This report, which has been updated to include data published or presented at conferences up to the end of August 2001, summarizes the data presented and issues discussed at the meeting. This article will guide the reader through the data and discussions that have allowed the panel to formulate a series of position statements regarding the current status and future applications of TDM in antiretroviral therapy. These statements have been formulated to provide suggestions for the design of future TDM clinical trials, as well as to provide useful points of reflection for centres in which TDM is already in use.

The pharmacokinetics of ertapenem and ceftriaxone were investigated in an open, randomized, two-period crossover study after single-and multiple-dose administration in 10 healthy volunteers (five women and five men). Both antibiotics were administered intravenously once daily for 7 days at dosages of 1 g (ertapenem) and 2 g (ceftriaxone). The concentrations of the antibiotics in serum and urine were quantified by the agar well diffusion method bioassay and, in addition, for ertapenem only, by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). For ertapenem the maximum concentration of the drug in plasma (C max ) was 256 mg/liter, the half-life was 20.7 h, and the area under the plasma concentration-time curve (AUC) was 830 mg ⅐ h/ liter. The concentrations in fecal samples were (mean value) 37.2 and 32.7 mg/kg on day 4 and day 8, respectively. Ceftriaxone exhibited a mean C max of 315 mg/liter, a half-life of 7.6 h, and an AUC of 1,556 mg ⅐ h/liter. The mean concentrations in fecal samples were 153 and 258 mg/kg on day 4 and day 8, respectively. No accumulation of ertapenem or ceftriaxone was detected at steady state. A slightly but significantly decreased AUC for ertapenem was detected for the female volunteers. No serious adverse event was observed. Both antibiotics induced a marked decrease in the anaerobic microflora (4-log-unit decreases in lactobacilli, bifidobacteria, clostridia, and bacteroides) and Escherichia coli, whereas the number of enterococci increased (4 log units). A slight overgrowth of yeasts was observed with both regimens. In all cases the microflora returned to normal levels on days 21 to 35.Ertapenem, recently described as the first class 1 carbapenem (11), is a parenteral broad-spectrum beta-1-methyl-carbapenem with a long half-life in serum. It has been shown to be effective for the treatment of community-acquired pneumonia (9); intra-abdominal infections, skin and skin structure infections, and acute pelvic infections (14); and urinary tract infections (15). In contrast to imipenem and meropenem, ertapenem lacks sufficient activity against Pseudomonas aeruginosa, enterococci, and Acinetobacter spp.; but clinical trials have shown that Pseudomonas infections can be treated with ertapenem.Ertapenem can be administered once daily due to its long half-life in plasma. The long half-life in plasma reflects its high level of plasma protein binding.Ceftriaxone matches ertapenem in both its pharmacokinetics and its antibacterial spectrum for the treatment of community-acquired pneumonia and has been used as a comparator drug for ertapenem in clinical trials (9, 17). Ceftriaxone is a broad-spectrum parenteral cephalosporin with a long half-life that also requires administration only once daily.The application of antibacterial agents for the treatment of infections may have a number of potentially adverse effects on the normal oropharyngeal and intestinal microflora. The normal microflora acts as a barrier against colonization by potentially pathogenic microorganisms and agai...

Acute therapy with pyrimethamine plus sulfadiazine is the treatment of choice for reactivated toxoplasmic encephalitis (TE). Acute therapy is followed by lifelong maintenance therapy (secondary prophylaxis) with the same drugs at lower dosages. The use of pyrimethamine plus sulfadiazine is hampered by severe side effects including allergic reactions and hematotoxicity. Alternative treatment regimens with pyrimethamine plus clindamycin or other antiparasitic drugs are less efficacious. Atovaquone nanosuspensions show excellent therapeutic effects for "acute" intravenous (i.v.) treatment of reactivated TE in a murine model. In the present study, the therapeutic efficacy of atovaquone for oral "maintenance" therapy was investigated. Mice with a targeted mutation in the interferon regulatory factor 8 gene were latently infected with Toxoplasma gondii, developed reactivated TE, and received acute i.v. therapy with atovaquone nanosuspensions. Mice were then treated orally with atovaquone suspension or other antiparasitic drugs to prevent relapse of TE. Maintenance therapy with atovaquone at daily doses of 50 or 100 mg/kg (body weight) protected mice against reactivated TE and death. This maintenance treatment was superior to standard therapy with pyrimethamine plus sulfadiazine. The latter combination was superior to the combination of pyrimethamine plus clindamycin. Inflammatory changes in the brain parenchyma and meninges, as well as parasite numbers, in the brains of mice confirmed the therapeutic efficacy of atovaquone for maintenance therapy. Atovaquone was detectable in sera, brains, livers, and lungs of infected mice by high-performance liquid chromatography and/or mass spectrometry. In conclusion, atovaquone appears to be superior to the standard maintenance therapy regimens in a murine model of reactivated TE. The therapeutic efficacy of atovaquone for maintenance therapy against TE should be further investigated in clinical trials.Toxoplasma gondii is an intracellular protozoan parasite of humans and animals with worldwide distribution. Seroprevalence varies with geographical location and reaches 70% in Germany and France (7, 21). After initial uptake of the parasite in the gut and dissemination throughout the body, the latent stage of infection is characterized by the presence of parasites in cysts in the central nervous system and muscle tissues (21). Immunocompromised hosts, i.e., patients with AIDS or organ transplant recipients, are at risk of reactivation of the infection by rupture of cysts (21). Toxoplasmic encephalitis (TE) is the most common clinical manifestation of reactivated disease in AIDS patients who do not receive highly active antiretroviral therapy (HAART) or antiparasitic prophylaxis. TE is the most frequent infectious cause of focal intracerebral lesions in these patients (20)(21)(22). Untreated, reactivation of disease leads to death of the patient. The acute therapy (pyrimethamine plus sulfadiazine) of TE is followed by lifelong maintenance therapy (19,21). The standard regimen for ma...

Objectives: To obtain data on the pharmacokinetics of efavirenz in children in clinical practice.Methods: HIV-1-infected children received efavirenz capsules or tablets in accordance with manufacturer's dosing recommendations. Plasma was collected at regular visits and analysed by HPLC. The therapeutic range of efavirenz was defined as 1.0-4.0 mg/L.Results: Thirty-three children were included. Median (range) age, body weight, dose and dose/kg were 8.2 (2.1 -16.7) years, 24 (12 -62) kg, 300 (200-800) mg and 13.3 (9.7 -22.5) mg/kg, respectively. Median (range) efavirenz plasma concentration at first sampling was 2.8 (0.13-11.6) mg/L. Plasma concentrations were not dependent on age (P 5 0.97) or dose/kg (P 5 0.87). A total of 307 efavirenz plasma concentrations were determined. Forty-five samples (14.7%) contained >4.0 mg/L, and 27 samples (8.8%) contained <1.0 mg/L. Eight children (24%) reported persistent adverse events probably caused by efavirenz [concentration problems (5), sleep disorder (1), psychotic reaction (1) and seizure (1)]; six discontinued efavirenz for this reason. A non-significant trend existed towards a higher proportion of toxic efavirenz plasma concentrations (>4.0 mg/L) in subjects who reported efavirenz adverse events: 25.9% versus 12.8% (P 5 0.23; t-test). Viral load was <50 copies/mL in all 27 subjects who continued efavirenz, despite occasional subtherapeutic efavirenz plasma concentrations in 12 children. The occasional subtherapeutic levels suggest that temporal non-adherence was present.Conclusions: Efavirenz as part of highly active antiretroviral therapy was highly effective in children able to tolerate the drug. Therapeutic drug monitoring (TDM) as part of toxicity management may prevent discontinuation in a subset of patients. Temporal non-adherence occurs frequently. TDM may allow initiation of adherence interventions before viral load becomes detectable.

The addition of atazanavir to saquinavir/ritonavir increased saquinavir Ctrough, Cmax and AUC0-24 by 112, 42 and 60%. Ritonavir Cmax and AUCo-24 increased by 34 and 41%. The regimen was well tolerated, with no significant change in laboratory parameters, except for the occurrence of hyperbilirubinemia.