Genesis of Antibiotic Resistance (AR) LI: Mechanism(s) of Biosimilar(s) induced AR Clinical Persistence – persister(s) pathogen(s) (ARCP) consequent Antibiotic Resistance Pandemic (ARP)

Abstract

To date, the adverse clinical outcome due to “Biosimilar” therapeutics administered for the inflammatory disorders, and its role in the evolution of ARCP, is yet to be elucidated. The objective of this report is to postulate plausible mechanisms by which biosimilar in vivo could engender ARCP (J Med Microbi. 2011:60(Pt 6):699; J Bacteriol. 2018; 200(20); Cell Host Microbe. 2019 Jul 10;26(1):15‐2; Trends Genet. 2019;35(6):401–411; Mol Oral Microbiol. 2019;34(3):97–107; Nat Rev Micro. 2019;;17(7):441–44) affecting the efficacy of antibiotic therapy and consequently ARP. Based on a comprehensive review of the data posted on the FDA Adverse Event Reporting System (FAERS) ( https://www.fda.gov/drugs/fda‐adverse‐event‐reporting‐system‐faers/potential‐signals‐serious‐risksnew‐safety‐information‐identified‐fda‐adverse‐event‐reporting‐system‐12) on adverse clinical outcome upon administering “Biosimilar” in acute and/or chronic inflammatory disorders, here we present plausible mechanism(s) for augmenting ARCP. In retrospect, from the FAERS data base, we have made an effort to derive a correlation of the following plausible factor(s) as a cause for biosimilar induced molecular aberration impairing the ability of the patient’s adaptive response to antibiotic sensitivity leading to cross resistance to original therapeutic formulation (brand name medication), and also generics: a. non‐specific biologically active molecules derived from recombinant origin that are not a component of therapeutic formulation, evoking nonspecific immune response (hypersensitivity)”; b. manufacturing artifacts such as leachates from the use of stabilizers, and contaminant from plastic derived residues altering immunogenicity; c. the route of administration: intravenous route of administration of biosimilar being less immunogenic than intramuscular or subcutaneous administration; d. neutralization of endogenous molecules followed by inadvertent host immune response; e. metabolic activation and breakdown products of biosimilar in vivo could alter the enzyme structure, consequently kinetics of the antibiotic sensitivity; and f. cross Resistance: The patient’s unresponsiveness to an original therapeutic (brand name) interchanged with biosimilar could be due to receptor desensitization (due to altered pharmacokinetic properties) induced drug tolerance impairing the patient’s ability to mount immune response to infectious pathogenic bacteria plausibly through lack of sensitivity to antibiotic therapy; g. Extrapolation of a biologic formulations (brand name) for biosimilar lacking identical therapeutic outcome; and h. Efficacy & interchangeability, of a biosimilar for brand name formulations by pharmacists without the feedback from an attending physician. Taken together, it is suggested that aforesaid factors could impart selection pressure on the infectious bacterial pathogen(s) while being treated for inflammatory disorders. Bacterial pathogen(s) susceptible for selection pressure and attenuated to antibiotics may plausibly evolve as ARCP.Support or Funding InformationSupported by the professional development funds by SWTJC to Subburaj Kannan