Molecular basis of resistance to macrolides and lincosamides
5. Selection for constitutively expressed erm(C) genes
The results obtained by the in vitro selection assay confirmed the assumption that constitutively resistant erm(C) mutants develop under the selective pressure of non-inducing MLSB antibiotics. Equivalent data for erm(C)-91,121 as well as for erm(A)-carrying93 staphylococci have been previously derived for the lincosamide clindamycin,121 the streptogramin B antibiotic quinupristin91,93 and the ketolides telithromycin and ABT-773 in vitro.91,93 These data give important evidence for the risk that constitutively resistant mutants will also occur in vivo during the therapy with non-inducers. In fact, such observations have been made in human medicine. Recently, cases of treatment failure based on the development
of constitutively resistant staphylococcal strains during clindamycin treatment have been reported.33,61,87,108
Unfortunately, the molecular background of MLSB resistance was not investigated. Since most of these strains had been identified as methicillin-resistant S. aureus (MRSA) and the two genes erm(A) and erm(C) are the most prevalent erm genes in MRSA isolates,92,111 it is most probable that any of these genes were present in these clinical cases.
In veterinary medicine corresponding data are lacking. The detection of clinical isolates carrying constitutively expressed erm(C) genes48,66,67,102,121
strongly indicates that such development also occurs in animal staphylococci exposed to non-inducing MLSB antibiotics.
MRSA and methicillin-resistant CoNS in animals are not that widespread as among human isolates.1,111 However, in such cases lincosamides provide an important alternative to penicillins, and the differentiation between inducible resistant and truly susceptible isolates is of relevance for a successful treatment.88
Figure 6. D-test, performed to identify the type of resistance. Discs are charged with MY: lincomycin, 15 µg; E:
erythromycin, 15 µg; and DA: clindamycin, 2 µ g. Differentiation between A. constitutive MLSB resistance, B.
inducible MLSB resistance and C. erythromycin resistance and true lincosamide susceptibility.
The methods routinely used in the diagnostic laboratory, namely broth dilution and agar disc diffusion, are not able to detect inducible resistance to non-inducing MLSB antibiotics such as 16-membered macrolides and lincosamides. An easily performed agar disc diffusion test, the D-test, has been proved to reliably indicate inducible resistance in apparently susceptible isolates.35,49 Moreover, isolates truly susceptible to a non-inducer are also identified (Figure 6). For the D-test an erythromycin-charged disc is placed adjacent to a disc charged with a non-inducer. For this purpose, a standard disc dispenser can be used.35 In inducibly resistant isolates the inhibition zone caused by the non-inducer is flattening at the site exposed to the erythromycin-charged disc (Figure 6, B.). Alternatively, PCR assays for the genes of interest, mainly erm(C) and msr(A) in animal isolates, can be performed.
In constitutively resistant mutants, structural alterations, such as deletions, tandem duplications and point mutations within the regulatory region of the erm(C) gene, have been detected. These mutations explain the inactivation of the translational attenuator. In naturally occurring isolates, constitutive resistance is more often based on deletions than tandem duplications; point mutations that interfere with the formation of stable secondary structures are very rarely seen [Chapter 2].48,102,121 Certain deletions are frequently observed in epidemiologically unrelated isolates.121 That points towards a common mechanism, which involves the recombination system of the host cell. A proposed model explains the development of these deletions by RecA-dependent recombination based on short stretches of homology adjacent to the deleted region.121 A common mechanism which explains the development of duplications, however, is unlikely. Replication slippage or illegitimate recombination may be responsible and results in unique, randomly occurring alterations.121
Regardless of the genetic background of the mutations that led to constitutive resistance, the described observations underline the recommendation given by the working group “Antibiotic Resistance” of the German Society for Veterinary Medicine (DVG).69 For the standard in vitro susceptibility testing they propose to use erythromycin as representative for the class of macrolides. By this, the misinterpretation of apparent susceptibility to 16-membered macrolides can be prevented. For the confirmation of susceptibility to lincosamides, such as pirlimycin, in erythromycin-resistant isolates, however, further tests are necessary (D-test or the detection of the resistance gene) before non-inducers can be considered as suitable agents for therapy.
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