Much early experience with antibiotic therapy involved oral administration of sulfonamides, penicillins, tetracyclines, and chloramphenicol. Newer acid-labile, less-soluble agents created the need for intravenous (i.v.) administration, and i.v. technology (hyporeactive catheter polymers, infusion pumps, etc.) improved to where i.v. administration became normative for the treatment of serious infections. Recently, this preference is being reconsidered in light of agents that are highly effective orally, growing appreciation that i.v. treatment has serious complications, and economic pressures to provide the best care at the lowest cost. This article presents a brief history of administration routes and reviews the rationale for considering oral treatment for serious infections, including consideration of pharmacokinetics and minimum inhibitory concentrations. Published reports supporting the efficacy of orally administered antibiotics either as sole treatment or following an initial parenteral course are reviewed in detail, and examples of programs that educate physicians about the rationale, acceptibility, and benefits of oral administration are given.

Concentrations of vancomycin in bones of 14 patients undergoing total hip arthroplasty (group 1) and 5 patients with osteomyelitis (group 2) were studied. Group 1 received vancomycin, 15 mg/kg intravenously, 1 h prior to anesthesia. Group 2 received doses adjusted to achieve peak levels in serum of 20 to 30 ,ug/ml and trough levels of <12 ,Ig/ml; bone specimens were collected during surgical debridement. The specimens were pulverized and eluted into phosphate buffer, and the supernatants were analyzed for vancomycin content by fluorescence polarization immunoassay. In group 1, vancomycin was detectable in all cancellous specimens with a mean concentration of 2.3 ± 4.0 ,ug/g (range, 0.5 to 16 ,ug/g); 10 of 14 cortical specimens had detectable vancomycin; the mean cortical concentration was 1.1 ± 0.8 ,ug/g (range, not detectable to 2.6 ,ug/g). In group 2, vancomycin was detectable in only two of five cortical bone specimens (mean concentration, 5.9 ± 3.5 ,ug/ g). Cancellous bone was obtained in one patient; the vancomycin concentration was 3.6 ,ug/g. In most patients the vancomycin levels in bones were higher than the MIC for susceptible staphylococci following single prophylactic doses. In the few infected patients studied, penetration was variable and deserves further study.Vancomycin is often recommended for the treatment of osteomyelitis caused by methicillin-resistant staphylococcal species, as well as for all forms of gram-positive staphylococcal and streptococcal osteomyelitis in patients with allergies to beta-lactam antibiotics. Nonetheless, no studies of vancomycin penetration into human bone have been reported. Therefore, we measured concentrations in noninfected bone specimens from humans following a single preoperative intravenous dose of vancomycin and in infected bone specimens following multiple-dose therapy for osteomyelitis. MATERIALS AND METHODSStudy groups. Nineteen adult patients were studied. Group 1 consisted of 14 patients undergoing total hip arthroplasty for osteoarthritis. Group 2 consisted of five patients with osteomyelitis undergoing surgical bone debridement.(i) Group 1. Vancomycin (15 mg/kg of total body weight, to a maximum dose of 1 g) was administered intravenously over 60 min beginning approximately 1 h prior to induction of anesthesia. A 2-to 3-g sample of cortical and cancellous bone was obtained from the femoral neck intraoperatively.Blood was collected for vancomycin assay 15 min after the end of the infusion and at the time of bone sampling.(ii) Group 2. Patients in group 2 had been receiving vancomycin for at least 48 h for treatment of sternal (four patients) or tibial (one patient) osteomyelitis. Doses were adjusted to achieve peak levels of 20 to 40 jig/ml of serum and trough levels of -12 ,ug/ml. Peak levels were obtained 15 min after the end of a 60-min infusion. Bone debrided intraoperatively was collected for analysis. On the day of bone sampling, blood was obtained simultaneously and at the nadir of the dosing interval. * Corresponding author. Specimen analysis. Se...

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The safety and pharmacokinetics of weekly dapsone and weekly dapsone plus pyrimethamine were examined in adult patients with human immunodeficiency virus infection who were at risk for pneumocystis pneumonia because of a prior episode or a CD4+ T-cell count less than 250 cells per mm3. Groups of patients received 100, 200, and 300 mg of dapsone as a single weekly dose. The Twenty-six patients each were followed for a median of 33 weeks on dapsone alone and 45 weeks on the combination. Seven patients in each group withdrew because of toxicity. Five patients receiving dapsone developed documented pneumocystis pneumonia, while four and two patients receiving dapsone plus pyrimethamine developed documented and presumptive pneumocystis pneumonia, respectively. To evaluate the tolerability of a higher dose of pyrimethamine, 11 patients had their regimen changed to dapsone at 200 mg plus pyrimethamine at 75 mg, which was well tolerated by 10 of the patients for a median period of 11 weeks. The pharmacokinetics of dapsone and pyrimethamine were examined by using a population pharmacokinetic model. Decreases in the apparent volume of the peripheral compartment were observed when multiple-dose regimens of dapsone were compared with single-dose dapsone and when multiple-dose regimens of dapsone with pyrimethamine were compared with multiple-dose dapsone alone. When administered weekly, dapsone at 200 mg and dapsone at 200 mg with pyrimethamine at 25 mg are both well-tolerated regimens. This preliminary study suggests that the efficacy of these regimens in preventing pneumocystis pneumonia, however, may be less than that of trimethoprim-sulfamethoxazole.There is a need for the development of inexpensive, oral, systemic agents for antipneumocystis prophylaxis for those patients with human immunodeficiency virus (HIV) infection who cannot tolerate trimethoprim-sulfamethoxazole. This need is especially pressing for those who have had a pulmonary or extrapulmonary breakthrough episode of Pneumocystis carinii disease despite the use of aerosolized pentamidine.Dapsone has many features to recommend its use as a prophylactic agent: a long half-life, oral bioavailability, excellent activity against P. carinii in vitro and in animal models, possible better tolerability than sulfonamides, and a wholesale cost of less than $0.20/100-mg tablet. In the corticosteroidtreated rat model of pneumocystis pneumonia, dapsone was effective prophylaxis when administered as infrequently as once monthly (16). Dapsone has been used in humans for antipneumocystis prophylaxis in daily doses of 50 to 100 mg and intermittent doses of 100 to 300 mg (5, 6, 9, 10, 13, 17, 18, 20-22, 26, 28 every 2 weeks via a Pulmosonic nebulizer and one comparing dapsone at 50 mg daily plus pyrimethamine at 50 mg weekly plus folinic acid at 25 mg weekly with aerosolized pentamidine at 300 mg monthly by a Respirgard II nebulizer, have recently been reported (13, 28). In both, dapsone was well tolerated and demonstrated efficacy similar to that of aerosolized pentamidin...

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