Brinkhof, Martin W. G.

Egger, Matthias

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1482 • CID 2008:46 (1 May) • CORRESPONDENCE7. SedlacekM, Gemery JM, CheungAL, BayerAS,Remillard BD. Aspirin treatment is associatedwith a significantl decreased risk of Staphy-lococcus aureus bacteremia in hemodialysis pa-tients with tunneled catheters. Am J Kidney Dis2007; 49:401–8.Reprints or correspondence: Dr. Damon Eisen, Victorian In-fectious Diseases Service, Royal Melbourne Hospital, GrattanSt., Parkville, Victoria, Australia 3050 (damon.eisen@mh.org.au).Clinical Infectious Diseases 2008; 46:1481–2 2008 by the Infectious Diseases Society of America. Allrights reserved. 1058-4838/2008/4609-0030$15.00DOI: 10.1086/587181Determination of theIncidence of Tuberculosisin Low-Income CountriesTo the Editor—We read with interestthe report by The Antiretroviral Therapyin Low-Income Countries Collaborationof the International epidemiological Da-tabases to Evaluate AIDS (IeDEA) andTheART Cohort Collaboration on tubercu-losis (TB) after initiation of antiretroviraltherapy in low-income and high-incomecountries [1]. The authors do notmentionthe number of patients who were alreadyreceiving treatment for TB when the an-tiretroviral therapy was started (were thedata not available?). However, they domention that programs in lower-incomecountries routinely screened patients forTB before they commenced HAART. It isunclear to us whether patients being giventreatment for TB at the start of HAARTwere included in the analysis. We proposethat they should have been excluded fromthe study population if the aim of thestudy was to determine the incidence ofTB and to compare the incidence rate-ratios for new TB infections. Indeed, incontrast to in high-income countries, inlow-income countries, TB is one of themain reasons to initiate HAART. In Ma-lawi, for example, from July through Sep-tember 2005, 12% of the patients whostarted HAART did so because of TB [2].During treatment for TB, by definitionthese patients cannot develop a new TBinfection. We suppose that, if this ap-proach were taken, the conclusions of thereport would remain the same, but thecalulations may change slightly. If thenumber of patients not receiving treat-ment for TB who started HAART is usedas the denominator, the real incidence ofTB in low-income countries will be evenhigher, particularly soon after the initia-tion of HAART.AcknowledgmentsPotential conflict of interest. R.C. and S.C.:no conflictsRobert Colebunders1,2and Se´verine Caluwaerts11Institute of Tropical Medicine and 2University ofAntwerp, Antwerp, BelgiumReferences1. The Antiretroviral Therapy in Low-IncomeCountries Collaboration of the Internationalepidemiological Databases to Evaluate AIDS(IeDEA) and The ART Cohort Collaboration.Tuberculosis after initiation of antiretroviraltherapy in low-income and high-income coun-tries. Clin Infect Dis 2007; 45:1518–21.2. Makombe SD, Harries AD, Yu JK, et al. Out-comes of tuberculosis patients who start anti-retroviral therapy under routine programmeconditions in Malawi. Int J Tuberc Lung Dis2007; 11:412–6.Reprints or correspondence: Dr. Robert Colebunders, Instituteof Tropical Medicine, Nationalestraat 155, Antwerp, Belgium(bcoleb@itg.be).Clinical Infectious Diseases 2008; 46:1482 2008 by the Infectious Diseases Society of America. Allrights reserved. 1058-4838/2008/4609-0031$15.00DOI: 10.1086/587182Reply to Colebundersand CaluwaertsTo the Editor—We thank Colebundersand Caluwaerts [1] for their interest in therecent analysis by The AntiretroviralTher-apy in Low-Income Countries Collabo-ration of the International epidemiologicalDatabases to Evaluate AIDS (IeDEA) andThe ARTCohort Collaboration [2]. In thiscollaborative study, we compared the in-cidence rates of tuberculosis (TB) amongpatients receiving HAART in low-incomeand high-income countries. Colebundersand Caluwaerts ask whether the analysisincluded patients who were receivingtreatment for TB at the start of HAARTand argue that, if so, this might have bi-ased the incidence rates of TB downwardin lower-income countries andmight havedistorted the incidence-rate ratios duringthe firs year of HAART.As Caluwaerts and Colebunders [1]suspected, data on treatment for TB at thetime of initiation of HAART were notavailable for all the cohorts from low-in-come countries. But note that, as wepointed out in our report [2], the mainobjective of the analysis was not to esti-mate absolute rates but was to comparerelative changes in rates of TB during thefirs year of HAART in low-income andhigh-income settings. The incidence ratesobtained in such an analysis of data from15 different sites were a weighted averageof site-specifi rates, influence by varia-tion in background rates and diagnosticprocedures, and are not applicable to anyspecifi setting.We repeated analyses for 9 low-incomecohorts with data on previous treatmentfor TB, including 2050 patients who werenot receiving treatment whenHAARTwasstarted. Among these patients, the inci-dence of TB in the firs year of HAARTwas 8.8 cases per 100 person-years (95%CI, 7.5–10.3 cases per 100 person-years),which is slightly higher than the 7.4 casesper 100 person-years (95% CI, 6.6–8.4cases per 100 person-years) reported in thepreviously published analysis [2]. As pre-dicted by Caluwaerts and Colebunders[1], this difference was more pronouncedduring the firs 3 months of treatment:13.9 cases per 100 person-years (95% CI,11.0–17.6 cases per 100 person-years) inthis analysis, compared with 10.7 cases per100 person-years (95% CI, 8.9–12.9 casesper 100 person-years) in the original anal-ysis. The decrease in the incidence rateduring the firs year of HAART was, how-ever, similar for the 2 analyses. Comparedwith the rate for months 1–3, the rate ratiowas 0.65 (95% CI, 0.44–0.96) for months4–6 and was 0.39 (95% CI, 0.27–0.58) formonths 7–12. The corresponding ratiosfrom the original analysis were 0.70 (95%CI, 0.52–0.94) and 0.48 (95% CI, 0.36–0.64), respectively. Interestingly, the inci-CORRESPONDENCE • CID 2008:46 (1 May) • 1483Table 1. The association of vanco-mycin treatment group and OR ofmortality.TreatmentgroupORUnivariate MultivariableVMIC 1.0 1.0 1.0VMIC 1.5 1.9 (0.8–5) 2.9 (0.9–9.4)VMIC 2.0 2.6 (0.9–8) 6.4 (1.7–24.3)NA 2.3 (0.9–6) 3.6 (1.2–10.9)NOTE. Data are summarized from the arti-cle by Soriano et al. [1]. NA, receipt of inappro-priate empirical therapy; VMIC 1.0, receipt ofempirical vancomycin and an isolate with a van-comycin MIC of 1 mg/mL; VMIC 1.5, receipt ofempirical vancomycin and an isolate with a van-comycin MIC of 1.5 mg/mL; VMIC 2.0, receiptof empirical vancomycin and an isolate with avancomycin MIC of 2 mg/mL.dence-rate ratios from this analysis aresomewhat closer to those reported for thehigh-income cohorts in the original anal-ysis [2]. The sensitivity analysis promptedby the letter from Caluwaerts and Cole-bunders thus strengthens our conclusionsthat the reduction in rates of TB duringthe firs year of HAART is similar in low-income and high-income settings.AcknowledgmentsPotential conflict of interest. M.W.G.B. andM.E.: no conflictsMartin W. G. Brinkhof and Matthias EggerDepartment of Social and Preventive Medicine,University of Bern, Bern, SwitzerlandReferences1. Colebunders R, Caluwaerts S. Determinationof the incidence of tuberculosis in low-incomecountries. Clin Infect Dis 2008; 46:1482 (in thisissue).2. The Antiretroviral Therapy in Low-IncomeCountries Collaboration of the Internationalepidemiological Databases to Evaluate AIDS(IeDEA) and The ART Cohort Collaboration.Tuberculosis after initiation of antiretroviraltherapy in low-income and high-income coun-tries. Clin Infect Dis 2007; 45:1518–21.Reprints or correspondence: Dr. Martin W. G. Brinkhof, Dept.of Social and Preventive Medicine, University of Bern, Fin-kenhubelweg 11, CH-3012 Bern, Switzerland (brinkhof@ispm.unibe.ch).Clinical Infectious Diseases 2008; 46:1482–3 2008 by the Infectious Diseases Society of America. Allrights reserved. 1058-4838/2008/4609-0032$15.00DOI: 10.1086/587183Shock as a Covariate in aStudy of Treatment ofMethicillin-ResistantStaphylococcus aureusBacteremiaTo the Editor—Although the recentlypublished article by Soriano et al. [1] com-ments on an important and interestingtopic, I feel that the article has significanmethodological flaw that have an impacton the conclusions made by the authors.Specificall , there are large and importantdifferences between theOR estimates fromthe multivariate and univariate analysesfor the association of mortality and van-comycin treatment group (see table 1,which summarizes the ORs presented bySoriano et al. [1]). The authors placedshock as a covariate in their multivariablemodel. They give the rationalization thatthis is a negative confounder of the as-sociation between treatment group andmortality.I would argue, however, that shockshould not be in the model, because it ison the causal pathway from treatmentgroup to death. Including this in themodel would generate OR estimates forthe association of treatment group andmortality, which then are—theoretically—independent of shock.I am not sure how to interpret theirmodel in this context or the multivariableOR they present. What is the reason toinclude shock as a covariate?It would be helpful to see a multivari-ablemodel for the association of treatmentgroup and mortality without shock as acovariate in the model. It would also behelpful to see an assessment of the overallstatistical significanc of the treatment-group effect in the model, in addition tothe individual OR by subgroup.Potential conflict of interest. M.E.L.: noconflictsMark E. LustbergDivision of Infectious Diseases,Department of Internal Medicine,Ohio State University Medical Center, ColumbusReference1. Soriano A, Marco F, Martinez JA, et al. Influence of vancomycin minimum inhibitory con-centration on the treatment of methicillin-re-sistant Staphylococcus aureus bacteremia. ClinInfect Dis 2008; 46:193–200.Reprints or correspondence: Dr. Mark E. Lustberg, Div. ofInfectious Diseases, Dept. of Internal Medicine, Ohio StateUniversity Medical Center., N1147 Doan Hall, 410 W. 10thAve., Columbus, OH 43210 (mark.lustberg@osumc.edu).Clinical Infectious Diseases 2008; 46:1483 2008 by the Infectious Diseases Society of America. Allrights reserved. 1058-4838/2008/4609-0033$15.00DOI: 10.1086/587178Vancomycin MinimumInhibitory Concentrationas a Predictor of Mortalityin Methicillin-ResistantStaphylococcus aureusBacteremia: A Second LookTo the Editor—We read with interestthe article by Soriano et al. [1] that de-scribed vancomycin MIC as a predictor ofmortality in patients with methicillin-re-sistant Staphylococcus aureus bacteremia.The issue ofMIC “creep”was documentedelsewhere [2], and the conclusion that ahigherMIC is associated with an increasedrisk of mortality is not surprising. In ad-dition, the presence of shock associatedwith methicillin-resistant Staphylococcusaureus bacteremia was documented else-where as a risk factor for mortality [3].However, the negative associationbetweenthe development of shock and vancomy-cin MIC is extremely intriguing. Sorianoet al. [1] hypothesize that this relationshipcould be attributed to a decrease in path-ogenicity as resistance increases through avariety of mechanisms. We offer an alter-native explanation of the data and addresssome concerns with the study by Sorianoet al. [1].After examination of the absolute in-cidence of patient characteristics, it is clearthat the development of shock is nega-tively associated with vancomycin MICwithout adjustment for confounding var-iables (for 1 mg/mL, 28.4%; for 1.5 mg/mL,20.2%; for 2 mg/mL, 10.9%; ). ItPp .007is also clear that heart failure occurred ina significantl higher percentage of pa-

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