Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

Abstract

SUMMARYSmall colony variants (SCVs) were first described more than 100 years ago forStaphylococcus aureusand various coagulase-negative staphylococci. Two decades ago, an association between chronic staphylococcal infections and the presence of SCVs was observed. Since then, many clinical studies and observations have been published which tie recurrent, persistent staphylococcal infections, including device-associated infections, bone and tissue infections, and airway infections of cystic fibrosis patients, to this special phenotype. By their intracellular lifestyle, SCVs exhibit so-called phenotypic (or functional) resistance beyond the classical resistance mechanisms, and they can often be retrieved from therapy-refractory courses of infection. In this review, the various clinical infections where SCVs can be expected and isolated, diagnostic procedures for optimized species confirmation, and the pathogenesis of SCVs, including defined underlying molecular mechanisms and the phenotype switch phenomenon, are presented. Moreover, relevant animal models and suggested treatment regimens, as well as the requirements for future research areas, are highlighted.

Influence of IS 256 on Genome Variability and Formation of Small-Colony Variants in Staphylococcus aureus

“…4), which was particularly noticeable after 40 h of incubation. Typically, clinical SCVs and ΔhemB mutants show no or decreased pigment production compared to that of the wild type (20). However, when CtaB, the enzyme that catalyzes the very last step of the pathway and couples the farnesyl diphosphate chain to protoheme IX, is removed in S. aureus, an increased pigmentation is observed, indicating that farnesyl diphosphate is fed into the pigment production pathway (30).…”

“…SCVs are slowly growing cells that are able to cause chronic infections and often have lost susceptibility to antibiotics such as aminoglycosides or trimethoprim-sulfamethoxazole. Clinical SCV isolates are often formed during intracellular growth (19) or prolonged antibiotic therapy (20); they are often unstable and therefore very difficult to handle, especially in broth culture, and most laboratory experiments have been performed with stable genetically engineered variants that are inactivated in hemB and menD or that possess a deletion in hemH (21)(22)(23). Recently it was shown that in infection models, long-term persistence induced SCV phenotypes, which rapidly reverted to the wild-type phenotype when the organisms were subcultured in the laboratory (24).…”

“…Recently it was shown that in infection models, long-term persistence induced SCV phenotypes, which rapidly reverted to the wild-type phenotype when the organisms were subcultured in the laboratory (24). The mechanism of this switch is still unclear (20), but it was hypothesized that the stress factors encountered during infection might activate the transition and that SigB is involved in this mechanism (19,24). Here we show that the formation and fast reversion of SCV-like phenotypes may also be mediated by transposition and subsequent excision of IS256.…”

Commentary: Significance of Staphylococcus epidermidis in Health Care-Associated Infections, from Contaminant to Clinically Relevant Pathogen: This Is a Wake-Up Call!

“…These infections were previously predominantly regarded as being of endogenous origin, but considerable evidence has been accumulated confirming that nosocomial genotypes of S. epidermidis colonize patients and health care personnel and cause a substantial proportion of health care-associated infections (4)(5)(6)(7)(8)(9)(10)(11). S. epidermidis is currently the main pathogen in catheter-related bloodstream infections and early-onset neonatal sepsis and is also a frequent cause of prosthetic joint infections, prosthetic valve endocarditis, and other biomedical device-related infections (12)(13)(14)(15). A major clinical challenge is that these infections are often caused by multidrug-resistant S. epidermidis phenotypes and that the infections are chronic in nature due to adherence and biofilm formation on indwelling medical devices.…”

“…Several inherent features of S. epidermidis infections add to the difficulties in making a correct microbial diagnosis and distinguishing between contamination, colonization, and true infection. Such characteristics consist of phenotypic morphological variation, including small colony variants (SCVs) and different antibiograms (clonal variability), as well as polyclonal infections and multispecies CoNS infections (12,(20)(21)(22). Unfortunately, all these characteristics of S. epidermidis infection can add to the difficulty of assessing culture findings and hence increase the risk that the results will be dismissed as being due to contamination, preventing proper microbial diagnosis and treatment.…”