A systematic review and meta-analysis of preclinical trials testing anti-toxin therapies for B. anthracis infection: A need for more robust study designs and results

Abstract

BackgroundB. anthracis anti-toxin agents are approved and included in the Strategic National Stockpile based primarily on animal infection trials. However, in the only anthrax outbreak an approved anti-toxin agent was administered in, survival did not differ comparing recipients and non-recipients, although recipients appeared sicker.ObjectiveEmploy a systematic review and meta-analysis to investigate preclinical studies supporting anthrax anti-toxin agents.Data sourcePubMed, EMBASE, and Scopus.Study eligibilityCompared survival with an anti-toxin agent versus control in B. anthracis challenged, antibiotic treated animals.Study methodsExamine model and study design and the effect of anti-toxin agents on relative risk of death(95%CI) (RR).ResultsFrom 9 studies, 29 experiments were analyzed which included 4 species (748 animals) and 5 agents; LFI, AIG, AVP-21D9, Raxibacumab, and ETI-204. Only five experiments were blinded and no experiment included the cardiopulmonary support sick B. anthracis patients receive. Only one agent in a single un-blinded experiment reduced RR significantly [0.45(0.22,0.940]. However, in six studies testing an agent in more than one experiment in the same species, agents had consistent survival effects across experiments [I2 = 0, p≥0.55 in five and I2 = 42%, p = 0.16 in one]. Within each species, agents had effects on the side of benefit; in one study testing AVP-21D9 in mice [0.11(0.01,1.82)] or guinea pigs [0.70(0.48,1.03)]; across eight rabbit studies testing LFI, Raxibacumab, AIG or ETI-204 [0.62(0.45,0.87); I2 = 17.4%, p = 0.29]; and across three monkey studies testing Raxibacumab, AIG or ETI-204 [0.66(0.34,1.27); I2 = 25.3%, p = 0.26]. Across all agents and species, agents decreased RR [0.64(0.52,0.79); I2 = 5.3%, p = 0.39].LimitationsIncidence of selective reporting not identifiable.ConclusionsAlthough overall significant, individually anti-toxin agents had weak beneficial effects. Lack of study blinding and relevant clinical therapies further weakened studies. Although difficult, preclinical studies with more robust designs and results are warranted to justify the resources necessary to maintain anti-toxin agents in national stockpiles.

Questionable Efficacy of Therapeutic Antibodies in the Treatment of Anthrax

“…In the wake of FDA authorizations, the Centers for Disease Control and Prevention (CDC) updated their guidelines for anthrax postexposure prophylaxis and treatment, recommending that antitoxin should be added to antibiotic therapy for any patient suspected of a systemic anthrax infection. Recent closer examination of available clinical and preclinical data has cast doubt upon the beneficial effect afforded by the antibiotics and antitoxin combination in preclinical models (5, 6). Further clinical data collected on the particular form of injectional anthrax during the drug user outbreak in the United Kingdom indicated that death rates did not differ significantly between AIG-IV recipients and nonrecipients (33% versus 21%, with 43 patients included in the study [15 AIG-IV recipients and 28 nonrecipients]), suggesting no benefit of the therapeutics (7).…”

Bioterrorism: Clinical and public health aspects of anthrax

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