David Ashkin

Impact of tobacco use on the development of opportunistic respiratory infections in HIV seropositive patients on antiretroviral therapy

The increased risk of developing lung diseases in cigarette smokers has been well recognized. The association between smoking and the risk of developing pulmonary infections in HIV‐1‐infected patients, however, which has not been established, was evaluated in the present study. Twenty‐seven cases with lower respiratory infections (15 Pneumocystis carinii pneumonia (PCP), 12 TB cases) were compared with 27 age, gender, socio‐economic and HIV status‐matched patients, without history of respiratory diseases. Medical history and physical examinations were obtained every 6 months. Blood was drawn for CD4 and viral load measurements. A substantial number of HIV+ smokers who developed PCP (one‐third) had been on highly active retroviral therapy (HAART) for more than 6 months and prophylaxis had been discontinued. Multivariate analyses indicated that in HIV‐infected people, after controlling for HIV status and antiretrovirals, cigarette smoking doubled the risk for developing PCP (p =0.01). Multivariate analyses demonstrated that long‐term smoking also increased the risk (2×) of developing tuberculosis (p =0.04). Moreover, daily tobacco use seemed to attenuate by 40% the immune and virological response to antiretroviral therapies. These findings indicate that tobacco use significantly increases the risk of pulmonary diseases in HIV infected subjects and has a potential deleterious impact on antiretroviral treatment.

Pharmacokinetic Evaluation of Rifabutin in Combination with Lopinavir-Ritonavir in Patients with HIV Infection and Active Tuberculosis

BACKGROUND Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir. METHODS We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir-ritonavir. Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed. RESULTS Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (C(max)) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low C(max) values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) C(max) values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance. CONCLUSION The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.

Use of Rifabutin with Protease Inhibitors for Human Immunodeficiency Virus-Infected Patients with Tuberculosis

Drug interactions between rifamycins and highly active antiretroviral therapy (HAART) have raised concerns in the treatment of human immunodeficiency virus (HIV)-infected patients with tuberculosis. We conducted a study of this interaction by measuring serum drug levels of all HIV-infected patients with tuberculosis who were admitted to A. G. Holley State Tuberculosis Hospital (Florida) from October 1997 through December 1998, who were concomitantly treated with rifabutin and HAART. All 25 patients studied became culture-negative within 2 months of initiation of therapy for tuberculosis and remained negative for a median of 13 months follow-up after completion of therapy. HIV viral loads (mean+/-SEM) decreased significantly from 4.95+/-0.21 log10 copies/mL before initiation of HAART to 2.77+/-0.07 log10 copies/mL before discharge (P<.001); 20 of 25 patients achieved viral loads of <500copies/mL. In summary, the concomitant use of rifabutin and HAART can lead to successful treatment of HIV-infected patients with tuberculosis without increased side effects.

Population Pharmacokinetic Modeling of Pyrazinamide in Children and Adults with Tuberculosis

Study Objective. To determine population pharmacokinetic parameters of pyrazinamide after multiple oral doses given to children and adults with tuberculosis.

Tuberculosis Recurrence: Multivariate Analysis of Serum Levels of Tuberculosis Drugs, Human Immunodeficiency Virus Status, and Other Risk Factors

We examined risk factors for tuberculosis recurrence in patients admitted to a tuberculosis hospital in Florida in 1996 and 1997. Recurrence of tuberculosis was not significantly associated with tuberculosis drug levels or HIV status, which indicates that routine drug monitoring may not be beneficial in general patient management.

Feasibility of Shortening Respiratory Isolation with a Single Sputum Nucleic Acid Amplification Test

RATIONALE Serial smear analysis to guide respiratory isolation (RI) of patients with suspected tuberculosis (TB), the majority of whom will be found not to have TB, leads to expensive and unnecessary isolation, and may potentially result in decreased vigilance of subjects with respiratory compromise. OBJECTIVES To compare the performance of a single first-sputum, Mycobacterium tuberculosis-specific nucleic acid amplification (NAA) test with three sputum smears for assessing the need for RI. METHODS Prospective evaluation of 493 patients with suspected TB (74% HIV positive) admitted to RI in a major county hospital in the United States, who had at least three sputum smears and material available from the first sample for additional NAA testing. MEASUREMENTS AND MAIN RESULTS Accuracy of the first sputum NAA result and serial smears for identifying patients with potentially infectious TB who truly require RI was determined. Forty-six patients (9.3%) had TB confirmed by culture. First-sputum NAA test detected all patients with TB who had a positive smear (n = 35), even when the first of the three specimens was smear negative. In addition, when compared with serial smears, the first-sputum NAA had a higher sensitivity (0.87; 95% confidence interval [CI], 0.74-0.95) and specificity (1.0) in the detection of subjects with positive M. tuberculosis cultures (smear sensitivity, 0.76; 95% CI, 0.61-0.87; and specificity, 0.96; 95% CI, 0.94-0.98). CONCLUSIONS A single first-sputum NAA testing can rapidly and accurately identify the subset of patients with suspected TB who require RI according to serial sputum smears. Its potential use to shorten RI time does not preclude the need to obtain subsequent specimens for culture.

Acute Lung Injury Outside of the ICU : Incidence in Respiratory Isolation on a General Ward

BACKGROUND Epidemiologic investigations of acute lung injury (ALI) and ARDS have focused on mechanically ventilated patients in ICUs, and have reported high mortality rates. We sought to determine the incidence and lethality of these syndromes in the respiratory isolation areas of general wards, a non-ICU setting that often serves patients with acute lung processes. METHODS We prospectively studied all patients who were admitted to respiratory isolation rooms on the general wards of a large tertiary care hospital over a 1-year period. Patients were classified as having ALI or ARDS if they met consensus definitions for the syndromes. Characteristics and outcomes were compared to those of other patients who had been admitted to a respiratory isolation room with infiltrating lung disease but lacking bilateral infiltrates, hypoxemia, or both. RESULTS Of 715 patients admitted to respiratory isolation rooms on general wards, 474 (66%) had acute infiltrates. ALI criteria were met by 9% of patients (62 of 715 patients), with 2% of patients (15 of 715) satisfying the criteria for ARDS. Respiratory distress was present in 71% of ALI patients (44 of 62 patients) and 32% of patients (130 of 412 patients) with acute infiltrates who did not have ALI (p < 0.001). However, the 90-day survival rates (ALI patients, 88%; patients with acute infiltrates who did not have ALI, 90%) was similar between the two groups (p > 0.50). CONCLUSIONS ALI and ARDS may be frequent among patients who are admitted to respiratory isolation beds outside of ICUs. Mortality rates are substantially lower than those typically reported from surveys of ventilated ICU patients with ALI and ARDS.

Ofloxacin population pharmacokinetics in patients with tuberculosis.

SETTING Two tuberculosis hospitals in the United States. OBJECTIVE To determine the population pharmacokinetic (PK) parameters of ofloxacin following multiple oral doses. DESIGN A total of 73 patients with tuberculosis (TB) participated in the study. Subjects received multiple doses of ofloxacin as part of their treatment. They also received concurrent medications based on in vitro susceptibility data. Serum samples were collected over 10 h and assayed by a validated high performance liquid chromatography (HPLC) assay. Concentration-time data were analyzed using population methods. RESULTS Ofloxacin concentrations increased linearly with increasing oral doses. Delayed absorption was seen at least once in 29% of patients. Ofloxacin elimination decreased with declining renal function and increasing age. Higher daily doses were well tolerated, and appeared to maximize the peak concentration to minimal inhibitory concentration ratio (Cmax:MIC). CONCLUSION Ofloxacin PK parameters were comparable to those previously published for other patient populations. Higher daily doses may offer pharmacodynamic advantages for the treatment of TB.

Outcomes and Use of Therapeutic Drug Monitoring in Multidrug-Resistant Tuberculosis Patients Treated in Virginia, 2009-2014

Background Reports of therapeutic drug monitoring (TDM) for second-line medications to treat multidrug-resistant tuberculosis (MDR-TB) remain limited. Methods A retrospective cohort from the Virginia state tuberculosis (TB) registry, 2009-2014, was analyzed for TDM usage in MDR-TB. Drug concentrations, measured at time of estimated peak (Cmax), were compared to expected ranges. Results Of 10 patients with MDR-TB, 8 (80%) had TDM for at least one drug (maximum 6 drugs). Second-line drugs tested were cycloserine in seven patients (mean C2hr, 16.6±10.2 µg/mL; 4 [57%] below expected range); moxifloxacin in five (mean C2hr, 3.2±1.5 µg/mL; 1 [20%] below); capreomycin in five (mean C2hr, 21.5±14.0 µg/mL; 3 [60%] below); para-aminosalicylic acid in five (mean C6hr, 65.0±29.1 µg/mL; all within or above); linezolid in three (mean C2hr, 11.4±4.1 µg/mL, 1 [33%] below); amikacin in two (mean C2hr, 35.3±3.7 µg/mL; 1 [50%] below); ethionamide in one (C2hr, 1.49 µg/mL, within expected). Two patients died: a 38-year-old woman with human immunodeficiency virus/acquired immune deficiency syndrome and TB meningitis without TDM, and a 76-year-old man with fluoroquinolone-resistant (pre-extensively drug-resistant) pulmonary TB and low linezolid and capreomycin concentrations. Conclusion Individual pharmacokinetic variability was common. A more standardized approach to TDM for MDR-TB may limit over-testing and maximize therapeutic gain.

Diagnosis of Latent Tuberculosis Infection in HIV-infected Pregnant Women. “Baby Steps” toward Better Tuberculosis Control in Pregnancy

Despite significant reductions in incidence, the global burden of tuberculosis (TB) is immense. In 2014, there were an estimated 9.6 million new cases, accounting for 1.1 million deaths, with an estimated 1.2 million (12.5%) of these new cases being in patients infected with HIV. Although TB is more common among men, globally TB is a leading cause of death among women of childbearing age. The higher risk for TB during pregnancy, as well as adverse outcomes for mother and child, have been previously recognized (2–5) and are potentially related to the physiological partial inhibition of the cellular immune system necessary to tolerate the fetus.