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WHO REALLY NEEDS PARENTERAL ANTIBIOTICS?

WHO REALLY NEEDS PARENTERAL ANTIBIOTICS?

Bioavailability and Pharmacodynamic Issues of Oral Antibiotics
Availability of Oral Products
Host Factors to Consider in the Choice of Oral or Parenteral Antibiotics
Antibiotic Susceptibility Profiles
Oral Agents for Severe Infections
Conclusions
Bibliography

Although much has been written concerning the indications, abuses, and recommended dosing regimens of antibiotics for many diseases, far less is known about the most appropriate route of administration for these agents. Historically, clinicians in the United States acquired the notion that hospitalized patients should receive antibiotics parenterally, whereas those at home could be treated with oral antibiotic agents. This was no doubt based on a sense of differing degrees of illness between hospitalized and ambulatory patients. This feeling is not shared universally, and clinicians in other parts of the world employ oral antibiotics more regularly to treat hospitalized patients. This concept of the use of parenteral antibiotics in hospitalized patients has been nurtured by external forces that include insurers, community services, and governmental regulatory agencies. As an example, until the past decade, there was no generally available infrastructure for the administration of parenteral antibiotics outside the setting of acute care. Similarly, insurers did not ordinarily provide compensation to patients for the purchase of antibiotics, and the costs associated with the purchase and administration of parenteral antibiotics in the community would have been prohibitive.
During the past decade, as the result of various changes, the decision regarding when to use parenteral or oral agents has become less clearly defined. Table 81-1 summarizes many of these issues. Managed care has forced health care providers to reconsider the costs of treatment, including those associated with administration of antibiotics. Parenteral antibiotics administered in the hospital are expensive, and the adverse effects of both high-dose parenteral agents and the administration paraphernalia have been well publicized. In essence, clinicians have been challenged to demonstrate the superiority of more expensive therapies.

Table 81-1. Changing face of antibiotic treatment

In the mid-1980s, the concept of outpatient parenteral antibiotic therapy was addressed in earnest, and numerous investigations now document the safety, efficacy, and cost effectiveness of this modality of care. Most urban and suburban areas are now equipped with an infrastructure to deliver outpatient parenteral antibiotic therapy in the home, infusion center, or physician’s office. During this time, substantial progress has been made in the development of oral antibiotic agents. Numerous drugs now exist that can be given once or twice daily, have excellent bioavailability, “cover” likely pathogens for many infections, are well tolerated, and can be obtained at a reasonable price. Indeed, the cost of the most expensive oral antibiotic is less than 3% of that associated with parenteral antibiotics given in the acute care setting. Several investigators have now documented the safety and efficacy of oral antibiotic therapy for diseases historically treated parenterally. Examples include selected cases of osteomyelitis, pyelonephritis, septic arthritis, and infective endocarditis. The discussion that follows attempts to put these issues in perspective, define populations that can reasonably be treated with oral antibiotics, and realistically address the question of who really needs parenteral antibiotics.
Bioavailability and Pharmacodynamic Issues of Oral Antibiotics
Several antibiotics are well absorbed after oral administration, and serum levels are obtained that are similar to those following parenteral therapy. Metronidazole, doxycycline, many quinolones, rifampin, trimethoprim-sulfamethoxazole, and chloramphenicol are examples. Thus, provided the patient has a functional gastrointestinal tract, there are few reasons to administer these agents parenterally. Additionally, one or a combination of them can provide coverage for many infections. Drug and food interactions are a concern with selected oral antibiotics. The absorption of quinolones and tetracycline may be inhibited by divalent cations. Others, including penicillin G and the early form of azithromycin, must be given without food, whereas selected antimicrobials such as itraconazole and ketoconazole require the presence of food (gastric acid) for adequate absorption. These issues become critical when antiretroviral agents are considered (see Chapter 90).
Many b-lactam antibiotics and clindamycin represent examples of agents for which oral and parenteral dosing regimens are substantially different. As an example, the dose of nafcillin or oxacillin for serious staphylococcal infections may be 8 to 12 g/d, whereas the usual dose of dicloxacillin rarely exceeds 2 g/d. Presumably, this is because of likely gastrointestinal adverse reactions associated with higher oral doses. Because the efficacy of b-lactams is based on the length of time the minimum inhibitory concentration for the organism is exceeded (time-dependent killing), oral and parenteral products could be anticipated to have different clinical outcomes. This is a reason why hospitalized patients treated with b-lactam antibiotics for severe infections generally are treated parenterally.
Availability of Oral Products
A number of important antimicrobial agents cannot be administered orally for systemic infections. Examples include amphotericin B, vancomycin, aminoglycosides, and foscarnet. Amphotericin B has historically been considered the gold standard for serious systemic fungal infection; aminoglycosides were important agents for significant gram-negative infections, and vancomycin remains the standard of care for infections associated with methicillin-resistant Staphylococcus aureus, systemic infections caused by Staphylococcus epidermidis, and many other severe, gram-positive infections in patients with histories of immediate b-lactam allergy.
Host Factors to Consider in the Choice of Oral or Parenteral Antibiotics
The host factors to consider in the decision to use oral antibiotics are summarized in Table 81-2. Compliance with an oral regimen administered outside the hospital requires (a) ability to purchase the agent, (b) understanding of how to take it, and (c) ability to cope with adverse reactions. The writing of the script does not guarantee the intake of the product. Numerous examples of patients unable to afford an oral agent exist, and the prescribing physician needs to ascertain the patient’s ability to pay. Compliance has been simplified with the recent availability of products requiring dosing once (or twice) daily. Several investigations demonstrate that products requiring three to four doses per day are less likely to be taken regularly (and so could result in poor outcomes). Adverse reactions range from life-threatening to annoying. The patient must understand that certain adverse reactions are possible and do not mandate drug discontinuation.

Table 81-2. Host factors to consider in use of oral antibiotics

Gastrointestinal function must be sufficient to allow drug absorption. Patients with severe nausea, vomiting, or diarrhea are not candidates for initial oral antibiotic therapy. Achlorhydria may aid in the absorption of selected agents and be deleterious for others.
Allergy may preclude the use of selected products. However, it is the opinion of the author that its importance is overemphasized and often results in the use of expensive, less effective agents. Immediate reactions to penicillin occur in fewer than one in 10,000 patients. Maculopapular rash, probably the most common manifestation of allergy, is generally not associated with defined mechanisms of true allergy and often will not recur with repeated dosing of the offending product. The clinician must question the patient about the type of allergy and consider whether the adverse reaction truly represents an allergic problem.
Age and end-organ function are of occasional importance. The quinolones are contraindicated in persons less than 18 years old and should be used in persons less than this age only in highly specific circumstances and with the consent of the patient. Tetracyclines should not be given to young children, typically until all the secondary teeth are in place. Tetracyclines and quinolones are contraindicated in pregnancy, and sulfa preparations should be administered with care, especially late in the third trimester. Patients with neurologic disturbances may be at risk for complications with the use of selected quinolones, and patients with severe renal failure may need dosage adjustments with many oral antibiotics.
Antibiotic Susceptibility Profiles
Antibiotics now exist that provide in vitro activity against most pathogens. The availability of newer quinolones (sparfloxacin, grepafloxacin, levofloxacin, and trovafloxacin) has provided the clinician with a class of product that has excellent in vitro activity against most enteric gram-negative bacilli and many gram-positive cocci (including many strains of S. aureus and penicillin-resistant Streptococcus pneumoniae), and reasonable activity against Pseudomonas aeruginosa. Trovafloxacin is the first of the available quinolones to have excellent anaerobic activity. Thus, for many infections in appropriate hosts, the oral quinolones may be considered for treatment of infections historically treated parenterally.
Metronidazole is an oral agent with excellent bioavailability and is active against the majority of anaerobes associated with human infection. It is also the agent of choice for Clostridium difficile diarrhea. Trimethoprim-sulfamethoxazole has good activity against many strains of S. aureus and many enteric gram-negative bacilli. It is also an agent of choice for Pneumocystis carinii pneumonia and is well-studied as an oral agent to treat mild-to-moderate infection with this pathogen. Rifampin has broad-spectrum antibacterial activity, but it is now associated with the problem of rapid emergence of resistance when employed as monotherapy. In vitro, it is one of the most active agents against S. aureus and has been clinically utilized successfully (in conjunction with a second antistaphylococcal agent) against this pathogen. Chloramphenicol is active against many gram-positive, enteric gram-negative, and anaerobic bacteria. It also is active against rickettsiae. It is well absorbed, associated with few adverse reactions, and inexpensive in most parts of the world. Bone marrow aplasia is a life-threatening but rare complication that has precluded its use in the United States for most indications. However, studies assessing the risk of this agent against the risks of alternative parenteral antibiotic therapy (e.g., IV line sepsis) have not been performed.
Oral Agents for Severe Infections
Studies that have been performed during the past decade indicate the value of oral antibiotic therapy for numerous conditions historically treated parenterally. Several examples are presented. The combination of ciprofloxacin plus rifampin has been successfully employed in patients with uncomplicated right-sided endocarditis associated with S. aureus. This condition has also been successfully treated with trimethoprim-sulfamethoxazole, and outcomes in patients with methicillin-resistant S. aureus infection were slightly better than with vancomycin. Oral antistaphylococcal agents now represent the therapy of choice for uncomplicated staphylococcal osteomyelitis and septic arthritis in children. In most instances, the dose is several times higher than usual, and the serum bactericidal test is used to help assess the optimal dose. In adults, a quinolone plus rifampin usually results in satisfactory serum bactericidal levels. A recent study of ciprofloxacin plus rifampin in the management of infected orthopedic prostheses demonstrated that patients who received this combination (plus appropriate early debridement) were all cured after 3 to 6 months of oral treatment. The quinolones have revolutionized the management of acute pyelonephritis, and in patients otherwise fit to be treated outside the hospital, they now represent the treatment of choice (in the absence of pregnancy and other contraindications).
Step-down from parenteral to oral therapy has received increasing recognition as a method to decrease the length of parenteral treatment and hasten discharge from the hospital. This has been best studied with community-acquired pneumonia, for which numerous studies have now demonstrated the safety and efficacy of this approach. In many instances, patients with community-acquired pneumonia can be placed on oral antibiotics after 2 to 3 days in the hospital and discharged on the same day. Criteria for the switch to oral antibiotics include (a) a functional gastrointestinal tract, (b) improving clinical and laboratory parameters, and (c) being afebrile for two consecutive 8-hour intervals.
Conclusions
The availability of newer oral products plus the publication of several important investigations now demonstrate the adequacy of oral antibiotic therapy for many conditions historically treated parenterally. Parenteral administration of antibiotics should be reserved for highly selected patients in the following situations: (a) No oral antibiotic is available, (b) the patient’s gastrointestinal function will not support absorption of an oral antibiotic, (c) drug-food or drug-drug interactions are present that preclude the use of an oral antibiotic, (d) severe sepsis is present and high concentrations of antibiotic must be attained rapidly (often at a sequestered focus, such as a heart valve or the meninges). Clinicians, insurers, and patients must understand that oral antibiotic therapy does not represent poor treatment, and that in many circumstances it is equally effective, less expensive, and potentially safer than parenteral antibiotic therapy. (R.B.B.)
Bibliography
Gentry LO, Rodriguez GG. Oral ciprofloxacin compared with parenteral antibiotics in the treatment of osteomyelitis. Antimicrob Agents Chemother 1990;34:40–43.
A prospective, randomized trial of ciprofloxacin versus standard parenteral antibiotic therapy was conducted for adults with biopsy-proven osteomyelitis. Success rates were approximately 75% in both groups. Adverse effects were more common in patients treated parenterally. Most failures were noted in patients with polymicrobial infections involving P. aeruginosa. For many patients with osteomyelitis, oral quinolone therapy is a rational alternative to parenteral antibiotics.
Greenberg RN. Overview of patient compliance with medication dosing: a literature review. Clin Ther 1984;6:592–596.
In studies of compliance with antibiotic dosing, once- and twice-daily regimens were associated with substantially better compliance than regimens that required dosing three or four times daily. With regimens that required dosing more frequently than twice daily, compliance dropped to less than 50%, and this was not related to social class, income, or occupation. The current availability of numerous products that can be taken once or twice daily makes oral antibiotic treatment far more appealing than previously.
Heldman AW, et al. Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. Am J Med 1996;101:68–76.
Ciprofloxacin plus rifampin was compared with either oxacillin or vancomycin to treat febrile drug users hospitalized with suspected right-sided infective endocarditis. Treatment failures and drug toxicity were more common among those treated parenterally. For selected patients with endocarditis, a totally oral antibiotic regimen appears reasonable.
MacGregor RR, Graziani AL. Oral administration of antibiotics: a rational alternative to the parenteral route. Clin Infect Dis 1997;24;457–467.
Many of the issues that have led to the reassessment of the role of oral antibiotics are summarized, pharmacokinetic data are presented for several oral agents, and various studies that justify oral antibiotic treatment for many infections historically treated parenterally are reviewed. The authors make a good case for the expanded use of oral antibiotics, and they ask for the input of physicians to foster the ongoing study of older oral antibiotics, for which industrial sponsorship is unlikely.
Zimmerli W, et al. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections. JAMA 1998;279:1537–1541.
The authors conducted a randomized trial of ciprofloxacin with and without rifampin for orthopedic implant-related staphylococcal infections. Patients were treated orally after an initial 2-week course of parenteral antibiotics. Initial debridement of infected materials was carried out, but the implant was left in place. All isolates were susceptible to both ciprofloxacin and rifampin. Patients who completed a 3- to 6-month course of ciprofloxacin plus rifampin were cured without removal of the implant. The rate of cure was substantially lower among those who received only ciprofloxacin (100% vs. 58%). This investigation is the most recent one demonstrating a role for the oral treatment of a condition that has historically been treated parenterally. The antibiotics used were highly bioavailable, well tolerated, and given no more than twice daily.

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