Daniel H. Deck, PharmD, & Lisa G. Winston, MD*
CASE STUDY
A 59-year-old woman presents to an urgent care clinic with a 4-day history of frequent and painful urination. She has had fevers, chills, and flank pain for the past 2 days. Her physician advised her to come immediately to the clinic for evaluation. In the clinic she is febrile (38.5°C [101.3°F]) but otherwise stable and states she is not experiencing any nausea or vomiting. Her urine dipstick test is positive for leukocyte esterase. Urinalysis and urine culture are ordered. Her past medical history is significant for three urinary tract infections in the past year. Each episode was uncomplicated, treated with trimethoprim-sulfamethoxazole, and promptly resolved. She also has osteoporosis for which she takes a daily calcium supplement. The decision is made to treat her with oral antibiotics for a complicated urinary tract infection with close follow-up. Given her history, what would be a reasonable empiric antibiotic choice? Depending on the antibiotic choice are there potential drug interactions?
ANTIFOLATE DRUGS
SULFONAMIDES
Chemistry
The basic formulas of the sulfonamides and their structural similarity to p-aminobenzoic acid (PABA) are shown in Figure 46–1. Sulfonamides 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 nucleus. Sulfonamides tend to be much more soluble at alkaline than at acid pH. Most can be prepared as sodium salts, which are used for intravenous administration.
FIGURE 46–1 Structures of some sulfonamides and p-aminobenzoic acid.
Mechanism of Action & Antimicrobial Activity
Sulfonamide-susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it from PABA. This pathway (Figure 46–2) is thus essential for production of purines and nucleic acid synthesis. As structural analogs of PABA, sulfonamides inhibit dihydropteroate synthase and folate production. Sulfonamides inhibit both gram-positive and gram-negative bacteria, Nocardia sp, Chlamydia trachomatis, and some protozoa. Some enteric bacteria, such as Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and Enterobacter sp are also inhibited. It is interesting that rickettsiae are not inhibited by sulfonamides but are instead stimulated in their growth. Activity is poor against anaerobes. Pseudomonas aeruginosa is intrinsically resistant to sulfonamide antibiotics.
FIGURE 46–2 Actions of sulfonamides and trimethoprim.
Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis (Figure 46–2).
Resistance
Some bacteria lack the enzymes required for folate synthesis from PABA and, like mammals, depend on exogenous sources of folate; therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may also 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, or (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. Sulfonamide-resistant dihydropteroate synthase mutants also can emerge under selective pressure.
Pharmacokinetics
Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral, nonabsorbable; and (3) topical. The oral, absorbable sulfonamides can be classified as short-, intermediate-, or long-acting on the basis of their half-lives (Table 46–1). They are absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the central nervous system and cerebrospinal fluid), placenta, and fetus. Protein binding varies from 20% to over 90%. Therapeutic concentrations are in the range of 40–100 mcg/mL of blood. Blood levels generally peak 2–6 hours after oral administration.
TABLE 46–1 Pharmacokinetic properties of some sulfonamides and pyrimidines.
A portion of absorbed drug is acetylated or glucuronidated in the liver. Sulfonamides and inactive metabolites are then excreted into the urine, mainly by glomerular filtration. In significant renal failure, the dosage of sulfonamides must be reduced.
Clinical Uses
Sulfonamides are infrequently used as single agents. Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant. The fixed-drug combination of trimethoprim-sulfamethoxazole is the drug of choice for infections such as Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections.
A. Oral Absorbable Agents
Sulfisoxazole and sulfamethoxazole are short- to medium-acting agents used almost exclusively to treat urinary tract infections. The usual adult dosage is 1 g of sulfisoxazole four times daily or 1 g of sulfamethoxazole two or three times daily.
Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. The combination of sulfadiazine with pyrimethamine, a potent inhibitor of dihydrofolate reductase, is synergistic because these drugs block sequential steps in the folate synthesis pathway (Figure 46–2). The dosage of sulfadiazine is 1 g four times daily, with pyrimethamine given as a 75 mg loading dose followed by a 25 mg once-daily dose. Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression.
Sulfadoxine is a long-acting sulfonamide that is coformulated with pyrimethamine (Fansidar). This combination is no longer commercially available in the USA but may be found in other parts of the world where it is used as a second-line treatment of malaria (see Chapter 52).
B. Oral Nonabsorbable Agents
Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease (see Chapter 62).
C. Topical Agents
Sodium sulfacetamide ophthalmic solution or ointment is effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for trachoma. Another sulfonamide, mafenide acetate, is used topically but can be absorbed from burn sites. The drug and its primary metabolite inhibit carbonic anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds.
Adverse Reactions
Historically, drugs containing a sulfonamide moiety, including antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypoglycemic agents, were considered to be cross-allergenic. However, recent evidence suggests cross-reactivity is uncommon and patients who are allergic to nonantibiotic sulfonamides may safely receive sulfonamide antibiotics. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract (see below). Stevens-Johnson syndrome, although relatively uncommon (< 1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see below), hepatitis, and, rarely, polyarteritis nodosa and psychosis.
A. Urinary Tract Disturbances
Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole). Sulfadiazine when given in large doses, particularly if fluid intake is poor, can cause crystalluria. Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine and fluids to increase urine flow. Sulfonamides have also been implicated in various types of nephrosis and in allergic nephritis.
B. Hematopoietic Disturbances
Sulfonamides can cause hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid reactions. Sulfonamides may provoke hemolytic reactions in patients with glucose-6-phosphate dehydrogenase deficiency. Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns.
TRIMETHOPRIM & TRIMETHOPRIM-SULFAMETHOXAZOLE MIXTURES
Mechanism of Action
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA (Figure 46–2). Trimethoprim is a much less efficient inhibitor of mammalian dihydrofolic acid reductase. Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic acid reductase of protozoa compared with that of mammalian cells. As noted above, trimethoprim or pyrimethamine in combination with a sulfonamide blocks sequential steps in folate synthesis, resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone.
Resistance
Resistance to trimethoprim can result from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with reduced drug binding. Resistance can emerge by mutation, although more commonly it is due to plasmid-encoded trimethoprim-resistant dihydrofolate reductases. These resistant enzymes may be coded within transposons on conjugative plasmids that exhibit a broad host range, accounting for rapid and widespread dissemination of trimethoprim resistance among numerous bacterial species.
Pharmacokinetics
Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, which has a similar half-life. Trimethoprim-sulfamethoxazole can also be given intravenously. Trimethoprim is well absorbed from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid.
Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. Therefore, when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole (the ratio in the formulation), the peak plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs in vitro. About 30–50% of the sulfonamide and 50–60% of the trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours. The dose should be reduced by half for patients with creatinine clearances of 15–30 mL/min.
Trimethoprim (a weak base) concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs.
Clinical Uses
A. Oral Trimethoprim
Trimethoprim can be given alone (100 mg twice daily) in acute urinary tract infections. Many community-acquired organisms are susceptible to the high concentrations that are found in the urine (200–600 mcg/mL).
B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)
A combination of trimethoprim-sulfamethoxazole is effective treatment for a wide variety of infections including P jiroveci pneumonia, shigellosis, systemic salmonella infections, urinary tract infections, prostatitis, and some nontuberculous mycobacterial infections. It is active against most Staphylococcus aureus strains, both methicillin-susceptible and methicillin-resistant, and against respiratory tract pathogens such as pneumococcus, Haemophilus sp, Moraxella catarrhalis, and K pneumoniae (but not Mycoplasma pneumoniae). However, the increasing prevalence of strains of E coli (up to 30% or more) and pneumococci that are resistant to trimethoprim-sulfamethoxazole must be considered before using this combination for empiric therapy of upper urinary tract infections or pneumonia.
One double-strength tablet (each tablet contains trimethoprim 160 mg plus sulfamethoxazole 800 mg) given every 12 hours is effective treatment for urinary tract infections and prostatitis. One half of the regular (single-strength) tablet given three times weekly may serve as prophylaxis in recurrent urinary tract infections of some women. One double-strength tablet every 12 hours is effective treatment for infections caused by susceptible strains of shigella and salmonella. The dosage for children treated for shigellosis, urinary tract infection, or otitis media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole every 12 hours.
Infections with P jiroveci and some other pathogens can be treated orally with high doses of the combination (dosed on the basis of the trimethoprim component at 15–20 mg/kg/d) or can be prevented in immunosuppressed patients by one double-strength tablet daily or three times weekly.
C. Intravenous Trimethoprim-Sulfamethoxazole
A solution of the mixture containing 80 mg trimethoprim plus 400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5% dextrose in water can be administered by intravenous infusion over 60–90 minutes. It is the agent of choice for moderately severe to severe pneumocystis pneumonia. It may be used for gram-negative bacterial sepsis, including that caused by some multidrug-resistant species such as Enterobacter and Serratia; shigellosis; typhoid fever; or urinary tract infection caused by a susceptible organism when the patient is unable to take the drug by mouth. The dosage is 10–20 mg/kg/d of the trimethoprim component.
D. Oral Pyrimethamine with Sulfonamide
Pyrimethamine and sulfadiazine are used in the treatment of toxoplasmosis. In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been used (see Chapter 52).
Adverse Effects
Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and granulocytopenia. The combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances occasionally occur also. Patients with AIDS and pneumocystis pneumonia have a particularly high frequency of untoward reactions to trimethoprim-sulfamethoxazole, especially fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and hyponatremia.
DNA GYRASE INHIBITORS
FLUOROQUINOLONES
The important quinolones are synthetic fluorinated analogs of nalidixic acid (Figure 46–3). They are active against a variety of gram-positive and gram-negative bacteria.
Mechanism of Action
Quinolones 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 topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.
Antibacterial Activity
Earlier quinolones such as nalidixic acid did not achieve systemic antibacterial levels and were useful only in the treatment of lower urinary tract infections. Fluorinated derivatives (ciprofloxacin, levofloxacin, and others; Figure 46–3 and Table 46–2) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues.
FIGURE 46–3 Structures of nalidixic acid and some fluoroquinolones.
TABLE 46–2 Pharmacokinetic properties of some fluoroquinolones.
Fluoroquinolones were originally developed because of their excellent activity against gram-negative aerobic bacteria; they had limited activity against gram-positive organisms. Several newer agents have improved activity against gram-positive cocci. This relative activity against gram-negative versus gram-positive species is useful for classification of these agents. Norfloxacin is the least active of the fluoroquinolones against both gram-negative and gram-positive organisms, with minimum inhibitory concentrations (MICs) fourfold to eightfold higher than those of ciprofloxacin. Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, and pefloxacin comprise a second group of similar agents possessing excellent gram-negative activity and moderate to good activity against gram-positive bacteria. MICs for gram-negative cocci and bacilli, including Enterobacter sp, P aeruginosa, Neisseria meningitidis, Haemophilus sp, and Campylobacter jejuni, are 1–2 mcg/mL and often less. Methicillin-susceptible strains of S aureus are generally susceptible to these fluoroquinolones, but methicillin-resistant strains of staphylococci are often resistant. Streptococci and enterococci tend to be less susceptible than staphylococci, and efficacy in infections caused by these organisms is limited. Ciprofloxacin is the most active agent of this group against gram-negative organisms, P aeruginosa in particular. Levofloxacin, the L-isomer of ofloxacin, has superior activity against gram-positive organisms, including Streptococcus pneumoniae.
Gatifloxacin, gemifloxacin, and moxifloxacin make up a third group of fluoroquinolones with improved activity against gram-positive organisms, particularly S pneumoniae and some staphylococci. Gemifloxacin is active in vitro against ciprofloxacin-resistant strains of S pneumoniae, but in vivo efficacy is unproven. Although MICs of these agents for staphylococci are lower than those of ciprofloxacin (and the other compounds mentioned in the paragraph above), it is not known whether the enhanced activity is sufficient to permit use of these agents for treatment of infections caused by ciprofloxacin-resistant strains. In general, none of these agents is as active as ciprofloxacin against gram-negative organisms. Fluoroquinolones also are active against agents of atypical pneumonia (eg, mycoplasmas and chlamydiae) and against intracellular pathogens such as Legionella and some mycobacteria, including Mycobacterium tuberculosis and Mycobacterium avium complex. Moxifloxacin also has modest activity against anaerobic bacteria. Because of toxicity, gatifloxacin is no longer available in the United States.
Resistance
During fluoroquinolone therapy, resistant organisms emerge in about one of every 107–109 organisms, especially among staphylococci, P aeruginosa, and Serratia marcescens. Resistance is due to one or more point mutations in the quinolone binding region of the target enzyme or to a change in the permeability of the organism. However, this does not account for the relative ease with which resistance develops in exquisitely susceptible bacteria. More recently two types of plasmid-mediated resistance have been described. The first type utilizes Qnr proteins, which protect DNA gyrase from the fluoroquinolones. The second is a variant of an aminoglycoside acetyltransferase capable of modifying ciprofloxacin. Both mechanisms confer low-level resistance that may facilitate the point mutations that confer high-level resistance. Resistance to one fluoroquinolone, particularly if it is of high level, generally confers cross-resistance to all other members of this class.
Pharmacokinetics
After oral administration, the fluoroquinolones are well absorbed (bioavailability of 80–95%) and distributed widely in body fluids and tissues (Table 46–2). Serum half-lives range from 3 to 10 hours. The relatively long half-lives of levofloxacin, gemifloxacin, gatifloxacin, and moxifloxacin permit once-daily dosing. Oral absorption is impaired by divalent and trivalent cations, including those in antacids. Therefore, oral fluoroquinolones should be taken 2 hours before or 4 hours after any products containing these cations. Serum concentrations of intravenously administered drug are similar to those of orally administered drug. Most fluoroquinolones are eliminated by renal mechanisms, either tubular secretion or glomerular filtration (Table 46–2). Dosage adjustment is required for patients with creatinine clearances less than 50 mL/min, the exact adjustment depending on the degree of renal impairment and the specific fluoroquinolone being used. Dosage adjustment for renal failure is not necessary for moxifloxacin. Nonrenally cleared fluoroquinolones are relatively contraindicated in patients with hepatic failure.
Clinical Uses
Fluoroquinolones (other than moxifloxacin, which achieves relatively low urinary levels) are effective in urinary tract infections caused by many organisms, including P aeruginosa. These agents are also effective for bacterial diarrhea caused by Shigella, Salmonella, toxigenic E coli, and Campylobacter. Fluoroquinolones (except norfloxacin, which does not achieve adequate systemic concentrations) have been used in infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections, including those caused by multidrug-resistant organisms such as Pseudomonas and Enterobacter. Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax, although the newer fluoroquinolones are active in vitro and very likely in vivo as well.
Ciprofloxacin and levofloxacin are no longer recommended for the treatment of gonococcal infection in the United States as resistance is now common. However, both drugs are effective in treating chlamydial urethritis or cervicitis. Ciprofloxacin, levofloxacin, or moxifloxacin is occasionally used for treatment of tuberculosis and atypical mycobacterial infections. These agents are suitable for eradication of meningococci from carriers and for prophylaxis of infection in neutropenic cancer patients.
With their enhanced gram-positive activity and activity against atypical pneumonia agents (chlamydiae, Mycoplasma, and Legionella), levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin—so-called respiratory fluoroquinolones—are effective and used increasingly for treatment of upper and lower respiratory tract infections.
Adverse Effects
Fluoroquinolones are generally well tolerated. The most common effects are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests develop. Photosensitivity has been reported with lomefloxacin and pefloxacin. Prolongation of the QTc interval may occur with gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin; these drugs should be avoided or used with caution in patients with known QTcinterval prolongation or uncorrected hypokalemia; in those receiving class 1A (eg, quinidine or procainamide) or class 3 antiarrhythmic agents (sotalol, ibutilide, amiodarone); and in patients receiving other agents known to increase the QTc interval (eg, erythromycin, tricyclic antidepressants). Gatifloxacin has been associated with hyperglycemia in diabetic patients and with hypoglycemia in patients also receiving oral hypoglycemic agents. Because of these serious effects (including some fatalities), gatifloxacin was withdrawn from sale in the United States in 2006.
Fluoroquinolones may damage growing cartilage and cause an arthropathy. Thus, these drugs are not routinely recommended for patients under 18 years of age. However, the arthropathy is reversible, and there is a growing consensus that fluoroquinolones may be used in children in some cases (eg, for treatment of pseudomonal infections in patients with cystic fibrosis). Tendonitis, a rare complication that has been reported in adults, is potentially more serious because of the risk of tendon rupture. Risk factors for tendonitis include advanced age, renal insufficiency, and concurrent steroid use. Fluoroquinolones should be avoided during pregnancy in the absence of specific data documenting their safety. Oral or intravenously administered fluoroquinolones have also been associated with peripheral neuropathy. Neuropathy can occur at any time during treatment with fluoroquinolones and may persist for months to years after the drug is stopped. In some cases it may be permanent.
SUMMARY Sulfonamides, Trimethoprim, and Fluoroquinolones
PREPARATIONS AVAILABLE
REFERENCES
Briasoulis A et al: QT prolongation and torsade de pointes induced by fluoroquinolones: Infrequent side effects from commonly used medications. Cardiology 2011;120:103.
Cohen JS: Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother 2001;35:1540.
Davidson R et al: Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:747.
Gupta K et al: International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women. Clin Infect Dis 2011;52:103.
Keating GM, Scott LJ: Moxifloxacin: A review of its use in the management of bacterial infections. Drugs 2004;64:2347.
Mandell LA et al: Infectious Disease Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia. Clin Infect Dis 2007;44:S27.
Mwenya DM et al: Impact of cotrimoxazole on carriage and antibiotic resistance of Streptococcus pneumoniae and Haemophilus influenzae in HIV-infected children in Zambia. Antimicrob Agents Chemother 2010;54:3756.
Nouira S et al: Standard versus newer antibacterial agents in the treatment of severe acute exacerbation of chronic obstructive pulmonary disease: A randomized trial of trimethoprim-sulfamethoxazole versus ciprofloxacin. Clin Infect Dis 2010;51:143.
Rodriguez-Martinez JM et al: Plasmid-mediated quinolone resistance: An update. J Infect Chemother 2011;17:149.
Scheld WM: Maintaining fluoroquinolone class efficacy: Review of influencing factors. Emerg Infect Dis 2003;9:1.
Schmitz GR et al: Randomized controlled trial of trimethoprim-sulfamethoxazole for uncomplicated skin abscesses in patients at risk for community-associated methicillin-resistant Staphylococcus aureus infection. Ann Emerg Med 2010;56:283.
Strom BL et al: Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349:1628.
Talan DA et al: Prevalence of and risk factor analysis of trimethoprim-sulfamethoxazole- and fluoroquinolone-resistant E. coli infection among emergency department patients with pyelonephritis. Clin Infect Dis 2008; 47:1150.
Ziganshina LE et al: Fluoroquinolones for treating tuberculosis (presumed drug sensitive). Cochrane Database Syst Rev 2013;(6):CD004795.
CASE STUDY ANSWER
A fluoroquinolone that achieves good urinary levels (ciprofloxacin or levofloxacin) would be a reasonable choice for empiric treatment of this patient’s complicated urinary tract infection. Her recent exposure to multiple courses of trimethoprim-sulfamethoxazole increases her chances of having a urinary tract infection with an isolate that is resistant to this antibiotic, making empiric trimethoprim-sulfamethoxazole a poor choice. The patient should be told to take the oral fluoroquinolone 2 hours before or 4 hours after her calcium supplement as divalent and trivalent cations can significantly impair the absorption of oral fluoroquinolones.
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*The authors thank Henry F. Chambers, MD, for his contributions to previous editions.