Combination Antimicrobial Therapies

Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)

Combination of antimicrobial agents for various infectious diseases including bacterial, viral, parasitic, and fungal infections have proliferated in the past 50 years. For several conditions, combination of antimicrobial agents is established as first line of defense (such as Mycobacterium tuberculosis, human immunodeficiency virus [HIV], and malaria, etc.). However, much controversy exists for combination therapy for several bacterial infections and new emerging data on invasive fungal infections. This chapter will not delve into the well-established proven combinations above, but will discuss combinations, which are more controversial and are emerging issues.

The rationale for using combination over single chemotherapeutic agent varies with the infection being treated, but include: (i) delaying or prevention of resistant mutants; (ii) broaden spectrum of activity especially for infection with mixed microorganisms; (iii) enhance activity to achieve additive or synergistic effect; (iv) sequential activity on different stages of the organism; (v) utilizing different mechanism of action (lysis versus protein synthesis inhibition) to impair toxin release by the microorganism. The combination of three or four drugs for M. tuberculosis and HIV infection are paradigms for the first instance. With M. tuberculosis, mutation occurs at a low but constant rate so that treatment with a single drug, however powerful, will eventually lead to selection of resistant mutants.1 The problem of treatment failure due to emergence of drug resistance became evident soon after the introduction of anti-tuberculosis therapy and led to the development of multiple drug regimens. Similarly, single and dual antiretroviral agents (ARVs) resulted in failure to control HIV infection with development of resistant mutants from incomplete viral suppression. Resistance mutations to ARVs may arise spontaneously as a result of error-prone replication of HIV-1 and, in addition, are selected in vitro and in vivo by pharmacological pressure.2 The high rate of spontaneous mutation in HIV-1 has been attributed to the absence of a 3′–5′ exonuclease proof-reading mechanism; and can be as high as 800 × 10−4 per nucleotide.


Minimal Inhibitory Concentration Visceral Leishmaniasis Invasive Aspergillosis Antimicrob Agent Invasive Candidiasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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