Small colony variants of Staphylococcus aureus can cause persistent and recurrent infections. There are only a few reports of small colony variants of coagulase-negative staphylococci. Herein a case of infection with a teicoplanin-resistant small colony variant of Staphylococcus epidermidis is presented. The small colony variant was isolated from blood cultures of a patient with acute leukaemia and therapy-induced neutropenia who was treated with vancomycin for catheter-associated bloodstream infection. Despite removal of the catheter and adequate antibiotic therapy, the infection did not clear and the patient died 20days after continuous antibiotic therap

Adler, H.

Frei, R.

Widmer, A.

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Eur J Clin Microbiol Infect Dis (2003) 22:746–748DOI 10.1007/s10096-003-1029-9C ONC I S E AR T I C L EH. Adler · A. Widmer · R. FreiEmergence of a Teicoplanin-Resistant Small Colony Variantof Staphylococcus epidermidis During Vancomycin TherapyPublished online: 6 November 2003 Springer-Verlag 2003Abstract Small colony variants of Staphylococcus au-reus can cause persistent and recurrent infections. Thereare only a few reports of small colony variants ofcoagulase-negative staphylococci. Herein a case ofinfection with a teicoplanin-resistant small colony variantof Staphylococcus epidermidis is presented. The smallcolony variant was isolated from blood cultures of apatient with acute leukaemia and therapy-induced neu-tropenia who was treated with vancomycin for catheter-associated bloodstream infection. Despite removal of thecatheter and adequate antibiotic therapy, the infection didnot clear and the patient died 20 days after continuousantibiotic therapy.IntroductionSmall colony variants (SCVs) of Staphylococcus aureushave been found in a variety of clinical specimens andhave been associated with persistent and recurrentinfections [1, 2, 3]. Only a few cases of infection withSCVs of coagulase-negative staphylococci (CoNS) havebeen reported. SCVs of Staphylococcus epidermidis havebeen linked to prosthetic heart valve endocarditis andinfection of pacemaker electrodes [4, 5]. Bloodstreaminfection caused by Staphylococcus epidermidis andStaphylococcus capitis following pacemaker implantationhas also been reported [6]. Here we describe a te-icoplanin-resistant SCV of Staphylococcus epidermidiswhich emerged during vancomycin therapy of a catheter-associated bloodstream infection in a neutropenic patient.Case ReportA 69-year-old patient was admitted to hospital for treatment ofacute myeloid leukaemia. He was treated with high-dose chemo-therapy and became neutropenic and febrile. Despite broad-spectrum antibiotic and amphotericin B therapy, the fever persisted.Between day 5 and day 16 of hospitalisation 15 blood cultures weretaken, which yielded no growth. On day 20 of hospitalisationStaphylococcus epidermidis was isolated from two of two bloodcultures (blood culture results from day 20–42 are listed in Table 1).The isolates were methicillin resistant and susceptible to vanco-mycin and teicoplanin. Treatment with vancomycin 1 g b.i.d. wasstarted, adjusted to renal insufficiency. In addition, an antibiotic-lock (with vancomycin 1000 g/ml in liquemin) was infused intothe central venous catheter in an attempt to save it. A normalcolony form and an SCV of Staphylococcus epidermidis wereisolated from a blood culture taken 11 h after the start ofvancomycin therapy. Both colony forms were methicillin resistantand vancomycin sensitive. While the normal form was teicoplaninsensitive, the SCV was teicoplanin resistant. A blood culture taken24 h after the start of antibiotic therapy yielded no bacterial growthbut Staphylococcus epidermidis was again isolated from a bloodculture of the following day. Three days after the initiation ofvancomycin therapy the central-venous catheter was replaced.Cultures of the catheter tip yielded no growth. On day 31 ofhospitalisation amikacin was added to the treatment regimen.Despite adequate therapy, the patient continued to be septic andboth colony forms of Staphylococcus epidermidis were isolatedfrom several blood cultures. The central venous catheter wasremoved on day 35 of hospitalisation. No bacteria could be culturedfrom the catheter. On day 38, rifampicin was added to the treatmentregimen. Ultrasound examination excluded the presence of septicthrombophlebitis. Transesophageal echocardiography did not showany evidence of endocarditis. Life support was suspended becausethe patient did not recover from neutropenia and fungal pneumoniawas suspected. High-dose corticosteroid therapy was added to theregimen to control continuous febrile episodes with shivering. Thepatient died on day 20 after the start of antimicrobial treatment as aresult of non-responding clinical sepsis. Autopsy results confirmedthere was no evidence of endocarditis or septic thrombophlebitis.Histologic examination revealed multiple nodes with fungalelements compatible with aspergillosis in the lower right lobe ofthe lung. However, no fungi grew in cultures from lung tissue,presumably due to the antifungal therapy.H. Adler ()) · R. FreiBacteriology Laboratory,University of Basel Hospitals and Clinics,Petersgraben 4, 4031 Basel, Switzerlande-mail: hadler@uhbs.chTel.: +41-61-6254228Fax: +41-61-2655355A. WidmerDivision of Hospital Epidemiology,University of Basel Hospitals and Clinics,Petersgraben 4, 4031 Basel, SwitzerlandMaterials and MethodsBlood cultures were processed with an automated system (BacT/ALERT; bioMrieux, USA). Aliquots of the broth were subculturedon Columbia agar with 5% sheep blood and incubated at 37C in5% CO2 and under anaerobic conditions for 48 h. Intravenouscatheter tips were cultured as described by Maki et al. [7]. Theclinical isolates of Staphylococcus epidermidis were identifiedbased on their biochemical profile with the API Staph Kit(bioMrieux, France). Identification was confirmed using theMicroSeq 16S rRNA gene kit (Applied Biosystems, USA). Theamplified DNA was sequenced on an automated DNA sequencer(ABI PRISM 310 Sequencer, Applied Biosystems). Moleculartyping was performed by pulsed-field gel electrophoresis (PFGE) aspreviously described [8], genomic DNA being digested by therestriction endonuclease SmaI. Susceptibility testing was performedaccording to NCCLS guidelines [9] by broth microdilution usingcommercially manufactured plates (Micronaut-S; Merlin Diagnos-tics, Germany). Resistance to methicillin was confirmed bydetection of penicillin-binding protein 2’ (MRSA-Screen; DenkaSeiken, Japan) after induction with oxacillin [10]. MICs ofteicoplanin and vancomycin were confirmed by the E test (AB-Biodisk, Sweden), applying an inoculum of 0.5 McFarland onMueller Hinton agar with 5% sheep blood. In addition, isolateswere screened for hetero-resistance to vancomycin using thevancomycin E test with an inoculum of 2.0 McFarland on brainheart infusion agar [11].Results and DiscussionThe normal colonies of Staphylococcus epidermidis werefound after overnight incubation of subculture plates.SCVs were usually detected after 24–72 h of incubation.Their colony diameter was around 1 mm. SCVs showed atendency to revert to the normal form upon furthersubculturing and we were not able to conserve the smallcolony phenotype over prolonged periods of time. Bothcolony forms were identified as Staphylococcus epider-midis. Sequence analysis of a 500-bp fragment of therRNA gene showed 100% homology with the type strain.PFGE restriction fragment patterns of normal colony formand of the SCVs were indistinguishable. All isolates ofStaphylococcus epidermidis (normal form and SCVs)were resistant to methicillin, tobramycin, cotrimoxazole,ciprofloxacin and levofloxacin and sensitive to netilmicin.They were uniformly susceptible to vancomycin (MIC3 mg/l) and there was no evidence of vancomycin hetero-resistance. While the normal colony forms were suscep-tible to teicoplanin (MIC 1 mg/l), all but one of theisolates of SCVs were teicoplanin resistant (MIC 24 mg/l).SCVs of Staphylococcus aureus have been reported tocause persistent and recurrent infections [1, 2, 3].Compared with their normal phenotypes, they often showreduced susceptibilities to several antimicrobial agents,namely aminoglycosides and cotrimoxazole [3, 12]. In thefew reported cases of infection with SCVs of CoNS [4, 5,6] such differences between the two colony forms werenot observed. Here we describe the first case of aninfection with a teicoplanin-resistant staphylococcal SCV.The patient was treated with vancomycin includingvancomycin-lock for suspected bloodstream infectionafter methicillin-resistant Staphylococcus epidermidishad been isolated from two blood cultures. A normalcolony form and an SCV of Staphylococcus epidermidiswere recovered from a blood culture performed 11 h afterthe start of vancomycin therapy. In contrast to the normalphenotype, the SCV was resistant to teicoplanin. BothTable 1 Blood culture resultsfrom days 20–42 of hospital-izationDay ofhospital-isationBloodcultureno.Isolation of S. epidermidis RemarksLarge colonies SCVs20 16 +, teicoplanin S 17 +, teicoplanin S 21 18 +, teicoplanin S 22 19 +, teicoplanin S  start of vancomycin therapy20 +, teicoplanin S +, teicoplanin R23 21  24 22 +, teicoplanin S 25 23   replacement of catheter24 +, teicoplanin S 26 25 +, teicoplanin S +, teicoplanin S27 26 +, teicoplanin S +, teicoplanin R28 27 +, teicoplanin S +, teicoplanin R29 28 +, teicoplanin S 30 29 +, teicoplanin S 31 30 +, teicoplanin S +, teicoplanin R addition of amikacin to therapy35 31 +, teicoplanin S +, teicoplanin R replacement of catheter32 +, teicoplanin S 33 +, teicoplanin S 37 34 +, teicoplanin S 35 +, teicoplanin S 38 addtion of rifampicin to therapy39 36  40 37 +, teicoplanin S 41 38 +, teicoplanin S 39  42 40   patient died+, growth; , no growth; S, susceptible; R, resistant747phenotypes were susceptible to vancomycin. IdenticalPFGE patterns showed both forms to be clonal.Two scenarios exist for the occurrence of the tei-coplanin-resistant SCV. Firstly, resistance to teicoplanindeveloped during exposure to the high concentration ofvancomycin associated with vancomycin-lock. Similarly,SCVs isolated from patients after local treatment forosteomyelitis with gentamicin beads had up to 32-foldhigher MICs of gentamicin than the parent strain (1 mg/mlvs. <0.031 mg/ml) [2]. It is remarkable that resistance toteicoplanin, but not to vancomycin, may have evolvedunder vancomycin therapy. Even though development ofvancomycin-resistant SCVs of Staphylococcus haemolyti-cus after exposure to vancomycin has been reported [13],resistance to teicoplanin might still be easier to obtainunder selective pressure from vancomycin than resistanceto vancomycin itself. Cercenado et al. [14] found CoNSwith reduced susceptibilities to teicoplanin but fullsusceptibility to vancomycin in 32 patients, eight ofwhom had been treated with vancomycin. Secondly,taking into account the tendency of SCVs to revert to thenormal form, we cannot exclude the possibility that theydeveloped spontaneously before vancomycin therapy butwere missed in the corresponding blood cultures. Emer-gence of a teicoplanin-resistant SCV of Staphylococcusaureus during experimental foreign body infection in a ratwithout antibiotic therapy has been reported [15]. How-ever, this is the first report of the emergence of ateicoplanin-resistant SCV of a Staphylococcus species ina patient.Based on the following evidence, it is conceivable thatpersistence of the bloodstream infection was caused bythe development of the SCV. (i) Antibiotic therapy wasperformed according to established treatment guidelinesand susceptibility testing. (ii) The central-venous line waspromptly removed once persistent bacteremia was ob-served, whereas bacteria could not be cultured from thecatheter. A new catheter was inserted at a differentlocation. (iii) Neither doppler ultrasound of the subclavianvein and transesophageal echocardiography nor theautopsy showed any evidence of septic thrombophlebitisor endocarditis. Treatment failure despite adequate anti-biotic therapy has been reported in four patients withosteomyelitis due to SCVs of Staphylococcus aureus [2]and in a patient with pacemaker-associated vegetationsdue to SCVs of Staphylococcus capitis [6]. SCVs ofStaphylococcus epidermidis were also isolated in a fatalcase of prosthetic heart valve endocarditis [4].Between the start of vancomycin therapy and the deathof the patient, both colony forms were isolated from sixblood cultures while ten blood cultures yielded solely thenormal form. Taking into account its tendency to revert,we believe that Staphylococcus epidermidis survived asSCV and reverted to the normal form upon cultivation.Because of both their tendency to revert and their slowgrowth, SCVs of staphylococci may easily go undetected.Thus, the number of cultures should be increased andincubation of subcultures should be extended if infectionwith SCVs of staphylococci is suspected.References1. Proctor RA, van Langevelde P, Kristjansson M, Maslow JN,Arbeit RD (1995) Persistent and relapsing infections associatedwith small-colony variants of Staphylococcus aureus. ClinInfect Dis 20:95–1022. von Eiff C, Bettin D, Proctor RA, Rolauffs B, Lindner N,Winkelmann W, Peters G (1997) Recovery of small colonyvariants of Staphylococcus aureus following gentamicin beadplacement for osteomyelitis. Clin Infect Dis 25:1250–12513. 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Emergence of a Teicoplanin-Resistant Small Colony Variant of Staphylococcus epidermidis During Vancomycin Therapy

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Emergence of a Teicoplanin-Resistant Small Colony Variant of Staphylococcus epidermidis During Vancomycin Therapy

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