How Should the Inoculum Effect and its Clinical Interpretation be in the Treatment of Invasive Group A Streptococcal Infection?

Question: In general, we know that combinations of bactericidal (like penicillin/cephalosporin) and bacteriostatic (like clindamycin, macrolide) antibiotics can show antagonistic properties. It is recommended to give clindamycin in addition to penicillin (or cephalosporins) even if it is susceptible in invasive group A streptococcal infection. Could you tell us about the mechanism of this and its role in treatment? Gülsüm Mammadlı, MD.

Answer (Fatma Dilşad Aksoy, MD; Mustafa Kemal Hacımustafaoğlu, MD)

Introduction and general information: As it is known, bactericidal drugs are most effective especially against actively dividing bacteria. Bacteriostatic drugs, on the other hand, generally inhibit bacterial metabolism and inhibit their growth. As a general information, the combination of bactericide + bacteriostatic drug; may reduce the potential effect of the bactericidal drug, leading to a general decrease in efficacy. Therefore, such combinations are generally considered antagonistic (1). However, this general situation may not be fully valid for some clinical situations (such as invasive group A streptococcal infections) and for some etiologic agents (such as Group A streptococci; GAS; Streptococcus pyogenes, sometimes for staphylococci). In addition, specificially, the combination of penicillin (bactericide) and clindamycin (bacteriostatic) does not reveal significant additive, synergistic or antagonistic effects in-vitro (2,3).

The inoculum effect (IE) is generally defined as a significant increase in the minimal inhibitory concentration (MIC) against bacteria in the presence of much more bacteria in the environment, under laboratory conditions (4). In the literature various criteria can be used to define IE. Generally, the presence of viable bacteria concentration of 10 times or more than the standard bacterial density, or an increase in MIC, or a decrease in killing rates over time, are considered among the evaluation criteria of IE (3). IE is mainly defined as a decrease in the effect of antibiotics under laboratory conditions, but this also has clinical implications. In other words, under the conditions where the IE effect occurs; clinical failure may occur with an antibiotic (such as penicillin or cephalosporin) that is normally effective against the causative agent (such as GAS). In this context, IE can be defined as a decrease in anti- biotic effect in the presence of increased bacterial density (in vitro or in vivo) (5). If the bacterial density in the environment is much higher than expected, the bacterial population...