Cardiovascular Drugs and Therapy 15 209–210 2001

C© Kluwer Academic Publishers. Printed in The Netherlands

Antibiotic Therapy in Coronary Heart Disease—Where DoWe Currently Stand?

Vijay Anand1 and Sandeep Gupta2

1Whipps Cross University Hospital, London, UK; 2Whipps Crossand St Bartholomew’s University Hospitals, London, UK

Summary. A casual association between Chlamydia pneu-

moniae infection and atherosclerosis remains unresolved

but plausible. Evidence comes from sero-epidemiological

data, pathological specimen examinations, animal models

and in vitro experiments. A number of prospective antibi-

otic intervention trials targeted against C pneumoniae in-

fection in patients with coronary heart disease are now un-

derway. We remain wary that C pneumoniae infection can

persist in cell lines (associated with atherosclerosis) de-

spite antibiotic therapy and also that reactivation of infec-

tion can occur. Issues such as delineating the patient group

that could be targeted for treatment, choice of optimal an-

tibiotic regimens, duration of therapy and effective methods

of monitoring treatment response remain controversial and,

as yet, unresolved. The relevance of persistence of C pneu-

moniae infection and potential antimicrobial resistance will

require equal consideration.

Key Words. Chlamydia pneumoniae, atherosclerosis, coro-

nary heart disease, antibiotics

As the evidence for an inflammatory and ‘infectious’basis to atherosclerosis continues to emerge, debate onthe potential therapeutic role of antibiotics in coronaryheart disease (CHD) gains equal momentum.

Infectious agents may directly or indirectly triggerand/or modulate inflammation in the vessel wall, lead-ing to plaque progression, plaque ‘destabilisation’ andsubsequent atherothrombotic clinical events [1]. The in-tracellular microorganism Chlamydia pneumoniae ap-pears to be the strongest ‘culprit’ pathogen implicatedin atherosclerosis. This is based on sero-epidemiologicalstudies, identification of the organism within plaque,animal models of infection-induced atherogenesis andin vitro evidence of C pneumoniae contributing tomonocyte-macrophage activation and upregulation ofother cellular processes linked to the development ofatherosclerosis [2–4]. Furthermore, several small-scalestudies have now explored the role of anti-Chlamydialantibiotics in the clinical setting of CHD—althoughwith equivocal results.

Eradication of a chronic vascular infection—whether in vitro or in vivo—is poorly defined. Thestudy by Gieffers et al. (in this issue of the journal)shows that in actively replicating, C pneumoniae can beeliminated by certain antibiotics from infected cell lines

typically associated with atherosclerosis. Whether theresults from this model can simply translate to the clin-ical setting of antimicrobial therapy in CHD, as yet,remains unclear.

We know that C pneumoniae is notorious for caus-ing re-infection and persistent infection and treatmentfailure is common [5]. The establishment of a ‘non-replicating’ (but viable state) of C pneumoniae in hostcells is likely to be one of its main causes. Persistence ofC pneumoniae has been noted to occur spontaneouslyin monocytes-macrophages and is refractory to antibi-otic treatment [6]. The host immune response mediatedby interferon-gamma and TNF-alpha restricts the in-tracellular growth of chlamydia but fails to eliminateit, thereby contributing to the development of a per-sistent infection [7]. There is in vitro evidence thatpersistence of C pneumoniae infection may also be in-duced in endothelial and epithelial cells by the abovestimuli [8]. Endogenous re-infection of vascular cellsafter decline of tissue antibiotic levels is possible andhas to be considered if antibiotic trials in CHD proveto be negative—i.e. inadequate dosage and duration oftherapy.

Gupta et al. in the UK [3] and Gurfinkel et al. inArgentina [4], in separate studies in 1997, showed thatshort courses of macrolide antibiotics (azithromycin androxithromycin respectively) reduced the occurrence offuture cardiovascular events in patients with estab-lished CHD. Subsequent Muhlestein et al. and oth-ers demonstrated how azithromycin protected againstthe aortic wall thickening seen in infected rabbitsgiven no antibiotics [9]. The ‘Azithromycin in coro-nary artery disease: Elimination of myocardial in-fection with Chlamydia’ (ACADEMIC) study didnot demonstrate significant reduction in adverse car-diac events at six months and two years follow upin patients with CHD [10]. The authors acknowl-edged that, like earlier pilot studies, [3,4] ACADEMICwas perhaps clinically underpowered and definitivelarger-scale, randomised prospective trials were stillneeded.

Address for correspondence: Dr. Sandeep Gupta M.D. M.R.C.P.,Department of Cardiology, Whipps Cross University Hospital,Leytonstone, London E11 1NR, UK. Tel.: 44-20-8535-6442; Fax:44-20-8500-9352; E-mail: sgupta111@aol.com

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The scientific evidence examining the associationof ‘C pneumoniae, inflammation and atherosclerosis’has rapidly advanced in recent years and currentlya large number of prospective antibiotic interventiontrials in CHD are underway. Such include ‘Weekly in-tervention with Zithromax in atherosclerosis-relateddisorders’ (WIZARD), ‘Azithromycin and coronaryevents study’ (ACES), ‘Azithromycin in acute coro-nary syndromes’ (AZACS), ‘Might Azithromycinreduce bypass-list events?’ (MARBLE) and most re-cently ‘Pravastatin or Atorvastatin evaluation andinfection therapy’ (PROVE-IT). Some n= 20,000patients in total have now been recruited and ran-domised to receive antibiotics or placebo and to befollowed-up for further adverse cardiovascular events.

While one eagerly awaits the findings of such largeclinical trials a number of unresolved issues remain.Selecting patients for treatment, the optimal antibi-otic regimen and duration of therapy in addition to thequestion of re-infection and undertreated ‘persistent’infection are particular issues. There is a need for fur-ther research into the mechanisms that favour persis-tence of C pneumoniae infection and those responsiblefor reactivation. In part, addressed by Gieffers et al.Effective methods of monitoring treatment response—for example the relevance of antibody titre changes,alterations in C pneumoniae load in peripheral mono-cytes and/or changes in high sensitivity C-reactive pro-tein levels may need further evaluation. The wider po-tential concern regarding antibiotic resistance also hasto be taken into account, once antibiotics are estab-lished to have, if at all, any role in secondary preventionof CHD.

The ‘pendulum’ of negative and positive results con-tinues to swing. It should settle one way or other inthe next few years. There is no doubt that the bur-den of the ‘epidemic’ of CHD hangs over both the in-dustrialised world and the emerging and developingcountries. But clinicians will only be able to justifythe role of antibiotics as therapeutic agents in CHD if

the ongoing research helps to guide optimal treatmentstrategies and the ongoing antibiotic trials (unequiv-ocally) show protective benefit against cardiovascularevents.

References

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