Striking “Seesaw Effect” between Daptomycin Nonsusceptibility and β-Lactam Susceptibility in Staphylococcus haemolyticus

Abstract

The expression “seesaw effect” was originally used by Sieradzki and Tomasz (7), and subsequently by others, to denote a frequently observed inverse relationship between evolving glycopeptide and β-lactam MICs in Staphylococcus aureus. The same expression has recently been revived in two interesting studies by Yang et al. (9) and Lee et al. (4) to signify a similar phenomenon, again seen in S. aureus, involving daptomycin instead of glycopeptides. On the other hand, it is well known that S. aureus strains progressively acquiring daptomycin nonsusceptibility during daptomycin exposure also exhibit progressively increasing vancomycin MICs (3, 6). Among coagulase-negative staphylococci, Staphylococcus haemolyticus, second only to Staphylococcus epidermidis in the frequency of its association with human infections (1), is unique in being predisposed to developing glycopeptide resistance and was the first Gram-positive pathogen to acquire such resistance in the 1980s (2). After exposure to increasing daptomycin concentrations, by a procedure successfully used with glycopeptides in previous studies in our laboratory (8), a stable clone with a daptomycin MIC of 4 μg/ml was obtained from a daptomycin-susceptible (MIC, 0.5 μg/ml) clinical isolate of S. haemolyticus. Vancomycin and teicoplanin MICs also increased from 4 and 8 μg/ml in the parent to 8 and 32 μg/ml in the laboratory derivative, respectively. The parent strain was both penicillin and methicillin resistant: penicillin and cefoxitin MICs were >256 μg/ml; molecular analysis disclosed a type I SCCmec cassette and regular mec and bla operons; β-lactamase production was confirmed by the nitrocefin test. The seesaw effect was striking (Fig. 1): in the daptomycin-nonsusceptible derivative, the penicillin MIC dropped to 0.125 μg/ml, in spite of persistent detection of the bla operon and of β-lactamase activity, and the cefoxitin MIC dropped to 2 μg/ml, despite persistent detection of the mecA gene and the mec operon in a type I SCCmec. Fig. 1. Diffusion tests using Etest strips (penicillin and cefoxitin). (A) Clinical isolate of daptomycin-susceptible S. haemolyticus (parent strain). (B) Daptomycin-nonsusceptible laboratory derivative. Although a number of theories have been advanced to account for the vancomycin/β-lactam and the daptomycin/β-lactam seesaw effect (7, 9), the underlying mechanisms remain poorly understood. Moreover, while previous hypotheses were essentially aimed at explaining a fall in methicillin resistance, thus largely pointing to some modulation of mecA expression, this case also involves a plunge in penicillin resistance, despite apparently normal—phenotypically and genotypically—β-lactamase production in the laboratory derivative. In other words, here the seesaw effect needs to be explained in light not only of the mec operon/PBP2a-mediated β-lactam resistance system but also of the bla operon/β-lactamase-mediated one. It is worth noting that, in a reported case of decreased susceptibility to daptomycin and vancomycin in S. aureus during prolonged therapy, a decreased penicillin MIC was found to be associated with the apparent loss of β-lactamase activity (5).