CHAPTER 46: SULFONAMIDES, TRIMETHOPRIM, & QUINOLONES ANTIFOLATE DRUGS SULFONAMIDES Chemistry Similar to p-aminobenzoic acid (PABA) Sulfonamides

es with varying physical, chemical, pharmacologic, and antibacterial properties are produced by attaching substituents to the amido group (-SO2-NH-R) or the amino group (-NH2) of the sulfanilamide group More soluble at alkaline pH Can be prepared as sodium salts for IV administration Mechanism of Action and Antimicrobial Activity Sulfonamide-susceptible organisms cannot use exogenous folate but must synthesize it from PABA essential for production of purines and nucleic acid synthesis Structural analogs of PABA Inhibit dihydropteroate synthase and folate production Inhibit both gram (+) and gram (-) bacteria, Nocardia, Chlamydia trachomatis, some protozoa, E. coli, Klebsiella pneumoniae, Salmonella, Shigella, Enterobacter Rickettsiae are not inhibited but are instead stimulated in their growth Poor activity against anaerobes Pseudomonas aeruginosa is intrinsically resistant Combination with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) sequential inhibition of folate synthesis synergistic activity Resistance Mammalian cells, some bacteria lack the enzymes required for folate synthesis from PABA; depend on exogenous sources not susceptible to sulfonamides Occur as a result of mutations that: 1. Cause overproduction of PABA 2. Cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides 3. Impair permeability to the sulfonamide Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely Pharmacokinetics 3 major groups: 1. Oral, absorbable: short-, intermediate-, or long-acting 2. Oral, nonabsorbable 3. Topical Absorbed from the stomach and small intestine Distributed widely to tissues and body fluids (including CNS and CSF), placenta, and fetus 20 90% protein binding Therapeutic concentrations: 40 100 mcg/mL of blood Peak: 2 6 hours after oral administration Portion of absorbed drug is acetylated or glucuronidated in the liver Excreted into the urine, mainly by glomerular filtration Reduce dosage in renal failure Short-acting Sulfacytine Sulfisoxazole 6 hours Sulfamethizole 9 hours Intermediate-acting Sulfadiazine 10 to 17 hours Sulfamethoxazole 10 to 12 hours Sulfapyridine 17 hours Long-acting Sulfadoxine 7 to 9 days Clinical Uses Infrequently used as single agents

Former susceptible species are now resistant (meningococci, penumococci, streptococci, staphylococci, gonococci) Trimethoprim-sulfamethoxazole o DOC for Pneumocystis jiroveci pneumonia, toxoplasmosis, nocardiosis

A. Oral Absorbable Agents Urinary tract infections o Sulfisoxazole 1 g 4x daily o Sulfamethoxazole 1 g 2 or 3 times daily Sulfadiazine-pyrimethamine o First-line therapy for acute toxoplasmosis o Synergistic o Sulfadiazine = 1 g 4x daily o Pyrimethamine = 75-mg loading dose followed by a 25mg once-daily dose o Administer folinic acid 10 mg orally each day to minimize bone marrow suppression Sulfadoxine o Only long-acting sulfonamide currently available in the USA o Combination formulation with pyrimethamine (Fansidar) Second-line agent for malaria B. Oral Nonabsorbable Agents Sulfasalazine (salicylazosulfapyridine) o Ulcerative colitis o Enteritis o Other inflammatory bowel disease C. Topical Agents Sodium sulfacetamide ophthalmic solution or ointment o Bacterial conjunctivitis o Adjunct therapy for trachoma Mafenide acetate o Can be absorbed from burn sites o Inhibit carbonic anhydrase o Can cause metabolic acidosis Silver sulfadiazine o Much less toxic than topical sulfonamide o Preferred to mafenide for prevention of infection of burn wounds Adverse Reactions Partially cross-allergenic Most common AEs: o Fever o Skin rashes o Exfoliative dermatitis o Photosensitivity o Urticaria o Nausea o Vomiting o Diarrhea o Difficulties referable to the urinary tract Stevens-Johnson syndrome o Relatively uncommon o Serious and fatal type of skin and mucous membrane eruption Others o Stomatitis o Conjunctivitis o Arthritis o Hematopoietic disturbances o Hepatitis o Rarely: polyarteritis nodosa, psychosis A. Urinary Tract Disturbances Sulfonamides may precipitate in the urine, especially at neutral or acid pH crystalluria, hematuria, obstruction Large doses + poor fluid intake crystalluria o Treat by administration of sodium bicarbonate alkalinize urine o Fluids to increase urine flow Various types of nephrosis, allergic nephritis

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B. Hematopoietic Disturbances Hemolytic or aplastic anemia Granulocytopenia Thrombocytopenia Leukemoid reactions Provoke hemolytic reactions in patients with G6PD deficiency Taken near the end of pregnancy kernicterus inn newborns TRIMETHOPRIM & TRIMETHOPRIM-SULFAMETHOXAZOLE MIXTURES Mechanism of Action Trimethoprim o Trimethoxybenzylpyrimidine o Selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to purine and DNA synthesis o 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase Pyrimethamine o Benzylpyrimidine o Selectively inhibits dihydrofolic acid reductase of protozoa In combination with a sulfonamide blocks sequential steps in folate synthesis marked enhancement (synergism) Combinations: bactericidal o Sulfonamide alone: bacteriostatic Resistance Result from: 1. Reduced cell permeability 2. Overproduction of dihydrofolate reductase 3. Production of an altered reductase with reduced drug binding 4. Mutation; more commonly due to plasmid-encoded trimethoprim-resistant dihydrofolate reductases o Coded within transposons on conjugative plasmids that exhibit a broad host range rapid and widespread dissemination Pharmacokinetics Usually given orally, alone or in combination with sulfamethoxazole o Trimethoprim-sulfamethoxazole can also be given IV Well absorbed from the gut Distributed widely in body fluids and tissues, including CSF More lipid soluble than sulfamethoxazole larger volume of distribution o 1 part of trimethoprim : 5 parts of sulfamethoxazole o Peak plasma concentrations 1:20 o 30 50% sulfonamide, 50 60% trimethoprim excreted in the urine within 24 hours o Reduce dosage by half for patients with creatinine clearances of 15 30 mL/min Weak base Concentrates in prostatic fluid and vaginal fluid (more acidic than plasma) Has more antibacterial activity in prostatic and vaginal fluids Clinical Uses A. Oral Trimethoprim Given alone (100 mg twice daily) in acute UTI 200 600 mcg/ mL community-acquired organisms B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ) P. jiroveci pneumonia, shigellosis, systemic salmonella infections, UTI, prostatitis, some nontuberculous mycobacterial infections Active against most S. aureus strains and respiratory tract pathogens (pneumococcus, Haemophilus, Moraxella catarrhalis, K. pneumoniae; not against Mycoplasma pneumoniae) Consider resistant E. coli and pneumococci strains first before using for empiric therapy of upper UTI or pneumonia Double-strength tablet o 160 mg trimethoprim, 800 mg sulfamethoxazole o Given q12h UTI Prostatitis Shigella

salmonella Single-strength tablet (half of regular) o 3x weekly for many months prophylaxis in recurrent UTI of some women Prevention of P. jiroveci in immunocompromised patients o 1 double-strength table daily or 3x weekly

C. Intravenous Trimethoprim-Sulfamethoxazole 80 mg trimethroprim + 400 mg sulfamethoxazole per 5 mL diluted in 125 mL of D5W o Administered over 60 90 minutes o Agent of choice for moderately severe to severe pneumocystis pneumonia o Gram (-) bacterial sepsis caused by multidrug-resistant species (Enterobacter, Serratia) o Shigellosis o Typhoid fever o UTI (for patients unable to take the drug by mouth) D. Oral Pyrimethamine with Sulfonamide Pyrimethamine-sulfadiazine o Leishmaniasis o Toxoplasmosis Pyrimethamine-sulfadoxine (Fansidar) o Falciparum malaria Adverse Effects Adverse effects of an antifolate drug megaloblastic anemia, leukopenia, granulocytopenia Trimethoprim-sulfamethoxazole combination may cause all of the untoward effects of sulfonamides Nausea, vomiting, drug fever, vasculitis, renal damage, CNS disturbances Patients with AIDS and pnuemocystis pneumonia high frequency of untoward reactions o Fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, hyponatremia DNA GYRASE INHIBITORS FLUOROQUINOLONES Synthetic fluorinated analogs of nalidixic acid Active against a variety of gram (+) and gram (-) bacteria Mechanism of Action Block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication Inhibition of topoIV interferes with separation of replicated chromosomal DNA into the respective daughter cells during replication Antibacterial Activity Earlier quinolones (nalidixic acid) o Does not achieve systemic antibacterial levels o Useful only in the treatment of lower UTI Fluorinated derivatives o Have greatly improved antibacterial activity o Achieve bactericidal levels in blood and tissues Norfloxacin o Least active against both gram (-) and (+) o MICs fourfold to eightfold higher than ciprofloxacin Second group: ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, perfloxacin o Excellent gram (-) activity o Moderate to good activity against gram (+) o MIC = 1 2 mcg/mL for: Enterobacter P. aeruginosa N. meningitides Haemophilus Campylobacter jejuni o Methicillin-susceptible S. aureus generally susceptible o Methicillin-resistant staph strains are resistant

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Streptococci and enterococci are less susceptible than staph o Ciprofloxacin most active agent of this group against P. aeruginosa o Levofloxacin L-isomer of ofloxacin Superior activity against gram (+) and Streptococcus pneumoniae Third group: gatifloxacin, gemifloxacin, moxifloxacin o Improved activity against S. pneumoniae and some staphylococci o Gemifloxacin Active in vitro agasint ciprofloxacin-resistant Strep pneumoniae o Moxifloxacin Modest activity against anaerobic bacteria o Gatifloxacin No longer available in the US due to toxicity Active against agents of atypical pneumonia (mycoplasmas, chlamydiae) and against intracellular pathogens (Legionella pneumophila, mycobacteria [M. tuberculosis, M. avium complex]) o

o Prophylaxis of infection in neutropenic cancer patients Levofloxacin, gatifloxacin, gemifloxacin, moxifloxacin o Enhanced activity against gram (+) and atypical pneumonia agents (chlamydiae, Mycoplasma, Legionella) o Upper and lower respiratory tract infections

Resistance Emerge in about one of every 107 109 organisms, especially among Staph, P. aeruginosa, and Serratia marcescens Due to: 1. One or more point mutations in the quinolone binding region of the target enzyme 2. A change in the permeability of the organism 2 types of plasmid-mediated resistance: 1. Utilizes Qnr proteins, which protect DNA gyrase 2. Variant of an aminoglycoside acetyltransferase capable of modifying cipro Resistance to one fluoroquinolone generally confers crossresistance to all other members Pharmacokinetics Well absorbed Bioavailability: 80 95% Distributed widely in body fluids and tissues Half-lives: 3 to 10 hours o Levofloxacin, gemifloxacin, gatifloxacin, moxifloxacin long half-lives once-daily dosing Oral absorption impaired by divalent and trivalent cations, including those in antacids o Should be taken 2 hours before or 4 hours after any products containing these cations Renal elimination; tubular secretion or glomerular filtration Dosage adjustment for patients with creatinine clearance less than 50 mL/min Dosage adjustment not necessary for moxifloxacin (nonrenal excretion) Nonrenally cleared fluoroquinolones are contraindicated for patients with hepatic failure Clinical Uses UTI, including P. aeruginosa o Except moxifloxacin (achieves low urinary levels) Bacterial diarrhea Shigella, Salmonella, toxigenic E. coli, Campylobacter Infections of soft tissues, bones, and joints, and intraabdomina and respiratory tract infections, including multidrug resistant Pseudomonas and Enterobacter o Except norfloxacin (does not achieve adequate systemic concentrations) Ciprofloxacin o DOC for prophylaxis and treatment of anthrax Ciprofloxacin, levofloxacin o No longer recommended for gonococcal infection (resistance now common) o Effective in treatment of chlamydial urethritis or cervicitis Ciprofloxacin, levofloxacin, or moxifloxacin o Occasionally used for treatment of tuberculosis and atypical mycobacterial infections o Suitable for eradication of meningococci from carriers

Adverse Effects Generally well tolerated Most common: o Nausea o Vomiting o Diarrhea Headache, dizziness, insomnia, skin rash, abnormal liver function tests Lomefloxacin, perfloxacin photosensitivity Gatifloxacin, levofloxacin, gemifloxacin, moxifloxacin QT prolongation o Avoid or use with caution in patients with: Known QT interval prolongation Uncorrected hypokalemia Those receiving class IA (quinidine, procainamide) or class III (sotalol, ibutilide, amiodarone) antiarrhythmics Erythromycin, TCAs Gatifloxacin o Hyperglycemia in diabetics o Hypoglycemia in patients receiving oral hypoglycemic o Withdrawn in the US May damage growing cartilage and cause arthropathy o Not recommended for patients under 18 years old o Arthropathy is reversible Tendonitis o Risk factors: advanced age, renal insufficiency, concurrent steroid use Avoided during pregnancy

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