Quinolones, Folic Acid Antagonists, and Urinary Tract-1.pdf

Pharmacology Chemotherapy Quinolones, Folic Acid Antagonists, and Urinary Tract Antiseptics Chemotherapy Content: Fluoroquinolone ………………………………… 3 Folate Antagonists ………………………………… 35 Sulfonamides ………………………………… 39 Trimethoprim ………………………………… 57 Cotrimoxazole ………………………………… 63 Urinary Tract Antiseptics/A...

Pharmacology Chemotherapy Quinolones, Folic Acid Antagonists, and Urinary Tract Antiseptics Chemotherapy Content: Fluoroquinolone ………………………………… 3 Folate Antagonists ………………………………… 35 Sulfonamides ………………………………… 39 Trimethoprim ………………………………… 57 Cotrimoxazole ………………………………… 63 Urinary Tract Antiseptics/Antimicrobials ………………………………… 74 Fluoroquinolone Fluoroquinolone The discovery of quinolone antimicrobials led to the development of numerous compounds utilized in clinical practice. Following the synthesis of nalidixic acid in the early 1960s, continued modification of the quinolone nucleus expanded the spectrum of activity, improved pharmacokinetics, and stabilized compounds against common mechanisms of resistance. Due to these enhancements, quinolone antimicrobials were rapidly integrated into human and agricultural medicine. Fluoroquinolone Unfortunately, overuse resulted in rising rates of resistance in gram-negative and gram-positive organisms, increased frequency of Clostridium difficile infections, and identification of numerous untoward adverse effects. Consequently, these agents have been relegated to second-line options for various indications. Fluoroquinolone Figure 1 – Summary of drugs described in this chapter. Fluoroquinolone Mechanism of Action: Most bacterial species maintain two distinct type II topoisomerases that assist with deoxyribonucleic acid (DNA) replication, (DNA gyrase), and topoisomerase IV. DNA gyrase is responsible for reducing torsional stress ahead of replicating forks by breaking double-strand DNA and introducing negative supercoils. Topoisomerase IV assists in separating daughter chromosomes once replication is completed. Fluoroquinolones bind to these enzymes and interfere with DNA ligation. Fluoroquinolone Fluoroquinolone Mechanism of Action: This interference increases the number of permanent chromosomal breaks, triggering cell lysis. In general, fluoroquinolones have different targets for gram-negative (DNA gyrase) and gram-positive organisms (topoisomerase IV), resulting in rapid cell death. Fluoroquinolone Antimicrobial Spectrum: Fluoroquinolones are bactericidal and exhibit area-under-the-curve/minimum inhibitory concentration (AUC/MIC)-dependent killing. A major facet of their development centered on improving microbiologic coverage. Modifications to the quinolone nucleus steadily improved topoisomerase inhibitory activity and facilitated bacterial cell wall penetration. These changes enhanced activity against a variety of pathogens including Aerobic gram-negative and gram-positive organisms, atypical organisms (for example, chlamydia, legionella, and mycoplasma spp.), and Anaerobes. Based on the impact of these structural changes, fluoroquinolones are often classified according to the spectrum of activity. Fluoroquinolone Antimicrobial Spectrum: First-generation compounds (for example, nalidixic acid) were narrow-spectrum agents with activity against aerobic gram-negative bacilli, mostly Enterobacteriaceae. Second-generation compounds (for example, ciprofloxacin) exhibit improved intracellular penetration and broadened coverage, which includes Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria spp., Chlamydia spp., and Legionella spp. Third-generation compounds (for example, levofloxacin) maintain the bacterial spectrum of second-generation agents, with improved activity against Streptococcus spp., including S. pneumoniae, methicillin-susceptible Staphylococcus aureus, Stenotrophomonas maltophilia, and Mycobacterium spp. Fluoroquinolone Fluoroquinolone Antimicrobial Spectrum: Fourth-generation compounds (moxifloxacin, gemifloxacin, and delafloxacin) have enhanced gram-positive activity, including Staphylococcus and Streptococcus spp. Delafloxacin has activity against methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis. Further, delafloxacin and moxifloxacin have activity against Bacteroides fragilis and Prevotella spp., while maintaining activity against Enterobacteriaceae and Haemophilus influenzae. From this group, only delafloxacin has activity against Pseudomonas aeruginosa. Fluoroquinolone Antimicrobial Spectrum: Lastly, these agents maintain atypical coverage, with moxifloxacin and delafloxacin showing activity against Mycobacteria spp. Fluoroquinolone Fluoroquinolone Resistance: Numerous mechanisms of fluoroquinolone resistance exist in clinical pathogens. High-level fluoroquinolone resistance is primarily driven by chromosomal mutations within topoisomerases, decreased entry, efflux systems, and modifying enzymes play a role. Mechanisms responsible for resistance include the following: 1. Altered Target Binding: Mutations in bacterial genes encoding DNA gyrase or topoisomerase IV (for example, gyrA or parC) alter target site structure and reduce the binding efficiency of fluoroquinolones. Fluoroquinolone Resistance: 2. Decreased Accumulation: Reduced intracellular concentration is linked to: 1. A reduction in membrane permeability or 2. Efflux pumps. Alterations in membrane permeability are mediated through a reduction in outer membrane porin proteins, thus limiting drug access to topoisomerases. Efflux pumps actively remove fluoroquinolones from the cell. Fluoroquinolone Resistance: 3. Fluoroquinolone Degradation: An aminoglycoside acetyltransferase variant can acetylate fluoroquinolones, rendering them inactive. Fluoroquinolone Pharmacokinetics: 1. Absorption: Fluoroquinolones are well absorbed after oral administration, with levofloxacin and moxifloxacin having a bioavailability that exceeds 90% (Figure 3). Ingestion of fluoroquinolones with sucralfate, aluminum- or magnesium-containing antacids, or dietary supplements containing iron or zinc can reduce the absorption. Calcium and other divalent cations also interfere with the absorption of these agents (Figure 4). Fluoroquinolone Figure 3 – Administration and fate of the fluoroquinolones. Fluoroquinolone Figure 4 – Effect of dietary calcium on the absorption of ciprofloxacin. Fluoroquinolone Pharmacokinetics: 2. Distribution: Binding to plasma proteins ranges from 20% to 84%. Fluoroquinolones distribute well into all tissues and body fluids. Concentrations are high in bone, urine (except moxifloxacin), kidney, prostatic tissue (but not prostatic fluid), and lungs as compared to serum. Penetration into cerebrospinal fluid is good, and these agents may be considered in certain central nervous system (CNS) infections. Accumulation in macrophages and polymorphonuclear leukocytes results in activity against intracellular organisms such as Listeria, Chlamydia, and Mycobacterium. Fluoroquinolone Pharmacokinetics: 3. Elimination: Most fluoroquinolones are excreted renally. Therefore, dosage adjustments are needed in renal dysfunction. Moxifloxacin is metabolized primarily by the liver, and while there is some renal excretion, no dose adjustment is required for renal impairment. Fluoroquinolone Adverse Reactions: In general, fluoroquinolones are well tolerated. Common adverse effects leading to discontinuation are nausea, vomiting, headache, and dizziness. These agents carry boxed warnings for tendinitis, tendon rupture, peripheral neuropathy, and CNS effects (hallucinations, anxiety, insomnia, confusion, and seizures). Patients taking fluoroquinolones are at risk for phototoxicity resulting in exaggerated sunburn reactions. Patients should use sunscreen and avoid excessive exposure to ultraviolet (UV) light. Fluoroquinolone Adverse Reactions: Fluoroquinolone Adverse Reactions: Arthropathy is uncommon, but arthralgia and arthritis are reported with fluoroquinolone use in pediatric patients. Use in the pediatric population should be limited to distinct clinical scenarios (for example, cystic fibrosis exacerbation). Hepatotoxicity or blood glucose disturbances (usually in diabetic patients receiving oral hypoglycemic agents or insulin) have been observed. Identification of any of these events should result in prompt removal of the agent. Fluoroquinolone Fluoroquinolone Adverse Reactions: Fluoroquinolones may prolong the QTc interval, and these agents should be avoided in patients predisposed to arrhythmias or taking medication associated with QT prolongation. Ciprofloxacin inhibits P450 1A2- and 3A4-mediated metabolism. Serum concentrations of medications such as theophylline, tizanidine, warfarin, ropinirole, duloxetine, caffeine, sildenafil, and zolpidem may be increased (Figure 6). Fluoroquinolone Fluoroquinolone Examples of Clinically Useful Fluoroquinolones: Due to increasing resistance and boxed warnings, fluoroquinolones should be used with caution in select circumstances. They may be considered in patients who do not tolerate other agents (for example, severe beta-lactam allergies) or as definitive therapy once susceptibilities are available. Listed below are potential indications for these agents: Fluoroquinolone Examples of Clinically Useful Fluoroquinolones: 1. Ciprofloxacin: Ciprofloxacin has good activity against gram-negative bacilli, including P. aeruginosa. Ciprofloxacin is used in the treatment of traveler’s diarrhea, typhoid fever, and anthrax. It is a second-line agent for infections arising from intra-abdominal, lung, skin, or urine sources. Of note, high-dose therapy should be employed when treating Pseudomonas infections. Fluoroquinolone Examples of Clinically Useful Fluoroquinolones: 2. Levofloxacin: Levofloxacin has similar activity to ciprofloxacin and they are often interchanged when managing gram-negative bacilli, including P. aeruginosa. Levofloxacin has enhanced activity against S. pneumonia and is first-line therapy for community-acquired pneumonia (CAP). It is a second-line agent for the treatment of S. maltophilia. Fluoroquinolone Examples of Clinically Useful Fluoroquinolones: 3. Moxifloxacin: Moxifloxacin has enhanced activity against gram-positive organisms (for example, S. pneumoniae), gram-negative anaerobes, and Mycobacterium spp. The drug may be used for CAP, but not hospital-acquired pneumonia due to poor coverage of P. aeruginosa. It may be considered for mild-to-moderate intra-abdominal infections but should be avoided if patients have fluoroquinolone exposure within the previous three months, due to increasing B. fragilis resistance. Moxifloxacin may be considered a second-line agent for the management of drugsusceptible tuberculosis. Fluoroquinolone Examples of Clinically Useful Fluoroquinolones: 4. Gemifloxacin: Gemifloxacin is indicated for the management of community-acquired respiratory infections. Unlike the other compounds, it is only available as an oral formulation. Fluoroquinolone Examples of Clinically Useful Fluoroquinolones: 5. Delafloxacin: Delafloxacin has improved activity against gram-positive cocci, including MRSA and Enterococcus spp. Due to its spectrum of activity, it is an option for managing acute bacterial skin and skin structure infections. It is available as an intravenous and oral formulation. Folate Antagonists Folate Antagonists Folic acid is a coenzyme essential in the synthesis of ribonucleic acid (RNA), DNA, and certain amino acids. In the absence of folate, cells cannot grow or divide. Humans use dietary folate to synthesize the critical folate derivative, tetrahydrofolic acid. By contrast, many bacteria are impermeable to folate derivatives and rely on their ability to synthesize folate de novo (Figure 7). Sulfonamides (sulfa drugs) are a family of antibiotics that inhibit de novo synthesis of folate. A second type of folate antagonist, trimethoprim, prevents microorganisms from converting dihydrofolic acid to tetrahydrofolic acid. Folate Antagonists Thus, both sulfonamides and trimethoprim interfere with the ability of an infecting bacterium to perform DNA synthesis and other essential cellular functions. The combination of the sulfonamide sulfamethoxazole with trimethoprim (the generic name for the combination is cotrimoxazole) provides a synergistic effect. Folate Antagonists Figure 7 – Inhibition of tetrahydrofolate synthesis by sulfonamides and trimethoprim. Sulfonamides Sulfonamides Sulfa drugs were among the first antibiotics used in clinical practice. Today, they are seldom prescribed alone except in developing countries, where they are employed because of low cost and efficacy. Sulfonamides Mechanism of Action: Microorganisms use the enzyme dihydropteroate synthetase to create dihydrofolic acid from the precursor molecule p-aminobenzoic acid (PABA). Sulfonamides are synthetic analogs of PABA. Because of their structural similarity, sulfonamides compete with PABA to inhibit dihydropteroate synthetase and the genesis of bacterial dihydrofolic acid (Figure 7). These agents, including cotrimoxazole, are bacteriostatic. Sulfonamides Antibacterial Spectrum: Sulfa drugs have in vitro activity against gram-negative and gram-positive organisms. Common organisms include Enterobacteriaceae, Haemophilus influenzae, Streptococcus spp., Staphylococcus spp., and Nocardia. Additionally, sulfadiazine in combination with the dihydrofolate reductase inhibitor pyrimethamine is the preferred treatment for toxoplasmosis. Sulfonamides Resistance: Bacteria that obtain folate from their environment are naturally resistant to sulfa drugs. Acquired bacterial resistance to the sulfa drugs can arise from plasmid transfers or random mutations. Resistance may be due to: 1. Altered dihydropteroate synthetase. 2. Decreased cellular permeability to sulfa drugs, or 3. Enhanced production of the natural substrate, PABA. Note: Organisms resistant to one member of this drug family are resistant to all. Sulfonamides Pharmacokinetics: 1. Absorption: Most sulfa drugs are well absorbed following oral administration. An exception is sulfasalazine. It is not absorbed when administered orally or as a suppository and, therefore, is reserved for the treatment of chronic inflammatory bowel diseases. Sulfonamides Pharmacokinetics: 1. Absorption: Note: Intestinal flora split sulfasalazine into sulfapyridine and 5- aminosalicylate, with the latter exerting the anti-inflammatory effect. Absorption of sulfapyridine can lead to toxicity in patients who are slow acetylators. Sulfonamides Sulfonamides Pharmacokinetics: 1. Absorption: Intravenous sulfonamides are generally reserved for patients who are unable to take oral preparations or have severe infections. Because of the risk of sensitization, sulfa drugs are not usually applied topically. However, in burn units, silver sulfadiazine or mafenide acetate (α-aminoptoluenesulfonamide) creams have been effective in reducing burn-associated sepsis because they prevent colonization of bacteria. Note: Silver sulfadiazine is preferred because mafenide produces pain on application and its absorption may contribute to acid–base disturbances. Sulfonamides Pharmacokinetics: 2. Distribution: Sulfa drugs are bound to serum albumin in circulation and widely distributed throughout body tissues. Sulfa drugs penetrate well into cerebrospinal fluid (even in the absence of inflammation) and cross the placental barrier to enter fetal tissues. Sulfonamides Pharmacokinetics: 3. Metabolism: Sulfa drugs are acetylated and conjugated primarily in the liver. The acetylated product is devoid of antimicrobial activity but retains the toxic potential to precipitate at neutral or acidic pH. This causes crystalluria (“stone formation”) and potential damage to the kidney. Sulfonamides Pharmacokinetics: 4. Excretion: Unchanged sulfa drugs and metabolites are eliminated via glomerular filtration and secretion, requiring dose adjustments with renal impairment. Sulfonamides may be eliminated in breast milk. Sulfonamides Adverse Effects: 1. Crystalluria: Nephrotoxicity may develop as a result of crystalluria (Figure 9). Adequate hydration and alkalinization of urine can prevent the problem by reducing the concentration of drug and promoting its ionization. 2. Hypersensitivity: Hypersensitivity reactions, such as rashes, angioedema, or Stevens-Johnson syndrome, may occur. When patients report previous sulfa allergies, it is paramount to acquire a description of the reaction to direct appropriate therapy. Sulfonamides Adverse Effects: 3. Hematopoietic Disturbances: Hemolytic anemia is encountered in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Granulocytopenia and thrombocytopenia can also occur. Fatal reactions have been reported from associated agranulocytosis, aplastic anemia, and other blood dyscrasias. Sulfonamides Adverse Effects: 4. Kernicterus: Bilirubin-associated brain damage (kernicterus) may occur in newborns, because sulfa drugs displace bilirubin from binding sites on serum albumin. The bilirubin is then free to pass into the CNS, because the blood– brain barrier is not fully developed. Sulfonamides Sulfonamides Adverse Effects: 5. Drug Potentiation: Sulfamethoxazole potentiates the anticoagulant effect of warfarin due to inhibition of CYP2C9, resulting in reduced clearance of warfarin. Sulfonamides may also displace warfarin from binding sites on serum albumin. Serum methotrexate levels may rise through protein binding displacement. Other CYP2C9 substrates, such as phenytoin, may have increased concentrations when given with sulfonamides. Sulfonamides Adverse Effects: 6. Contraindications: Due to the danger of kernicterus, sulfa drugs should be avoided in newborns and infants less than 2 months of age, as well as in pregnant women at term. Sulfonamides should not be given to patients receiving methenamine, since they can crystallize in the presence of formaldehyde produced by this agent. Trimethoprim Trimethoprim Trimethoprim: Trimethoprim, a potent inhibitor of bacterial dihydrofolate reductase, was initially available in combination with the sulfonamide sulfamethoxazole, and later approved for use as a single agent. Today, trimethoprim is most commonly used in combination with sulfamethoxazole. Trimethoprim Mechanism of Action: Trimethoprim is a potent inhibitor of bacterial dihydrofolate reductase (Figure 7). Inhibition of this enzyme prevents the formation of the metabolically active form of folic acid, tetrahydrofolic acid, and thus, interferes with normal bacterial cell functions. Trimethoprim binds to bacterial dihydrofolate reductase more readily than it does to human dihydrofolate reductase, which accounts for the selective toxicity of the drug. Trimethoprim Antibacterial Spectrum: The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole. However, trimethoprim is 20- to 50-fold more potent than the sulfonamides. Trimethoprim may be used alone in the treatment of urinary tract infections (UTIs) and in the treatment of bacterial prostatitis (although fluoroquinolones and cotrimoxazole are preferred). Resistance: Resistance in gram-negative bacteria is due to the presence of an altered dihydrofolate reductase that has a lower affinity for trimethoprim. Efflux pumps drug may play and decreased permeability to the drug may play a role. Trimethoprim Pharmacokinetics: Trimethoprim is rapidly absorbed following oral administration. Because the drug is a weak base, higher concentrations of trimethoprim are achieved in the relatively acidic prostatic and vaginal fluids. The drug is widely distributed into body tissues and fluids, including penetration into the cerebrospinal fluid. Trimethoprim undergoes some O-demethylation, but 60% to 80% is renally excreted unchanged. Trimethoprim Adverse Effects: Trimethoprim can produce the effects of folic acid deficiency. These effects include megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant patients and those with nutrient-poor diets. These blood disorders may be reversed by simultaneous administration of folinic acid (also known as leucovorin), which does not enter bacteria. Trimethoprim has a potassium-sparing effect and may cause hyperkalemia, especially at higher doses and when administered with other medication that causes hyperkalemia (for example, angiotensin-converting enzyme inhibitors). Cotrimoxazole Cotrimoxazole Cotrimoxazole: The combination of trimethoprim with sulfamethoxazole, called cotrimoxazole, shows greater antimicrobial activity than equivalent quantities of either drug used alone (Figure 10). The combination was selected because of the synergistic activity and the similarity in the half-lives of the two drugs. Cotrimoxazole Cotrimoxazole Mechanism of Action: The synergistic antimicrobial activity of cotrimoxazole results from its inhibition of two sequential steps in the synthesis of tetrahydrofolic acid. Sulfamethoxazole inhibits the incorporation of PABA into dihydrofolic acid precursors, and trimethoprim prevents the reduction of dihydrofolate to tetrahydrofolate (Figure 7). Cotrimoxazole Antibacterial Spectrum: Cotrimoxazole has a broader spectrum of antibacterial action than the sulfa drugs alone (Figure 11). It is effective in treating UTIs and respiratory tract infections, as well as Pneumocystis jirovecii, toxoplasmosis, Listeria monocytogenes, and Salmonella infections. It has activity against methicillin-resistant S. aureus and can be particularly useful for skin and soft tissue infections caused by this organism. It is the drug of choice for infections caused by susceptible Nocardia spp. and Stenotrophomonas maltophilia. Cotrimoxazole Cotrimoxazole Resistance: Resistance to the trimethoprim–sulfamethoxazole combination is encountered less frequently than resistance to either of the drugs alone, because it requires bacterium to maintain simultaneous resistance to both drugs. Significant resistance has been documented in a number of clinically relevant organisms, including E. coli. Cotrimoxazole Pharmacokinetics: Cotrimoxazole is generally administered orally (Figure 12). Intravenous administration may be utilized in patients with severe pneumonia caused by Pneumocystis jirovecii. Both agents are distributed throughout the body. Trimethoprim concentrates in the relatively acidic milieu of prostatic fluids, and this accounts for the use of trimethoprim–sulfamethoxazole in the treatment of prostatitis. Cotrimoxazole readily crosses the blood–brain barrier. Both parent drugs and their metabolites are excreted in the urine. Cotrimoxazole Cotrimoxazole Adverse Effects: Adverse reactions and drug interactions related to cotrimoxazole are similar to those expected with each of the individual components, sulfamethoxazole and trimethoprim (Figure 13). The most common adverse reactions are nausea and vomiting, skin rash, hematologic toxicity, and hyperkalemia. Cotrimoxazole Urinary Tract Antiseptics/Antimicrobials Urinary Tract Antiseptics/Antimicrobials Urinary Tract Antiseptics/Antimicrobials: UTIs are one of the most common bacterial infections in the world, primarily impacting women and the elderly. Historically, fluoroquinolones and cotrimoxazole have been the first-line therapy for the treatment of UTIs. Unfortunately, resistance has increased among common pathogens (for example, E. coli). As a result, methenamine, nitrofurantoin, and fosfomycin can be considered for treatment or suppression of recurrence, due to their efficacy against common pathogens and high concentrations in the urine. Urinary Tract Antiseptics/Antimicrobials A. Methenamine: Mechanism of action: Methenamine salts are hydrolyzed to ammonia and formaldehyde in acidic urine (pH ≤ 5.5). Formaldehyde denatures proteins and nucleic acids, resulting in bacterial cell death. Methenamine is combined with a weak acid (for example, hippuric acid) to maintain urine acidity and promote the production of formaldehyde (Figure 14). Urinary Tract Antiseptics/Antimicrobials Urinary Tract Antiseptics/Antimicrobials A. Methenamine: Antibacterial Spectrum: Methenamine is primarily used for chronic suppressive therapy to reduce the frequency of UTIs. Methenamine is active against E. coli, Enterococcus spp., and Staphylococcus spp. It has some activity against Proteus spp. and Pseudomonas aeruginosa, but urine pH must be kept acidic to achieve bactericidal activity. The main benefit of methenamine is the lack of selection for resistant organisms. Urinary Tract Antiseptics/Antimicrobials A. Methenamine: Pharmacokinetics: Methenamine is orally absorbed, with up to 30% decomposing in gastric juices, unless protected by enteric coating. It reaches the urine through tubular secretion and glomerular filtration. Concentrations are sufficient to treat susceptible organisms. Due to ammonia formation, use should be avoided in hepatic insufficiency. Urinary Tract Antiseptics/Antimicrobials A. Methenamine: Adverse Effects: The major adverse effect of methenamine is gastrointestinal distress, although at higher doses, albuminuria, hematuria, and rashes may develop. Methenamine mandelate is contraindicated in patients with renal insufficiency, because mandelic acid may precipitate. The methenamine hippurate formulation should be used instead. Urinary Tract Antiseptics/Antimicrobials A. Methenamine: Adverse Effects: Note: Sulfonamides, such as cotrimoxazole, react with formaldehyde and must not be used concomitantly with methenamine. The combination increases the risk of crystalluria and mutual antagonism. Urinary Tract Antiseptics/Antimicrobials B. Nitrofurantoin: Nitrofurantoin was introduced into clinical practice for the management of cystitis in the early 1950s. For decades, it was rarely used, but was resurrected due to increasing antibiotic resistance among Enterobacteriaceae and is considered first-line therapy for uncomplicated cystitis. Nitrofurantoin works by inhibiting DNA and RNA synthesis. Susceptible organisms include E. coli, Klebsiella spp., Enterococcus spp., and Staphylococcus spp. Following oral administration, it is rapidly absorbed, with nearly 40% excreted unchanged in the urine. Overall, nitrofurantoin is well tolerated. Urinary Tract Antiseptics/Antimicrobials B. Nitrofurantoin: Common adverse events include nausea, vomiting, and diarrhea. The use of the microcrystalline formulation decreases the incidence of gastrointestinal toxicity. Rare complications of therapy include pulmonary fibrosis, neuropathy, and autoimmune hepatitis. These events are observed with prolonged exposure greater than 1 month. Additionally, patients with impaired renal function should not receive nitrofurantoin due to an increased risk of adverse events.