Handbook of Antimicrobial Resistance by Albert Berghuis Greg Matlashewski Mark A. Wainberg & Donald Sheppard

Author:Albert Berghuis, Greg Matlashewski, Mark A. Wainberg & Donald Sheppard
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

New Insights: Cytostatic Versus Cytocidal Resistance

The above summary presents a satisfying model for PfCRT-mediated CQR further modulated by PfMDR1 and perhaps other factors. However, this assessment of CQR phenomena is based upon an incomplete definition of CQ pharmacology. With one exception (Paguio et al. 2011), for decades, all quantification of CQR has been via computing a ratio in CQ IC50 for CQR versus CQS strains or isolates. IC50 are determined from long-term growth inhibition assays wherein live parasites are grown for 1–3 iRBC cycles in the constant presence of CQ. These IC50 are in the 101–102 nM range (depending on the strain) and are relatively easy to obtain, including in high-throughput fashion with live cells (Smilkstein et al. 2004; Bennett et al. 2004a). Growth inhibition of parasites is highly relevant to the development of antimalarial therapy, because a good antimalarial drug should prevent increases in parasitemia and recrudescence. But it is also true that when CQ is administered to a malaria patient, the plasma concentration of the drug is typically >1 μM (not 10–100 nM), for at least the first 6–12 h. The most important initial effect of CQ therapy is significant reduction of parasitemia from 1012 to 1011 parasites to ≤109, within hours. Meaning, successful clinical administration of CQ kills many parasites, it does not merely prevent their growth. A patient infected with CQR P. falciparum does not show this dramatic drop in parasitemia due to parasite death from micromolar CQ dose. Meaning, clinically relevant CQR can also be defined via an elevated LD50 (“Lethal Dose”). LD50 (defined as survival after bolus dose of CQ, see Paguio et al. 2011; Cabrera et al. 2009) have only been reported for two laboratory strains of P. falciparum. Many more such studies obviously need to be done. In one recent study, when drug accumulation is analyzed for intact iRBC using LD50 levels of drug (not IC50 levels), reduction in DV accumulation is not found for the CQR parasites relative to CQS (Cabrera et al. 2009). In fact, this study reports that CQR parasites can accumulate more toxic CQ relative to CQS and still exhibit resistance to drug-induced cell death. It is of course not uncommon for antimicrobial or anticancer drugs to show both growth inhibitory (cytostatic) and cell killing (cytocidal) effects. When they do, cytocidal activity often (but not always) requires higher levels of drug or longer exposure to drug. It is also not uncommon for targets that are relevant for cytostatic functions of a drug to differ from those that are relevant for cytocidal. It is critical then to point out that, with two exceptions (Geary et al. 1986; Cabrera et al. 2009), nearly all detailed CQ transport analyses for CQR versus CQS parasites, vesicles, or oocytes that have been used to develop models for CQR and PfCRT function have been done at sub IC50 levels of drug (typically, 1–50 nM). This has led to logical explanations for CQR that are relevant for resistance to the cytostatic functions of CQ (“CQRCS”)

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