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# Clindamycin resistance in Staphylococcus aureus

## Problem

Antibiotic resistance among Staphylococcus aureus isolates is increasingly common. Resistance to macrolide antibiotics such as azithromycin, clindamycin (a lincosamide antibiotic) and streptogramins, has been demonstrated in vitro. This phenotype is termed start text, M, L, S, end text, start subscript, B, end subscript resistance. Clinical failures in staphylococcal infections treated with clindamycin have been reported with this phenotype, which is extremely concerning given that clindamycin is a convenient and commonly-used antibiotic.
MLSB resistance results from the production of a 23s rRNA methylating enzyme (methylase), which is the protein product of the erm gene. This methylase alters the usual ribosomal binding site for macrolides, lincosamides, and the B-streptogramins (quinupristin). It can be constitutively expressed, or induced by administration of macrolides. Erythromycin is a strong inducer of the methylase, whereas clindamycin is a weak inducer.
Inducible resistance results from the binding of a macrolide to specific upstream translational attenuator sequences, leading to changes in mRNA secondary structure, exposure of the ribosomal binding site, and translation of the erm methylase. Alterations in 5′ upstream attenuator sequences, including deletions, duplications, and other mutations, lead to constitutive expression of the methylase gene and, therefore, lead to constitutive start text, M, L, S, end text, start subscript, B, end subscript resistance.
Inducible start text, M, L, S, end text, start subscript, B, end subscript resistance is tested in vitro via what is called a “d-test”. Erythromycin- and clindamycin-impregnated disks are placed 15-20mm apart on a lawn of Staphylococcus aureus. In a positive d-test, the expected zone of clearance (the area of inhibited bacterial growth) around the clindamycin disk is blunted, creating a D shape (Figure 1).
Figure 1 Negative and positive clindamycin d-tests
Researchers performed a d-test on 100 distinct clinical isolates of Staphylococcus aureus and examined the different morphologies of the zone of clearance, as seen in Figure 2.
Figure 2 D-test zone-of-clearance morphologies in six distinct staphylococcal isolates: The dark region around the antibiotic disk represents the zone of clearance.
Image adapted from Steward et al. J Clin Microbiol. 2005 Apr;43(4):1716-21.
What is the mechanism of antibiotic resistance in Staphylococcus aureus as evidenced by a positive d-test?