Charles R. Horsburgh

High Incidence of Hospital Admissions with Multidrug Resistant and Extensively Drug Resistant Tuberculosis among South African Health Care Workers

BACKGROUND Nosocomial transmission has been described in extensively drug-resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden. OBJECTIVE To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among health care workers in KwaZulu-Natal, South Africa. DESIGN Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy. SETTING A public tuberculosis referral hospital in KwaZulu-Natal, South Africa. PARTICIPANTS 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment. MEASUREMENTS Hospital admission rates and hospital admission incidence rate ratios. RESULTS Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001). LIMITATION The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis. CONCLUSION Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection-control programs.

Long-Term Therapy of Chronic Mucocutaneous Candidiasis with Ketoconazole: Experience with Twenty-One Patients

Our experience in the treatment of chronic mucocutaneous candidiasis with ketoconazole is reviewed. Of 21 patients, 15 have evidence of deficient cellular immunity and eight have endocrine abnormalities. Six patients had concurrent dermatophytosis or chromomycosis. All patients responded to treatment. Mucosal lesions improved in 6.7 +/- 0.5 days and cutaneous lesions responded to 22.7 +/- 5.1 days. The responses by infected nails were more variable (mean response time 92.4 +/- 14.4 days). Concurrent dermatophytoses did not prolong response times. Adverse effects were infrequent: one patient had drug-induced hepatitis and two patients became hypertensive. The relationship of hypertension to ketoconazole treatment is unclear. One patient was able to remain in remission after treatment was discontinued. Two patients had relapses while on treatment. Candida albicans isolated from these patients was highly resistant to ketoconazole in vitro. We conclude that ketoconazole is an effective and well-tolerated drug for the treatment of the infectious component of chronic mucocutaneous candidiasis.

Acquired Immunodeficiency Syndrome in a Patient with Hemophilia

A patient with hemophilia A developed T-cell deficiency characterized by infection with several opportunistic pathogens. Immunologic investigation showed cutaneous anergy, lymphocyte unresponsiveness to mitogens and antigens, an abnormal ratio of T-helper and T-suppressor cells with absolute lymphopenia and elevated IgA. The clinical and immunologic characteristics of this patient fit the recently described syndrome of opportunistic infections or Kaposis sarcoma in patients with acquired T-cell deficiency; however, this patient does not have any of the associated underlying risk factors such as homosexuality, intravenous drug or amyl nitrite use, or positive serologic tests for syphilis. We conclude that the patients acquired T-cell deficiency can be explained by exposure to a virus or other transmissible agent during factor VIII transfusions.

Adherence in the treatment of patients with extensively drug-resistant tuberculosis and HIV in South Africa: a prospective cohort study.

Objective:Extensively drug-resistant tuberculosis (XDR-TB)/HIV coinfection is difficult to treat with frequent adverse drug reactions and associated with high mortality. Adherence to antiretroviral therapy (ARV) and second-line TB medications may reduce mortality, prevent amplification of drug resistance, and improve outcomes. Methods:Prospective cohort study of XDR-TB patients on treatment in KwaZulu-Natal, South Africa. Adherence to ARV and TB medications was assessed separately at baseline and monthly. Knowledge, attitudes, and beliefs were assessed at baseline. Optimal adherence was defined as self-report of taking all pills in the previous 7 days; missing any pills was defined as suboptimal adherence. Primary outcome was optimal adherence 6 months after initiation of XDR-TB treatment to TB medications, ARV, and both (“dual adherence”). Results:One hundred four XDR-TB patients (79.8% HIV coinfected, 84.3% on ARV at enrollment) were enrolled and followed monthly (median 8 visits; interquartile range: 4–12). Six-month optimal adherence was higher for ARV (88.2%) than TB medications (67.7%) (P < 0.001). Low educational attainment, male gender, and year of enrollment were independently associated with dual suboptimal adherence. At baseline, participants indicated that XDR-TB was curable (76.0%), HIV and TB were linked (81.7%), and ARV improves TB outcomes (72.1%). Baseline knowledge, attitudes, and beliefs did not predict subsequent adherence. Conclusions:Medication adherence was significantly higher for ARV than for TB medications in this cohort. Short-course treatment regimens for drug-resistant TB with lower pill burden may increase adherence and improve outcomes in XDR-TB/HIV. Programmatic support for dual adherence is critical in the treatment of drug-resistant TB and HIV.

Lymphokines and Platelets Promote Human Monocyte Adherence to Fibrinogen and Fibronectin In Vitro

Monocytes must accumulate in areas of tissue injury and inflammation to effect phagocytosis, antigen presentation, and monokine production. Fibrinogen/fibronectin matrices have been demonstrated in healing wounds and in delayed‐type hypersensitivity skin reactions. We have developed an in vitro system for investigation of the ability of fibrinogen and fibronectin matrices to serve as substrata for human peripheral blood monocyte adherence. Monocyte adherence was greatest on matrices of both fibrinogen and fibronectin, less to fibrinogen alone, and least to fibronectin alone. Lymphokines increased adherence of monocytes to all three surfaces but not to albumin‐coated surfaces.

The Acquired Immunodeficiency Syndrome and a Trimethoprim-Sulfamethoxazole Adverse Reaction

Excerpt To the editor: A 31-year-old homosexual man was admitted to Denver General Hospital withPneumocystis cariniipneumonia. The patients T-cell helper-to-suppressor ratio was 0.19 (normal, grea...

Fibronectin deposition in delayed-type hypersensitivity. Reactions of normals and a patient with afibrinogenemia.

During development of delayed hypersensitivity (DH) skin reactions, fibronectin accumulates in two distinct sites: (a) the dermal interstitium in a pattern similar to fibrin and with a time course similar to that of fibrin deposition and mononuclear cell infiltration, and (b) blood vessel walls in a pattern suggestive of basement membrane staining and with a time course similar to that of endothelial cell proliferation. In vitro fibronectin can bind to monocytes or endothelial cells and simultaneously bind to fibrin or collagen matrices; by such interaction in vivo it may affect cell migration or proliferation. Thus, fibronectin deposition in DH reactions may facilitate cell-matrix interactions; however, the possibility exists that extravascular fibronectin accumulation may be only secondary to interstitial fibrin clot formation, and that blood vessel-associated fibronectin may be only a function of adsorption onto basement membrane (type IV) collagen. To address these possibilities, we investigated the association of fibronectin with fibrin, type IV collagen, and mononuclear cell infiltrates in DH reactions. Skin sites of DH reactions in normal volunteers were biopsied at 24, 48, and 72 h after intradermal challenge and examined by immunofluorescence technique. At all time points most of the interstitial fibronectin coincided with fibrin; however, some interstitial fibronectin was coincident with mononuclear cells positive for HLA-DR or monocyte-specific antigen. The coincidence of fibronectin with mononuclear cells was more apparent in a 48-h DH reaction from a patient with congenital afibrinogenemia. Vessel wall fibronectin was increased by 48 h after challenge and appeared as a fine linear band on the luminal side of a much thicker band of type IV collagen. Thus, the coincidence of extravascular fibronectin with mononuclear cells, its appearance without fibrin in the site from a patient with afibrinogenemia, and incomplete correspondence of vessel wall fibronectin with type IV collagen suggest that fibronectin localization in DH reactions involves endothelial cell and mononuclear cell binding as well as adsorption to fibrin and/or type IV collagen.

Mycobacterium avium Complex and the Acquired Immunodeficiency Syndrome

Excerpt To the editor: Hawkins and colleagues (1) have made an important contribution in their article on infections withMycobacterium aviumcomplex in the acquired immunodeficiency syndrome (AIDS)....

Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

Background:Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug-susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed patients with XDR-TB in KwaZulu-Natal, South Africa. Methods:Retrospective cohort study of consecutive patients with XDR-TB admitted to a TB referral hospital without previous XDR-TB treatment. A subset of isolates had extended DST (including capreomycin), mutational analysis, and IS6110 restriction fragment length polymorphism assays. Results:A total of 216 eligible patients with XDR-TB were identified. The majority were treated with capreomycin (72%), were young (median age: 35.5 years), and were female (56%). One hundred five (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. A total of 47/52 (90.4%) patients with XDR-TB were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible, although this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin-resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%). Conclusions:Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly because of ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all patients with XDR-TB. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.

Acceptance of interferon-gamma release assay by a high-risk urban cohort.

BACKGROUND QuantiFERON ® -TB Gold (QFT-G), an interferon-gamma release assay, is approved for the diagnosis of latent tuberculosis infection (LTBI). It is unknown if patients at high risk for LTBI will more readily accept LTBI treatment based on tuberculosis skin testing (TST) or QFT-G. METHODS Prospectively enrolled participants were interviewed, were read an informational paragraph on QFT-G, completed a questionnaire and were tested with QFT-G. RESULTS A total of 230 consecutive participants with a history of hepatitis C virus infection and active or past illicit drug use were enrolled and underwent QFT-G testing: 77% had recent TST, 82% were human immuno- deficiency virus co-infected, 87% had a history of injection drug use, and 52% a history of homelessness. Of the 230 participants, 148 (64%) stated a preference for TST compared to QFT-G. The majority would take treatment based on either test (68%). A minority of patients (20%) stated a willingness to take LTBI treatment based on TST alone. Black race was associated with a willingness to take treatment based on TST (OR 2.72, 95%CI 1.05-7.10). CONCLUSIONS Patients at high risk for LTBI were found to prefer TST to QFT-G. Most would accept treatment based on either test, and a subset stated unwillingness to take treatment based on QFT-G results. Outreach and education should accompany QFT-G roll-out in high-risk urban populations.