Oral Antibiotics: Are the Old Still Gold? NIRMAL JOSHI Pennsylvania State University

Table 1. Cost of Selected Antibiotics*
Antibiotic	Cost ($)
CONVENTIONAL
Cephalexin 500 mg tid	9.00
Trimethoprim- Sulfamethoxazole 800 mg/160 mg bid	8.00
Doxycycline 100 mg bid	1.80
Clindamycin 150 mg tid	15.60
Metronidazole 250 mg tid	0.60
NEWER
Azithromycin 500 mg on day 1, 250 mg on days 2-5	38.40
Cefuroxime axetil 250 mg bid	70.00
Ciprofloxacin 500 mg bid	72.40
Trovafloxacin 200 mg qd	71.80
*Costs are the average wholesale price in U.S. dollars for 10 days of therapy. (From Drug Topics Red Book 1998, Medical Economics, Montvale, NJ)

Factors Influencing the Choice of Therapy The effectiveness of an antibiotic depends on three variables: the virulence of the infecting agent, the ability of the host to defend itself against infection, and the formulation of the antibiotic itself. In most ambulatory care patients, host factors probably play a more significant role in determining outcome than the specific antibiotic employed. In vitro drug susceptibility data may be an important predictor, but not the sole predictor, of clinical outcome. In one study of pneumococcal infections, for example, the clinical response to penicillin treatment was favorable even though the infecting pathogen was moderately resistant to penicillin in vitro. In other cases, respiratory infections have resolved despite seemingly inappropriate antibiotic therapy. The etiology of an infection is often unknown when therapy is initiated. The pathogens causing urinary-tract or sinus infections can usually be readily identified, but respiratory infections are caused by so many different organisms that it is impractical and unnecessary to test for them all. When planning empiric therapy, one need be concerned only that the drug selected is active against organisms commonly encountered. Cephalexin Like other first-generation cephalosporins, cephalexin is effective in vitro against most staphylococcal and streptococcal infections except those caused by methicillin-resistant organisms. Among the gram-negative aerobes, Escherichia coli and Proteus mirabilis are usually susceptible, but Haemophilus influenzae, Bordetella pertussis, and Proteus vulgaris are resistant. Anaerobes are also resistant. Because of its poor activity against H. influenzae, cephalexin is not generally employed for upper respiratory or sinus infections. Its primary use is in the treatment of cellulitis and other soft-tissue, skin, and urinary-tract infections. Cephalexin is well absorbed by the gastrointestinal tract and reaches peak activity levels very rapidly. It is not metabolized by the body but is excreted unchanged in active form by glomerular filtration and tubular secretion. It is thus present in high concentrations in the urinary tract. The mean half-life of the drug is normally 0.9 hr, but in patients with severe renal impairment the half-life can be as long as 20 to 30 hr. To avoid toxicity in such cases, drug dosage must be reduced (Table 2).

Side effects of cephalexin therapy are uncommon. Some patients experience hypersensitivity skin reactions or gastrointestinal symptoms such as diarrhea and vomiting. The drug also produces a positive response on Coombs' antiglobulin testing. Trimethoprim-Sulfamethoxazole The two components of trimethoprim-sulfamethoxazole (TMP-SMZ) sequentially inhibit folinic acid synthesis, an essential step in microbial production of DNA. TMP-SMZ is active against a broad spectrum of organisms, with the notable exception of anaerobes. It is not, however, reliably effective against penicillin-resistant pneumococci. Synergy between TMP and SMZ has been well documented in vitro but may not be characteristic of the drug's activity in vivo. Although well absorbed, TMP and SMZ do not reach therapeutic levels at the same time. TMP's activity peaks between one and three hours and SMZ's between three and four hours after ingestion. Plasma concentrations of about 20% TMP and 30% to 50% SMZ are attained in most tissues. A 10% to 20% penetration into the central nervous system is observed when the meninges are not inflamed. TMP concentrates in the prostate, reaching levels threefold greater than in serum. Both TMP and SMZ are metabolized in the liver, but to a different extent; 80% of TMP and 10% to 20% of SMZ are excreted unchanged in the urine. In patients with renal impairment, several changes occur: nonrenal elimination increases, protein binding patterns change, and SMZ metabolites accumulate, altering metabolic pathways. In such cases, the dosage of the drug must be adjusted (see Table 2). Urinary Tract Infections. In most settings, TMP-SMZ has remained reliably effective against E. coli, the predominant pathogen in community-acquired urinary tract infections. Quinolones offer a useful alternative but at a significantly higher cost. For acute uncomplicated cystitis in women, a three-day short course of TMP-SMZ is usually sufficient. For upper urinary tract infections, a longer course of one to two weeks is needed. Since TMP accumulates in the prostate, TMP-SMZ is also very effective in treating acute bacterial prostatitis. Respiratory Infections. Streptococcus pneumoniae and H. influenzae are the most common bacterial causes of uncomplicated respiratory infections, including acute otitis media, sinusitis, acute exacerbations of chronic bronchitis, and community-acquired pneumonia. TMP-SMZ retains excellent efficacy against H. influenzae (even beta-lactamase-producing, ampicillin-resistant strains) and Moraxella catarrhalis. Penicillin-resistant strains of S. pneumoniae are also frequently resistant to TMP-SMZ in vitro, but it is unclear whether they are similarly resistant in vivo. TMP-SMZ remains the drug of choice for treating P. carinii pneumonia in HIV-infected patients. Use is limited, however, by the high incidence of skin rash. TMP-SMZ is also useful in treating opportunistic infections caused by Nocardia asteroides, Salmonella, Shigella, E. coli, and Listeria and is employed as general prophylaxis in immunocompromised patients with hematologic malignancy. In many cases, however, other agents such as quinolones may be more appropriate. Adverse Effects. HIV-infected patients experience a significantly higher incidence of adverse effects with TMP-SMZ than do immunocompetent patients. In some series, up to 70% have skin rash, cytopenia, hepatotoxicity, or other problems. Serious side effects are rare in non-HIV-infected patients. When they do occur, they are primarily hematologic (leukopenia, thrombocytopenia, hemolytic anemia) or dermatologic (skin rash, Stevens-Johnson syndrome). Minor side effects, which are fairly common, usually take the form of skin rash, cytopenia, or hepatotoxicity. Doxycycline Doxycycline belongs to the tetracycline class of antibiotics. It is effective against many gram-positive and gram-negative aerobes, anaerobes, Mycoplasma, Chlamydia, Rickettsia, spirochetes, protozoa, and mycobacteria. It is a particularly useful, inexpensive agent for treatment of asymptomatic cystitis in women and a wide range of other conditions in both women and men, including Lyme disease, nongonococcal urethritis, cholera, brucellosis, several rickettsial infections, sinusitis, otitis, acute exacerbation of chronic bronchitis, and community-acquired pneumonia. American Thoracic Society guidelines for community-acquired pneumonia recommend doxycycline as an alternative to macrolides. Considering the expense of the macrolides, and the fact that erythromycin is poorly tolerated, doxycycline is the drug I most frequently use in outpatient treatment of pneumonia. Doxycycline is well absorbed orally, but about half of the dose is converted to inactive compounds. Approximately 30% to 40% of the remainder is excreted by the kidneys. In cases of renal failure, nonrenal clearance mechanisms take over--the serum level and half-life are not altered. Photosensitive skin reactions ranging in severity from paraesthesia in sun-exposed areas to frank erythema have been attributed to doxycycline use. More severe reactions are uncommon. Antacids and iron supplements may delay absorption, but food has no effect. An increased prothrombin time may occur if doxycycline is administered in the presence of warfarin. Clindamycin Clindamycin, a lincosamide derivative of lincomycin, is clinically active against most anaerobes, many aerobic gram-positive cocci (streptococci and methicillin-susceptible staphylococci), and some protozoa. It is ineffective against methicillin-resistant staphylococci and enterococci. Its primary use, therefore, is in the treatment of abdominal and pelvic infections, aspiration pneumonia, and diabetic foot infections, in which anaerobic organisms may play a role. In several such conditions, an additional agent may be necessary to combat coexisting gram-negative pathogens. Clindamycin is well absorbed orally, achieving clinically useful concentrations in most tissues; it does not penetrate into cerebrospinal fluid. It is metabolized mainly by the liver and is excreted in bile--only about 5% to 10% is excreted in urine. The drug's half-life of 2 to 2.5 hr is increased in patients with severe liver disease, necessitating a dose reduction. A reduction is usually unnecessary in patients with renal failure. The most common side effects are nausea, vomiting, and diarrhea. The reported incidence of diarrhea ranges from 2% to 20%. Gastrointestinal problems are usually mild but can take the form of pseudomembranous enterocolitis, which is potentially life-threatening. Other reported side effects include hypersensitivity reactions and alterations in hepatic transaminases. Metronidazole First used against trichomonal infections, metronidazole was found to have anaerobic activity when a patient being treated for such an infection was fortuitously cured of gingivitis. This antibiotic is clinically active against most anaerobic organisms (e.g., Clostridium difficile), some protozoa (Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica), and Helicobacter pylori. It is also used for Crohn's disease and perioperative prophylaxis. Unlike clindamycin, it has no activity against gram-positive aerobes. Metronidazole is very well absorbed and has a serum half-life of about eight hours. Tissue penetration to almost all sites, including the central nervous system, is excellent. The component responsible for anaerobic activity is a by-product of the drug's metabolism in the liver. About 60% to 80% of the initial dose is eliminated by the kidney. Dose reduction is recommended in cases of liver failure. In renal impairment, a reduction is usually unnecessary. Some authorities, however, recommend one half the regular dose for patients whose creatinine clearance rate is less than 10 mL/min. Nausea and a metallic taste in the mouth frequently limit the duration of therapy. Other adverse effects include neutropenia, cutaneous allergic reactions, and a disulfiram-like reaction with alcohol. Metronidazole should be avoided in the first trimester of pregnancy and during lactation. Selection of Antibiotics A comparison of these conventional antibiotics with newer alternatives provides persuasive evidence that the older agents are cost-effective (Table 3 and 4). The disadvantages cited as justification for using more expensive drugs are often refutable:

1) In answer to the criticism that cephalexin has too narrow a spectrum for use in treating skin and soft-tissue infections, I would say that a broad spectrum is not needed. Most such infections are caused by staphylococci and streptococci. 2) In planning empiric therapy for acute exacerbation of chronic bronchitis and other respiratory infections, it has been argued that TMP-SMZ should not be used because it has poor activity against penicillin-resistant pneumococci. However, the significance of penicillin-resistance, particularly if less than moderate, in treating infections outside the central nervous system is unknown. The only study addressing clinical outcome in patients infected with moderately resistant pneumococci found no difference between penicillin- and non-penicillin-treated patients. 3) Doxycycline is often similarly withheld when treating acute exacerbation of chronic bronchitis and other respiratory infections because it is believed that newer agents offer more adequate coverage against the most common pathogens. My response, however, is that doxycycline has excellent in vitro activity against Mycoplasma pneumoniae and other atypical microorganisms in addition to H. influenzae and S. pneumoniae and is likely to be clinically effective as well.

A second criticism of doxycline is that it interacts with too many other drugs. Comparatively speaking, however, it has few such interactions and almost none with serious consequences. Summary Most common infections in ambulatory care can be treated effectively and safely with conventional antibiotics. A rational approach using such antibiotics as primary choices and reserving newer antibiotics for selected, more difficult-to-treat infections will result in substantial cost savings and may help to prevent the rapid development of drug resistance. Selected Reading Cockerill FR, Edson RS: Trimethoprim-sulfamethoxazole. Mayo Clin Proc 66:1260, 1991 Cunha BA: New uses for older antibiotics: The "rediscovery" of four beneficial and cost-effective antimicrobials. Postgrad Med J 101:68, 1997 Falagas ME, Gorbach SL: Clindamycin and metronidazole. Med Clin North Am 79:845, 1995 Joshi N, Milfred D: The use and misuse of new antibiotics. Arch Intern Med 155:569, 1995 Joshi N, Miller DQ: Doxycycline revisited. Arch Intern Med 157:1421, 1997 Kucers A, Bennett MN: The Use of Antibiotics: A Comprehensive Review with Clinical Emphasis. 4th ed, JB Lippincott, Philadelphia, 1987 Paap CM, Nahata MC: Clinical use of trimethoprim/sulfamethoxazole during renal dysfunction. Ann Pharmacother 23:646, 1989 HOME | CURRENT ISSUE | PAST ARTICLES | GENETICS SERIES CAPSULE & COMMENT | CME | CLASSIFIED ADVERTISING | ABOUT US Copyright (C) 1999. The McGraw-Hill Companies. All Rights Reserved E-mail Privacy Notice