128 ≥17 15-16 ≤14
Enterococcus spp. ≤32 64 ≥128 ≥17 15-16 ≤14

A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the urine reaches the concentrations 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 a 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 urine reaches the concentrations usually achievable; other therapy should be selected.

Quality Control: Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures (3). Standard nitrofurantoin powder should provide the following range of values noted in Table 2.

Table 2. Acceptable Quality Control Ranges for Nitrofurantoin
QC Strain Acceptable Quality Control Ranges
Minimum InhibitoryConcentration (µg/mL) Disk Diffusion(zone diameter in mm)
a Not applicable
Escherichia coli
ATCC 25922
4 – 16 20 -25
Enterococcus faecalis
ATCC 29212
4 – 16 NAa
Staphylococcus aureus
ATCC 29213
8 – 32 NAa
Staphylococcus aureus
ATCC 25923
NAa 18-22
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