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PubMed2006

Virulence of Staphylococcus aureus small colony variants in the Caenorhabditis elegans infection model.

Small colony variants (SCVs) of Staphylococcus aureus are slow-growing morphological variants that have been implicated in persistent, relapsing, and antibiotic-resistant infections. The altered phenotype of SCVs in most strains has been attributed to defects in electron transport due to mutations in hemin or menadione biosynthesis. The pathogenic capacity of SCVs compared to phenotypically normal strains is variable depending on the attribute examined, with some studies showing reduced virulence of SCVs and others demonstrating normal or heightened virulence. Recently, the nematode Caenorhabditis elegans has been successfully employed as an alternative host to investigate virulence mechanisms of a variety of bacterial pathogens, including S. aureus. In this study, we show that clinical SCVs as well as hemB- and menD-deficient mutants of S. aureus are greatly reduced in virulence in the C. elegans infection model.

Animals↗

PubMed2006

Prevalence and clinical significance of Staphylococcus aureus small-colony variants in cystic fibrosis lung disease.

Small-colony variants (SCVs) of Staphylococcus aureus can be isolated from the chronically infected airways of patients suffering from cystic fibrosis (CF). These slow-growing morphological variants have been associated with persistent and antibiotic-resistant infections, such as osteomyelitis and device-related infections, but no information is available to date regarding the clinical significance of this special phenotype in CF lung disease. We therefore investigated the prevalence of S. aureus SCVs in CF lung disease in a 12-month prospective study and correlated the microbiological culture results with the patients' clinical data. A total of 252 patients were screened for the presence of SCVs. The prevalence rate was determined to be 17% (95% confidence interval, 10 to 25%) among S. aureus carriers. S. aureus isolates with the SCV phenotype showed significantly higher antibiotic resistance rates than those with the normal phenotype. Patients positive for SCVs were significantly older (P = 0.0099), more commonly cocolonized with Pseudomonas aeruginosa (P = 0.0454), and showed signs of more advanced disease, such as lower forced expiratory volume in 1 s (P = 0.0148) than patients harboring S. aureus with a solely normal phenotype. The logistic regression model determined lower weight (P = 0.016), advanced age (P = 0.000), and prior use of trimethoprim-sulfamethoxazole (P = 0.002) as independent risk factors for S. aureus SCV positivity. The clinical status of CF patients is known to be affected by multiple parameters. Nonetheless, the independent risk factors determined here point to the impact of S. aureus SCVs on chronic and persistent infections in advanced CF lung disease.

Adolescent↗

PubMed2000

Staphylococcus aureus small colony variants: formation and clinical impact.

S. aureus small-colony variants are a naturally occurring subpopulation which grow slowly and produce small colonies on routine media. They also demonstrate a number of other characteristics that are atypical for S. aureus including reduced alpha-toxin production and delayed coagulase activity. The connection of S. aureus SCVs with persistent and relapsing infections has been defined over the past decade, especially in patients with chronic osteomyelitis and in cystic fibrosis patients as demonstrated by prospective studies. While the studies with clinical isolates of SCVs suggested a link between electron transport-defective strains and persistent infections, a defined hemB mutant with the SCV phenotype provided strong additional evidence for these connections. The hemB mutant was phagocytosed by cultured endothelial cells, but did not lyse these cells, because the mutant produced very little alpha-toxin. The intracellular location may shield the SCVs from host defenses and antibiotics, thus providing one explanation for the difficulty in clearing S. aureus SCVs from host tissues.

Colony Count, Microbial↗

PubMed1979

Selection of small-colony variants of Enterobacteriaceae by in vitro exposure to aminoglycosides: pathogenicity for experimental animals.

Small-colony variants of gram-negative genera of Enterobacteriaceae were selected by in vitro exposure to gentamicin. These variants were shown to have decreased susceptibility in vitro to aminoglycosides. They were lethal for mice following intraperitoneal injection, with the LD50 (50% lethal dose) being the same as, or slightly less than, that for the parent organism. Variants of strain no. 2401 of Proteus mirabilis caused urinary tract infection in mice after implantation into their bladders. Although the variants grew somewhat less rapidly than did parent organisms, both parent and variant colonies alkalinized urine at the same rate. Electron microscopic study showed no differences between colonies of parents and variants. These studies indicated that small-colony variants of Enterobacteriaceae are pathogenic for experimental animals. Further, they may cause disease in humans and should not necessarily be regarded as only laboratory curiosities.

Aminoglycosides↗

PubMed2006

First case of febrile bacteremia due to a wild type and small-colony variant of Escherichia coli.

Reported here is a case of a febrile illness caused by a wild type and small-colony variant of Escherichia coli in an anorectic patient. A review of the literature revealed that the formation of small-colony variants in E. coli has been recognized since 1931. In recent years, an association has been established between those variants and chronic recurrent infections. This report describes for the first time the isolation of an E. coli small-colony variant from a blood culture of a patient who had suffered from chronic urinary tract infections in the past.

Adult↗

PubMed1988

Phenotypic selection of small-colony variant forms of Staphylococcus epidermidis in the rat model of endocarditis.

Four pathogenic strains of Staphylococcus epidermidis (sensu strictu)-EC, RP62A, LW, and HBSN--exhibited a mixed population of colony phenotypes when plated onto a high-salt, low-glucose agar ("Memphis agar"). When compared with challenge inocula, significant shifts in colony populations to the small-colony variant forms occurred for all four strains for isolates recovered from infected vegetations of rats with catheter-induced endocarditis. Various colony phenotypes of the HBSN strain were compared in virulence studies by using the rat model of endocarditis. The infectivity rate of the small-colony variant forms was significantly less than that of either the normal parent form (P less than .05) or the mixed phenotypic inoculum (P less than .05). These data indicate that the small-colony variant forms may be selected for, once endocardial infections are established, and that the small-colony variant forms alone are much less able to initiate and/or sustain intracardiac infections in experimental endocarditis.

Animals↗

PubMed2004

Effect of trimethoprim-sulfamethoxazole prophylaxis in AIDS patients on the formation of the small colony variant phenotype of Staphylococcus aureus.

Emergence of Staphylococcus aureus small colony variants (SCVs) has been associated with antibiotic use, particularly with trimethoprim-sulfamethoxazole (TMP-SMZ). In this study, 634 specimens of 125 patients with AIDS were prospectively screened for S. aureus with normal phenotype and for S. aureus SCVs. Charts of these patients were reviewed for previous prophylaxis with TMP-SMZ often used as long-term pneumocystosis prophylaxis. Thirty-seven patients (29.6%) harbored S. aureus in their anterior nares, three of these patients (8.1%) had S. aureus SCVs. Interestingly, TMP-SMZ does not appear to select for S. aureus SCVs in nasal swabs of these patients.

AIDS-Related Opportunistic Infections↗

PubMed2004

Persistence of a Staphylococcus aureus small-colony variant under antibiotic pressure in vivo.

Staphylococcus aureus small-colony variants (SCVs) have been implicated in chronic and persistent infections. Bovine mastitis induced by S. aureus is an example of an infection difficult to eradicate by conventional antimicrobial therapies. In this study, the ability to colonize mouse mammary glands and persist under antibiotic treatment was assessed for S. aureus Newbould and an isogenic hemB mutant, which exhibited the classical SCV phenotype. The hemB mutant showed a markedly reduced capacity to colonize tissues. However, although the hemB mutant was as susceptible as S. aureus Newbould to cephapirin in vitro, it was over a 100 times more persistent than the parental strain in the mammary glands when 1 or 2 mg kg(-1) doses were administrated. These results suggest that, although the hemB mutant has a reduced ability to colonize mammary glands, the SCV phenotype may account for the persistence of S. aureus under antibiotic pressure in vivo.

Animals↗

PubMed1997

Decreased susceptibility to antibiotic killing of a stable small colony variant of Staphylococcus aureus in fluid phase and on fibronectin-coated surfaces.

The frequency of small colony variants of staphylococci associated with persistent, antibiotic resistant and relapsing infections is probably underestimated. These variants demonstrate decreased metabolism, leading to slow growth, increased resistance to cell-wall-active antibiotics, and decreased uptake of aminoglycoside antibiotics. This altered phenotype arises from defects in menadione and haemin biosynthesis resulting in impaired electron transport and decreased ATP concentrations. The recent acquisition of a stable small colony variant (SCV strain JB1), generated from strain 6850 of Staphylococcus aureus, allowed us to study the susceptibilities to antibiotic killing of parent and variant strains. Because differences in susceptibilities have been found between unattached and surface-adherent organisms, we tested both strains in solid and fluid-phase assays. Suspensions of SCV strain JB1 exposed to 8 x MIC of either oxacillin, vancomycin or fleroxacin, exhibited lower reductions in viable counts than the parent strain 6850, especially when high bacterial concentrations (1-2 x 10(7) cfu/mL) of either strain were tested. Susceptibility to antibiotic killing of bacteria attached to fibronectin-coated coverslips was markedly influenced by their growing or nongrowing state on the surface. In the latter condition, surface-bound SCV organisms were highly resistant to the bactericidal action of oxacillin or vancomycin in contrast to the parental strain which was normally eliminated by each antimicrobial agent. In conclusion, the decreased susceptibility of the stable SCV strain of S. aureus to bactericidal concentrations of antibiotics may help to explain the persistence of such organisms in chronic infections.

Anti-Bacterial Agents↗

PubMed1999

Bloodstream infections caused by small-colony variants of coagulase-negative staphylococci following pacemaker implantation.

Small-colony variants (SCVs) of Staphylococcus aureus cause persistent and relapsing infections. Relatively little is known regarding infections caused by SCVs of coagulase-negative staphylococci. We report two cases of pacemaker electrode infections due to SCVs of Staphylococcus epidermidis and Staphylococcus capitis. Sequence analysis of a portion of the 16S rRNA gene (16S rDNA) confirmed the identity of the staphylococcal species as S. capitis and S. epidermidis. Isolates from cultures of blood obtained over at least a 2-week interval were compared by pulsed-field gel electrophoresis and found to be clonal even though the colony morphology was very different. Analysis for auxotrophism revealed hemin dependencies for all isolated SCVs. The two cases have several clinical and laboratory characteristics (which are also seen with S. aureus SCV infections) and strongly suggest that SCVs of coagulase-negative staphylococci must be actively sought, because they grow very slowly and can be easily missed.

Bacteremia↗

PubMed2004

Growth control of small-colony variants by genetic regulation of the hemin uptake system.

Small-colony variants (SCVs) are slow-growing variants of human bacterial pathogens. They are associated with chronic persistent infections, and their biochemical identification and antimicrobial treatment are impaired by altered metabolic properties. To contribute to the understanding of SCV-mediated infections, we analyzed a clinical SCV isolate derived from a chronic prosthetic hip infection. A sequence analysis of housekeeping genes identified an Enterobacter hormaechei-like organism. The SCV phenotype, with growth as microcolonies, was caused by a block within the heme biosynthesis pathway through deletion of the hemB locus, as shown by hybridization and complementation experiments. At a low frequency, large-colony variants (LCVs) arose that were dependent on exogenous hemin. To investigate this phenomenon, we cloned and sequenced the 5.8-kb hemin uptake system, denoted ehu. Gene expression analysis indicated regulation of this locus in wild-type bacteria by the global iron regulator Fur. Inactivation of Fur in LCVs caused the derepression of ehu expression and facilitated bacterial growth. Genetic alterations of the fur locus in LCVs were identified as insertions of IS1A elements and point mutations. In contrast, SCVs could utilize exogenous hemin only in the absence of iron. Thus, we provide the first molecular characterization of the growth properties of a clinical SCV isolate, which may help to improve the diagnostic and therapeutic management of patients with chronic persistent infections.

Bacterial Proteins↗

PubMed2003

Virulence of a hemB mutant displaying the phenotype of a Staphylococcus aureus small colony variant in a murine model of septic arthritis.

Persistence of Staphylococcus aureus during invasive infections has been associated with a small-colony variant (SCV) phenotype. SCVs are frequently auxotrophic for menadione or hemin, two compounds involved in the biosynthesis of the electron transport chain. SCVs have been shown to be more resistant to antibiotics such as aminoglycosides, grow slowly and persist intracellularly. The aim of this study was to assess the virulence of an hemB mutant, which has been shown to display the typical characteristics of clinical SCVs, in a murine model of septic arthritis. NMRI mice were inoculated intravenously with either the wild type strain Newman or with its mutant displaying the SCV phenotype. The clinical, bacteriological, and histopathological progression of the disease was studied. Mice inoculated with the hemB mutant displayed a higher frequency and a significantly higher severity of arthritis than mice inoculated with the wild type Newman strain. Despite that, the mutant inoculated mice displayed significantly lower bacterial burden in their kidneys and joints compared with mice exposed to the wild parental strain. Notably, the hemB mutant produced almost 20 times more protease in vitro than the parental strain. We conclude that the small colony variants of S. aureus are more virulent on a per organism basis than its isogenic parental strain in the model of septic arthritis. This can at least in part be explained by the ability of SCV to produce high amounts of destructive proteases.

Animals↗

PubMed1998

In vitro and In vivo characterization of a small-colony variant of the primary form of photorhabdus luminescens MD (Enterobacteriaceae)

A small-colony variant (Vsm) of the primary form (Vp) of Photorhabdus luminescens MD from in vitro and in vivo cultures is described. Unlike the primary form, Vp, the Vsm variant is not the preferred diet of its nematode symbiont, a Heterorhabditis sp., does not support development and reproduction of the nematode, and is less pathogenic than Vp to Galleria mellonella larvae. Vsm cells were carried by 25% of infective juveniles, but they comprised a very low percentage ( approximately 0.4%) of the total cells carried by the juvenile. In vitro subculture and in vivo injection into the larvae with either Vp or Vsm always produced a mixture of both Vp and Vsm. In nematode-bacterium-infected G. mellonella larvae, the Vp population in the hemocoel was high (4 x 10(9) to 5 x 10(9) CFU/g of wet insect tissue) at 24 h after infection, decreased about 10-fold by 48 h, and then regained a high level at day 5 before decreasing at day 7 and then remaining relatively constant through day 15 postinfection. The Vsm population, under the same conditions as those of Vp, increased gradually to a high level (9 x 10(8) CFU/g of wet insect tissue) at day 5 postinfection and then declined gradually through day 15.

Journal Article↗

PubMed1961

SMALL COLONY VARIANT IN CANDIDA ALBICANS.

Bianchi, Donald E. (San Fernando Valley State College, Northridge, Calif.). Small colony variant in Candida albicans. J. Bacteriol. 82:101-105. 1961.-Various techniques were used to attempt to alter the frequency of wild-type and small-type colonies in growing cultures of Candida albicans. Ultraviolet light and heat shocks were found to temporarily increase the occurrence of small colonies and several benzazoles were found to increase the number of large colonies. The alteration by the benzazoles was found to be only temporary, and brought about by an increase in the rate of growth of the small type colonies. This benzazole action may be enhanced or inhibited by the addition of purines depending upon the applied concentration.

Journal Article↗

PubMed1998

Small colony variants in staphylococcal infections: diagnostic and therapeutic implications.

The discovery of S. aureus small colony variants as persistent and intracellular has provided new insight into the understanding of pathogenesis associated with staphylococcal diseases. Survival advantages are afforded to SCVs on the basis of their ability to hide within host cells, which provide protection from the immune system and some antibiotics. In addition, because most clinical SCVs are defective in electron transport, their uptake of positively charged antimicrobial substances is reduced. The atypical clinical microbiologic characteristics make identification and susceptibility testing difficult. SCVs have been recovered from patients with unusually persistent infections, particularly those patients with long disease-free intervals, and from patients who are chronically exposed to aminoglycosides and TMP-SMZ, suggesting that these clinical situations are those in which SCVs should be suspected and the clinical laboratory should carefully search for them.

Anti-Bacterial Agents↗

PubMed2006

Transcription of virulence factors in Staphylococcus aureus small-colony variants isolated from cystic fibrosis patients is influenced by SigB.

Staphylococcus aureus small-colony variants (SCVs) are believed to account in part for the persistence of S. aureus during chronic infections. Little is understood about the gene expression profile that may explain the phenotype and distinguish SCVs from prototype S. aureus strains. In this study, DNA array transcriptional profiles of clinical SCVs isolated from the airways of cystic fibrosis patients were obtained and compared to those obtained from a laboratory-derived SCV strain (i.e., a respiratory-deficient hemB mutant) and prototype S. aureus strains. The genes commonly up-regulated in both hemB and clinical SCVs were found to be implicated in fermentation and glycolysis pathways. The well-known virulence regulator agr was not activated in SCVs, and such strains had low levels of alpha-toxin (hla) gene expression. Clinical SCVs also had a transcriptional signature of their own. Of striking interest is that many genes, most of them under the positive control of the alternate sigma factor SigB, were specifically up-regulated and differed in that way from that seen in prototype S. aureus and the hemB mutant. Since SigB influences up-regulation of adhesin type genes while indirectly down-regulating exoproteins and toxins, we evaluated the internalization and persistence of SCVs in mammalian cells. Results showed that clinical SCVs persisted much more efficiently in cells than the hemB and prototype strains and that a sigB mutant was a poor persister. Thus, it appears that the agr locus plays a minor role in the regulation of the virulon of SCVs, unlike SigB, which may have a key role in intracellular persistence.

Animals↗

PubMed2000

Small-colony variants of Staphylococcus aureus.

Staphylococcus aureus remains a versatile and dangerous pathogen. Small-colony variants (SCVs) of S. aureus are a naturally occurring sub-population, first described nearly 100 years ago. These variants, of which there are different classes, grow slowly and have many atypical characteristics thought to be due to defective electron transport, and include minute colony forms. SCVs have been isolated from sites of infection, particularly persistent recurrent ones (e.g. in chronic osteomyelitis and cystic fibrosis), and also may arise following exposure to certain antibiotics. During infection the intraendothelial-cell milieu stimulates the formation of SCVs, which can better survive the assault of cell-mediated immunity. SCV phenotypes produce less tissue damage than normal staphylococci. Although microscopic morphology and Gram's staining of SCVs are normal, clinical microbiology laboratories may fail to detect them because of their very slow growth. The full extent of the role of S. aureus SCVs in clinical disease, and the most appropriate means of identifying such strains or testing to predict the clinical usefulness of therapeutic regimens, remains unknown. Failure to recover SCVs results in a major susceptibility reporting error, as the more resistant component of the infection will not have been reported. No controlled trials of therapy have been conducted, and, thus, optimal therapy has yet to be defined. However, SCVs are resistant to aminoglycoside antibiotics, and may be resistant to trimethoprim-sulphmethoxazole. The effectiveness of cell-wall-active antibiotics is reduced. SCVs are transmissible, and current infection control recommendations for normal S. aureus infections are appropriate.

Humans↗

PubMed2006

The small colony variant (SCV) concept -- the role of staphylococcal SCVs in persistent infections.

The recovery of small colony variants (SCVs) from clinical specimens was first described at the beginning of the last century. However, not until the past decade was an association of these variants with chronic, recurrent, and persistent infections such as chronic osteomyelitis and persistent skin and softtissue infection described. Since then, a number of reports and prospective studies have supported a pathogenic role for SCVs in disease. Biochemical and other characteristics of SCVs have suggested a link between electron-transport defective SCV strains and persistent infections, however, the strains examined were genetically undefined SCVs. Therefore, a stable mutant in electron transport was generated by interrupting one of the hemin biosynthetic genes, hemB, in Staphylococcus aureus. This mutant showed characteristics typical of clinical SCVs such as slow growth, decreased pigment formation, low coagulase activity, reduced hemolytic activity, and resistance to aminoglycosides. Furthermore, the mutant was able to persist within cultured endothelial cells due to decreased a-toxin production. It was suggested that the intracellular location of this subpopulation might shield the variants from host defenses and antibiotics, thus providing one explanation for the difficulty in removing SCVs from host tissues. Therefore, a defect in the electron-transport system allows S. aureus SCVs to resist aminoglycosides and persist intracellularly. Because of their fastidious growth characteristics, they are easily missed or misidentified in the clinical laboratory. Therefore, when an infection persists for weeks or months or fails to respond to antimicrobial therapy, clinicians as well as laboratory personnel should consider further efforts to search for this staphylococcal subpopulation.

Animals↗