Final Diagnosis -- Small colony variant-Staphylococcus aureus)



This is a naturally occurring subpopulation of S. aureus, discovered nearly 100 years ago. They grow slowly and produce small nonpigmented, nonhemolytic colonies on a blood plate. They have reduced coagulase production and they also fail to use mannitol. They produce smaller amounts of alfa-toxin and have increased resistance to aminoglycosides (AG) and cell-wall active antibiotics making this strain difficult to treat.

Two major types of SCVs S. aureus are usually found in clinical isolates:

  1. Electron transport defective type (also called hemin- or menadione-auxotrophs). They have the ability to interrupt electron transport across the bacterial membrane by mutation in thiamine, menadione or hemin biosynthesis, which are essential substrates for the biosynthesis of electron transport chain components (cytochromes and menaquinone). By doing that, ATP production is reduced (by further alteration in proton pump function) and the transmembrane potential which is required for the effect of many cationic antimicrobial compounds like AG is altered, resulting in decreased susceptibility to these agents.
  2. Thymidine-auxotrophs type. They emerge as a result of long-term SXT therapy in cystic fibrosis (CF) patients. They usually are resistant to SXT and survive if extracellular thymidine is provided.

A number of SURVIVAL ADVANTAGES characterize SCV S. aureus, among which the following are the most important to consider:


Cultures for SCVs S. aureus should be incubated for six days or longer. They grow poorly on TSA agar with 5% horse blood, but they grow well if the same medium is enriched with 5% sheep blood. Chocolate agar enriched with isovitalex produces good growth of thiamine-requiring strains, but not of the menadione-requiring variety. Adding hemin, menadione and thiamine to media will produce normal growth of SCV. However, atypical clinical microbiologic characteristics make identification and susceptibility testing difficult, so that a pragmatic approach might be to subculture suspicious colonies, in duplicate, onto primary (deficient) isolation media and an appropriately enriched medium, incubated in 5-10% CO.

As far as sensitivity testing, currently the method of choice is eithr a broth- or agar-dilution MIC (minimum inhibitory concentration) method, with sufficiently low levels of auxotrophic factors to ensure that the SCV phenotype is tested.


The SCVs of S. aureus have been isolated directly from sites of infection or following either in vivo or in vitro exposure to AG. They are implicated in recurrent and antibiotic refractory infections, especially in patients with CF and osteomyelitis (OM). Several studies looking at OM patients showed that those patients with SCV S. aureus infections had recurrences, whereas those with normal S. aureus infections treated optimally did not, and the patients with SCV infections had been previously exposed to gentamicin (bone implants) over a period of time. Studies looking at CF patients (in USA and Europe) reported half of this patient population having been infected with S. aureus in the respiratory tract, half of which ended up to be SCV S. aureus. One of the conclusions of these studies was that the S. aureus resistance to SXT seen in the CF patients was due to the ability of such isolates to obtain thymidine from the environment, thus bypassing the folic acid synthetic pathway blocked by SXT. Such strains cannot grow on a medium with low thymidine content (thymidine-dependent S. aureus) but because bronchial secretions from CF patients usually are purulent and contain many degenerate cells, the DNAase produced by S. aureus would degrade the DNA released from these cells, resulting in the release of thymidine that the organism then could use for growth. More then 50 % of SCV strains isolated from the CF patients would show double auxotrophy for thymidine and menadione or hemin (Figures 4 and 5).

SCV infection is associated with high rates of recurrences and the clinical courses of acute and chronic bacterial infection differ significantly; some cases represent phenotypic switching of the bacteria, allowing them to become better-adapted parasites with a greater potential for survival and dispersal because of the formation of SCVs.


The treatment of SCV S. aureus infection has not being defined yet. In a tissue-culture system with SCV inside the endothelial cells, SXT in combination with Rifampin was the most active therapeutic regimen, but many other antibiotics that penetrated well into mammalian cells were not effective against SCV S. aureus. Another treatment option would be reversal of auxotrophy, which is encouraging, because in vitro studies did result in making the organism more susceptible to antibiotics. For the menadione auxotrophs, vitamin K administration is able to do the reversal of auxotrophy (clinical trials are to follow and see how beneficial it is).



  1. Looney, W J, Small-colony variants of Staphylococcus aureus, British Journal of Biomedical Science, 2000.
  2. Agarwal, Hemant MBBS *; Verrall, Rosemary BS ++; Singh, Sudha P. MD, et al. Small colony variant staphylococcus aureus multiorgan infection, Pediatric Infectious Disease Journal. 26(3):269-271, March 2007.
  3. Orjan Samulelsen, Hanne Husom Haukland, Barbara C. Kahl, et al., Staphylococcus aureus small colony variants are resistant to the antimicrobial peptide lactoferricin B, Journal of Antimicrobial Chemotherapy 2005 56(6):1126-1129.
  4. RA Proctor, G Peters, Small colony variants in Staphylococcal infections: Diagnostic and therapeutic implications, Clinical Infectious Diseases, 1998.
  5. von Eiff C, Bettin D, Proctor RA, et al., Recovery of small colony variants of Staphylococcus aureus following gentamicin bead placement for osteomyelitis. Clinical Infectious Diseases. 1997 Nov; 25(5):1250-1.
  6. RA Proctor, B Kahl, C von Eiff, et al., Staphylococcal small colony variants have novel mechanisms for antibiotic resistance, Clinical Infectious Diseases, 1998
  7. N. Baumert, C von Eiff, F Schaaff, et al., Physiology and antibiotic susceptibility of Staphylococcus aureus small colony variants, Microbial Drug Resistance, 2002

Contributed by Anca Florea, MD, William Pasculle, Sc.D and Mrs. Debbie Simonetti

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