Mycobacterium xenopi: innocent bystander or emerging pathogen?

Mycobacterium xenopi is a recognized cause of smoldering pulmonary disease in patients with chronic lung disease. This organism is frequently isolated from respiratory specimens from individuals infected with human immunodeficiency virus (HIV) and is often considered nonpathogenic. Cases of pulmonary and disseminated M. xenopi disease have been described in patients with HIV infection and other immunodeficiencies. Many physicians are unaware of the clinical significance of M. xenopi isolation. Whether this organism represents a commensal or a pathogen capable of causing considerable morbidity and mortality is not fully understood. In this study, we investigated the clinical significance of M. xenopi isolation and explored the clinical spectrum of M. xenopi disease. Clinical illness occurred both in elderly people with chronic lung disease and in young individuals with HIV infection. The repeated isolation of M. xenopi in association with pulmonary lesions suggests significant infection and mandates further workup and therapy.

Evidence for genetic regulation of susceptibility to toxoplasmic encephalitis in AIDS patients.

The frequency of HLA-DQ antigens in AIDS patients with toxoplasmic encephalitis (TE) were examined. HLA-DQ3 was significantly more frequent in white North American AIDS patients with TE (85.0%) than in the general white population (51.8%; P = .007, corrected P = .028) or randomly selected control AIDS patients who had not developed TE (40.0%; P = .016). In contrast, the frequency of HLA-DQ1 was lower in TE patients than in healthy controls (40.0% vs. 66.5%, P = .027), but this difference did not reach statistical significance when corrected for the number of variables tested (corrected P = .108 for the general white population). HLA-DQ3 thus appears to be a genetic marker of susceptibility to development of TE in AIDS patients, and DQ1 may be a resistance marker. These HLA associations with disease indicate that development of TE in AIDS patients is affected by a gene or genes in the HLA complex and that HLA-DQ typing may help in decisions regarding TE prophylaxis.

Mycobacterium xenopi infection masquerading as pulmonary tuberculosis in two patients infected with the human immunodeficiency virus.

Mycobacterium xenopi infections have rarely been reported among patients infected with the human immunodeficiency virus (HIV). We recently treated two HIV-infected men, neither of whom had a history of pulmonary disease or AIDS-defining conditions, and who had M. xenopi lung infections. Both patients presented with night sweats, cough, and pleuritic chest pain. Chest radiographs showed an upper-lobe nodule in the first patient and a perihilar cavitary infiltrate in the second patient. Both patients were initially believed to have pulmonary tuberculosis and were treated accordingly; however, only M. xenopi grew on cultures of multiple respiratory specimens. This diagnosis was confirmed by cultures of biopsied lung tissue from the first patient and of fluid from a peritracheal abscess in the second patient. Both patients' clinical conditions improved after multidrug therapy (isoniazid, rifampin, pyrazinamide, ethambutol, and ciprofloxacin in the first case; isoniazid, rifampin, and pyrazinamide in the second case). The second patient's condition improved despite in vitro resistance of his isolate to isoniazid and rifampin.

Prolonged, but not diminished, zidovudine absorption induced by a high-fat breakfast.

STUDY OBJECTIVE: To determine the effect of a high-fat breakfast on single-dose, zidovudine (ZDV) pharmacokinetics. DESIGN: Open-label, randomized, crossover study. PATIENTS: Eighteen asymptomatic subjects (12 men, 6 women) infected with the human immunodeficiency virus (mean CD4 cell counts of 512 +/- 178/mm3). INTERVENTIONS: Subjects received single 100-mg oral doses of ZDV as follows: after an 8-hour fast (treatment A), with a high-fat breakfast (treatment B), and 3 hours after a high-fat breakfast (treatment C). MEASUREMENTS AND MAIN RESULTS: The high-fat breakfast significantly reduced the mean (coefficient of variation) maximum plasma concentration (Cmax) from 806 (55%) ng/ml with treatment A to 341 (47%) and 424 (42%) ng/ml with treatments B and C, respectively. The time to Cmax was significantly prolonged from 0.68 (30%) hours with treatment A to 1.7 (54%) and 1.3 (42%) hours with treatments B and C, respectively. Area under the plasma ZDV concentration-time curve (AUC) was not statistically different across the study treatments. Men had significantly lower (35%) renal clearances of both ZDV and its glucuronide metabolite than women. CONCLUSIONS: When ZDV was given either with or 3 hours after a high-fat breakfast, its absorption was prolonged and Cmax was reduced relative to fasting. However, systemic exposure, as indicated by AUC, was unchanged.

Intravenous and oral zidovudine pharmacokinetics and coagulation effects in asymptomatic human immunodeficiency virus-infected hemophilia patients.

Pharmacokinetic and coagulation studies were carried out over a 12-week period with 11 asymptomatic hemophilia patients with human immunodeficiency virus infection receiving zidovudine (ZDV). The patients received 300 mg every 4 h while awake (the accepted dose at the time of this study); consecutive 24-h intravenous (i.v.) and 12-h oral pharmacokinetic studies were conducted at weeks 1, 6, and 12. Coagulation studies were conducted at weeks 0, 4, 8, and 12. The numbers of units of factors VIII and IX and cryoprecipitate transfused during the 12-week periods before, during, and after ZDV treatment were recorded. Following i.v. and oral ZDV administration, the concentration in plasma declined rapidly over the first 4 h, and in some patients, ZDV was still detectable at 4 to 10 h. The i.v. total clearances (means +/- standard deviations) were 14.9 +/- 7.3, 11.2 +/- 3.7, and 15.1 +/- 4.7 ml/min/kg of body weight. The i.v. distribution volumes were 1.08 +/- 0.5, 1.0 +/- 0.4, and 1.65 +/- 1.4 liters/kg. The bioavailabilities were 0.54 +/- 0.22, 0.46 +/- 0.19, and 0.59 +/- 0.13 at weeks 1, 6, and 12, respectively. The pattern of ZDV-glucuronide (GZDV) disposition was similar to that of ZDV, and the peak plasma GZDV-to-ZDV ratio was higher after oral dosing, consistent with first-pass metabolism. In some individuals, up to 33% of an i.v. dose was excreted unchanged. At weeks 6 and 12, greater than 300 mg of total ZDV (GZDV plus ZDV) was recovered in the urine of some patients, suggesting tissue redistribution. Concentration in plasma after oral ZDV administration were variable, both within and between patients. The von Willebrand antigen level consistently decreased throughout the study but was not accompanied by a parallel change in ristocetin cofactor A activity, and no clinical adverse effects on coagulation were noted. This study demonstrates that ZDV can be used in hemophilia patients without worsening of their bleeding tendencies. The clinical significance of decreased ZDV clearance and the prolonged terminal elimination phase of ZDV will require further study with patients receiving chronic ZDV.

Multiple-dose pharmacokinetics of oral zidovudine in hemophilia patients with human immunodeficiency virus infection.

The disposition of zidovudine (ZDV) was examined during chronic oral dosing (300 mg every 4 h while awake) for 12 weeks in eight asymptomatic patients with hemophilia who were infected with the human immunodeficiency virus. Pharmacokinetic studies were conducted at the initiation of drug administration and after 6 and 12 weeks. Baseline liver function tests indicated normal values for bilirubin, albumin, and prothrombin time, while hepatic enzyme levels ranged from one to three times the normal levels. Initially, the mean peak ZDV concentration in plasma was 2,052 ng/ml with a range of 1,033 to 3,907 ng/ml, while during chronic dosing the peaks were 1,619 +/- 1,062 ng/ml and 1,711 +/- 786 ng/ml at weeks 6 and 12, respectively. ZDV concentrations at 4 h declined to 77 +/- 53 ng/ml, 110 +/- 43 ng/ml, and 101 +/- 49 ng/ml at weeks 1, 6, and 12, respectively. Initially, the plasma concentration-versus-time decay in three patients was linear, with a mean half-life (t1/2) of 1.3 +/- 0.5 h, while five patients had detectable concentrations in plasma after 4 h with an apparent delayed terminal-phase t1/2 of 4.8 +/- 2.8 h. At week 6 the prolonged elimination pattern was noted in all patients (terminal t1/2 = 4.1 +/- 2.0 h). No correlation between hepatic enzyme levels and t1/2 was noted. These findings suggest that ZDV may display a prolonged elimination phase during multiple dosing. Further studies utilizing a more sensitive assay may help to further define this later phase of ZDV elimination.

Pharmacokinetics of orally administered zidovudine among patients with hemophilia and asymptomatic human immunodeficiency virus (HIV) infection.

Zidovudine (formerly azidothymidine, AZT) is used to treat certain patients infected with the human immunodeficiency virus (HIV). However, the clinical use of zidovudine (ZDV) in hemophilia patients may be complicated by the high incidence of chronic hepatitis in this patient population. To examine the pharmacokinetics of ZDV eight asymptomatic HIV-infected hemophilia patients received a single oral dose (300 mg). ZDV and its glucuronide metabolite (GZDV) were measured in serum by HPLC. ZDV was rapidly absorbed with a wide range of peak serum concentrations (2052 +/- 970 ng/ml) at 0.5 h. Peak GZDV serum concentrations were 4751 +/- 2269 ng/ml at 1 h. Both ZDV and GZDV declined in a biexponential manner over 4 h. After 4 h, the ZDV serum concentration decay in three patients continued a log-linear decline, while five patients demonstrated a tri-exponential curve which had a mean terminal elimination half-life of 4.8 +/- 2.8 h. No relationship between ZDV or GZDV kinetics and the degree of hepatic enzyme elevation was observed. Although a therapeutic window for ZDV has yet to be described, the wide range of serum concentrations that result from a standard dose suggests that clinical monitoring of ZDV levels may be of value in certain patients. In addition, the prolonged elimination half-life of ZDV in the present study may provide a rationale for less frequent dosing in certain patients.