Introduction: Nocardial arthritis in immunocompetent patients is rare, and the optimum duration of antimicrobial therapy is unknown, although several months of antibiotic treatment is often recommended. Case report: We here report the first case of human infection with a novel Nocardia sp., summarise the epidemiology of nocardial arthritis and outline the feasibility of relatively short antibiotic treatments after careful surgical drainag

Assal, M.

Bouchuiguir-Wafa, K.

Emonet, S.

Harbarth, S.

Ninet, B.

Schrenzel, J.

Uçkay, I.

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CASE REPORTPosttraumatic ankle arthritis due to a novel Nocardia speciesI. Uc¸kay • K. Bouchuiguir-Wafa • B. Ninet •S. Emonet • M. Assal • S. Harbarth • J. SchrenzelReceived: 11 March 2010 / Accepted: 3 May 2010 / Published online: 28 May 2010 Urban & Vogel 2010AbstractIntroduction Nocardial arthritis in immunocompetentpatients is rare, and the optimum duration of antimicrobialtherapy is unknown, although several months of antibiotictreatment is often recommended.Case report We here report the first case of humaninfection with a novel Nocardia sp., summarise the epi-demiology of nocardial arthritis and outline the feasibilityof relatively short antibiotic treatments after careful sur-gical drainage.Keywords Arthritis  Cotrimoxazole  Nocardia Posttraumatic  SurgeryIntroductionNocardia spp are aerobic Gram-positive bacteria that areconsidered to be ubiquitous soil saprophytes [1]. The genusencompasses more than 20 species [2], and new species arecontinuously being identified [2]. Human infections causedby Nocardia spp often appear as pneumonia [2] or dis-seminated diseases in severely immunocompromised hosts[1, 3]. Cotrimoxazole remains the antibiotic of choice[1, 3–7].Nocardial arthritis in immunocompetent patients is veryrare. Although no studies have compared the drainageprocedure to the no-drainage procedure, the vast majorityof experts recommend joint drainage in patients with septicarthritis [4]. In contrast, the duration of concomitant anti-biotic treatment remains unknown only single case reportshave been published.We report here the first human infection with a novelNocardia sp. that occurred as a posttraumatic arthritis in animmunocompetent host. We further discuss the feasibilityof a relatively short antibiotic treatment after an adequatesurgical drainage procedure and review the literature.Case reportA 40-year-old epileptic patient survived a car accident inthe Rhone Valley, France, in May 2, 2008. He sufferedopen fractures (grade IIIb) of both ankles that were con-taminated by earth, which were initially washed and thenstabilised with intramedullar nailing. The patient receivedempirical antibiotic treatment of amoxicillin/clavulanatefor 5 days. After his transfer to the Geneva UniversityHospitals, an elective surgical revision was necessarybecause of incongruence of the articular surfaces. On MayI. Uc¸kay and K. Bouchuiguir-Wafa contributed equally to this work.Parts of the manuscript have been presented as a poster at the 69thAnnual Congress of the Swiss Orthopaedic Society, 24–26 June,Geneva; Abstract P22.I. Uc¸kay (&)  M. AssalOrthopaedic Surgery Service, Geneva University Hospitalsand Faculty of Medicine, University of Geneva,4, Rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerlande-mail: ilker.uckay@hcuge.chI. Uc¸kay  S. Emonet  S. Harbarth  J. SchrenzelService of Infectious Diseases, Geneva University Hospitalsand Faculty of Medicine, University of Geneva,Geneva 14, SwitzerlandK. Bouchuiguir-Wafa  B. Ninet  S. Emonet  J. SchrenzelLaboratory of Bacteriology, Geneva University Hospitalsand Faculty of Medicine, University of Geneva,Geneva, SwitzerlandInfection (2010) 38:407–412DOI 10.1007/s15010-010-0027-y15, both intramedullar nails were removed, and the ankleswere stabilised with external tibio-tarsal fixation devices(Hoffmann II) with the intention that these devices remainin place for 6 weeks. However, on June 19, the patientdeveloped clinical signs of arthritis on his right ankle(erythema, tenderness, pain) with a purulent discharge ofthe scar. He had no concomitant fever, and the serumC-reactive protein level was 52 mg/L. All external fixationand thus all foreign material were therefore removed after5 weeks, 1 week earlier than initially scheduled. The bonewas considered to be sufficiently consolidated so that nonew fixation was necessary on the infected ankle. Thepatient was given instructions on how to discharge his legfor another 2 months. Gram-staining and microscopicexamination of the pus did not show any pathogen orcrystal. The patient was empirically treated with intrave-nous vancomycin 2 g/day and ceftriaxone 2 g/day. Fivedays later, colonies of a Nocardia sp. appeared on micro-biological cultures of the pus. The antibiotic treatment waschanged to intravenous cotrimoxazole (160 mg trimethro-prim/800 mg sulfamethoxazol; three times daily) for5 days, followed by oral cotrimoxazole 960 mg (double-strength tablets) twice daily for a total of 8 weeks (untilAugust 26). The fourth and last drainage performed on July4 revealed that the surgical site was sterile. The cure wasconsidered to be complete, and the patient has had norecurrence based on a follow-up at 20 months. No under-lying immunosuppression was detected at that time.MicrobiologyPhenotypical diagnosisThe Nocardia were cultured on Columbia agar incubatedaerobically at 35C in an atmosphere enriched with 5%CO2 [3, 8, 9]. Laboratory examination revealed beaded/branching, acid-fast, Gram-positive rods that were positivefor b-lactamase, glucolysis and urease production. All testsfor hydrolysis (casein, xanthine and tyrosine) were nega-tive, as was the reduction of nitrate, growth at 45C, fer-mentation of maltose and the test for esculin. The tests forcasein hydrolysis involved a culture period of 14 days,those for xanthine, 3 weeks and those for tyrosine,4 weeks.Based on these phenotypical characteristics, the culturedNocardia was classified as being closest to N. beijingensis[8, 9]. Antimicrobial minimal inhibitory concentrations(MICs) were determined by the E test (AB Biodisk, Solna,Sweden). The bacterium was susceptible to imipenem,tobramycin, kanamycin, tetracyclines and cotrimoxazolewith corresponding MICs of 0.38, 1.5, 0.12, 0.064 and0.25 mg/L, respectively.Gene sequencingThe sequence of the 16S rRNA gene [10] was determinedby a capillary sequence analyser (ABI 3130 XL DNAanalyser; Applied Biosystems, Foster City, CA). Over a979-bp fragment (region 49–1,027 of the 16S rRNA gene),our strain (GenBank Accession no. GQ281125) showedthree nucleotide differences when compared to N. beij-ingensis [2] (GenBank Accession no. AF154129) and onlyone nucleotide difference with strains from Thailand andJapan [8] (DDBJ Accession no. AB094639–AB094656).Different sequences of Nocardia sp. and one sequence ofN. asteroides (Accession no. Z82227) were also very closeto our strain. Although sequence analysis of the 16S rRNAgene is adequate for the identification of numerousNocardia sp., it is known that the speciation of some iso-lates requires the analysis of another gene target. The geneseqA1 has been described as a more discriminative method[11]. With this approach, our clinical isolate had a seqA1gene showing at least 21 mismatches over 522 bp whencompared to strains N. beijingensis, N. arthritidis orN. abscessus.Review of the literatureTable 1 summarises other clinical and epidemiologicalaspects of the 26 published cases of nocardial arthritis weidentified in the English literature. In one-third of all cases,nocardial arthritis presented secondary to pneumonia, andin one-fourth it was related to a traumatic origin. The kneejoint was involved in half of the cases, and most infectionswere due to N. asteroides. One-half of the patients wereimmunocompromised, and male patients predominated.Cotrimoxazole was used in two-thirds of cases, and theaverage number of surgical interventions per case was 2.3.DiscussionWe report here the first case of human infection with anovel Nocardia sp. that closely resembles N. beijingensisphenotypically. It clearly came from the soil that pene-trated the open fractures of the patient. In a study carriedout in 2001, N. beijingensis was detected in the soil aroundBeijing [2]. In 2004, microbiologists retrospectively iden-tified 19 human cases of N. beijingensis infection in Japanand Thailand [8, 12]. Our phenotypical results are inagreement with the phenotypic characteristics reported inthese earlier studies, with the exception of a negativegrowth test at 45C, while the Asian study reported positivegrowth. Phenotypically, N. abscessus is frequently nitrate-positive and imipenem-resistant, N. arthritidis is nitrate408 I. Uc¸kay et al.Table1Arthritis(andconcomitantinfections)duetoNocardiasppintheEnglishliteratureAuthorPublicationSexAgeofpatient(years)ImmunsuppressionJointInoculationrouteNocardiasppbSurgicaldrainageAntibiotic(dose/day)cDurationOutcomeMooreetal.ArchDermatolSyphilol,1951Male49NoneKneeTraumaN.brasiliensisDrainage(19)Chlortetracycline1,000mgUnknownCureBaikieetal.Lancet,1970Male37NoneLungkneePulmonaryN.asteroidesArthrocentesis(29)Drainage(19)DisarticulationofkneeSulfadiazine6,000mgStreptomycin1,000mgCotrimoxazole2,880mg3monthsDisarticulationofkneeCruickshanketal.CentrAfrJMed,1975Female52NoneAnkleUnknownN.asteroidesAmputationNone–AmputationRaoetal.ArthritisRheum,1981Male52KidneytransplantAcuterejectionKneeUnknownN.asteroidesArthrocentesis(49)Cotrimoxazole1,440mg6monthsCureDiVittorioetal.SouthMedJ,1982Male49LeukemiaLungelbowPulmonaryN.asteroidesArthrocentesis(39)Sulfadiazine6,000mg3monthsCureClagueetal.JRheumatol,1982Male54AlveolarproteinosisPrednisolone15mg/dayLunganklePulmonaryN.asteroidesArthrocentesis(79)Drainage(19)Amoxicillin3,000mgSulfisoxazole6,000mg3monthsCureWilkersonetal.ClinOrthopRelatRes,1984Male32NoneKneeTraumaN.asteroidesLavage(29)Minocycline150mgSulfizoxazol6,000mgSulfisoxazolMinocycline3monthsCureFemale29NoneKneeIntra-articularinjectionsN.asteroidesLavage(19)ClocxyclineCefoxatime3monthsCureConsetal.JRheumatol,1985Male19KidneytransplantLungkneePulmonaryN.brasiliensisArthrocentesis(19)Cotrimoxazole1,920mg5monthsCureBoudoulasetal.ArchDermatol,1985Female56DiabetesmellitusHortons’DiseasePrednisolone20mg/dayLungkneePulmonaryN.asteroidesArthrocentesis(79)Cotrimoxazole7,680mgintravenously2weeksNotreportedNocardial arthritis 409Table1continuedAuthorPublicationSexAgeofpatient(years)ImmunsuppressionJointInoculationrouteNocardiasppbSurgicaldrainageAntibiotic(dose/day)cDurationOutcomeRobinsonetal.BullHospJointDisOrthopInst,1989Female72NoneHip arthroplasty.UnknownN.asteroidesDrainage(several)RemovalofprosthesisCefazoline,AmikacinMicocycline200mgOflaxocin100mg6monthsCureFreibergetal.ClinOrthopRelatRes,1991Male11NoneKneeThornN.asteroidesLavage(19)Cotrimoxazole2,840mg3monthsCureOstrumClinOrthopRelatRes,1991Female51HearttransplantLunghipPulmonaryN.asteroidesLavage(19)Cotrimoxazole1,920mg[30monthsCureAsmaretal.SouthMedJ,1991Male9NoneKneeTraumaN.asteroidesArthrocentesis(29)Cotrimoxazole7weeksCureTorreetal.AnnRheumDis,1991Male75DiabetesmellitusLungkneePulmonaryN.caviaeArthrocentesis(severaltimes)Cotrimoxazole1,920mgAmoxicillin/clavulanicacid1,500mg3monthsCureKolletal.ClinInfectDis,1992Male36CerebralastrocytomaDexamethasoneLungkneePulmonaryN.brasiliensisNoneCotrimoxazole(3weeks)aDeathduetorespiratoryfailureCrouzetetal.RevRhumEdFr,1994Male45AlcoholismBronchialcarcinomaChemotherapyElbowUnknownN.asteroidesArthrocentesis(29)Cotrimoxazole1,920mg4monthsCureDeathduetocancerDinulosetal.PediatrInfectDisJ,1999Female10NoneKneeAnimalaggressionN.asteroidesArthrocentesis(39)Lavage(39)Cotrimoxazole1,440mgClarithromycin500mgAmikacin5monthsCureArnaletal.Lupus,2000Female43SystemiclupuserythematosusHip arthroplastyRecurrencefromlunginfectionN.novaRemovalofprosthesisLavage(29)Imipenem1,500mgAmikacin300mg,erythromycin3monthsCureKahramanetal.TransplantProc,2004Female30KidneytransplantLungkneePulmonaryN.asteroidesNoneCotrimoxazole1,920mg12monthsCure410 I. Uc¸kay et al.Table1continuedAuthorPublicationSexAgeofpatient(years)ImmunsuppressionJointInoculationrouteNocardiasppbSurgicaldrainageAntibiotic(dose/day)cDurationOutcomeAudenaertetal.ActaOrthopBelg,2004Male68COPD-steroidtherapyDiabetesmellitusKneeUnknownN.farcinicaNoneCotrimoxazole6monthsCureUc¸kayetal.AbstractSwissAnnualcongressofInfectiologyBasel,8–10June2005Male84RheumaticpolyarthritisSteroidmedicationKneeTraumaN.brasiliensisLavage(19)Imipenem2,000mgAmikacin1,000mgDoxycyclin200mgLinezolid1,200mgCotrimoxazole1,920mg3monthsCureShahetal.ScandJPlastRecontrSurgHandSurg,2005Male46AutoimmunediseaseSteroidsWristUnknownN.asteroidesLavage(19)CotrimoxazoleNotreportedCureShinetal.Orthopedics,2006Male82NoneKneeUnknownN.asteroidesLavage(19)Cotrimoxazole2,980mg6monthsCureNizametal.JOrthopSurg(HongKong),2007Female55NoneKnee-arthroplastyUnknownN.novaLavage(19)Cotrimoxazole960mgClarithromycin500mgAmoxicillin/clavulicacid1,750mg[24monthsCurePresentarticleMale40NoneAnkleTraumaNovelspeciesLavage(49)Cotrimoxazole1,920mg8weeksCureSummaryMales17/26(65%)Medianage48yearsImunosuppressionin14/26(53%)Kneein11/26(42%)Seedingfromlungin9/26(35%);traumain27%N.asteroides17/26cases(65%)Onaverage2.3surgicalinterventionpercaseCotrimoxazolein18/26cases(69%)Mediandurationof4monthsforsystemicandlocalarthritisinfectionCurewithoutamputationin22/26cases(85%)COPD,ChronicobstructivepulmonarydiseaseaThepatientdiedduetorespiratoryfailureat3weeksoftreatmentbN.asteroidesgroup,notubiquitouslyN.asteroidessensustrictocReminder:a1-dayoraldoseoftwodouble-strengthtabletsofcotrimoxazoleis1,920mgNocardial arthritis 411positive and grows at 45C and N. beijingensis is xanthine-positive. Our strain is also genetically close to N. astero-ides, N. abscessus and N. beijingensis based on 16S rDNAsequencing [10], but substantial differences were docu-mented in the seqA1 gene [11], thus formally excluding N.beijingensis. We found no match for our strain in GenBankand related public databases. Therefore, we have to con-sider this isolate as a novel Nocardia species. With thewidespread use of typing techniques and sequence-basedconfirmation of unusual isolates, it is likely that this novelstrain will be encountered more than once in the future.An important clinical message of this report is the fea-sibility of a rather short antibiotic therapy of only2 months, provided that adequate surgical drainage orrepetitive arthrocentesis has been performed. To date,treatments of several months are still recommended fornocardial arthritis due to the risk of recurrence [13] andsubstantial mortality in the case of disseminated disease[3, 14]. Our review of the literature revealed a mediantreatment duration of 4 months (with the exception of ourtreatment protocol), with one report of a 2-year treatment[6]; these treatments are ubiquitously associated with highcure rates of almost 90% (Table 1). Unfortunately, wewere unable to answer the question of whether the con-tinuous presence of a foreign body—i.e. infection of thejoint prosthesis—with implant retention would influencethe duration of the concomitant antibiotic treatment. Mostnocardial arthritis cases involve native joints or joints withremoved osteosynthesis material.In systemic nocardiosis, the infection usually stems fromthe lungs of a severely immunocompromised host, andarthritis is typically related to haematogenous seeding [1,3]. Consequently, prolonged antibiotic treatment durationsare probably justified. In contrast, in immunocompetentpatients with localised posttraumatic disease in the absenceof a foreign body, one probably could combine adequatesurgical drainage or arthrocentesis with a much shorterantibiotic course, as illustrated in this case, with 8 weeks oftherapy, or in a previous case, with 7 weeks [15]. Thiscombined regimen should reduce the adverse events of aprolonged cotrimoxazole therapy [7]. However, a carefulfollow-up is warranted when the duration of the antibiotictreatment is reduced, given the paucity of experience withthis approach and the novelty of this and future strains.Randomised trials are very likely impossible due to therarity of the disease, and further reports on the efficacy ofrelatively short-course antibiotic treatments are clearlywarranted.Acknowledgments We are indebted to the teams of the Orthopae-dic Service and the Laboratory of Bacteriology.The patient approved this case report by written signature.Conflicts of interest statement None.References1. Beaman BL, Beaman L. Nocardia species: host–parasite rela-tionships. Clin Microbiol Rev. 1994;7:213–64.2. Wang L, Zhang Y, Lu Z, Shi Y, Liu Z, Maldonado L, GoodfellowM. Nocardia beijingensis sp. nov., a novel isolate from soil. Int JSyst Evol Microbiol. 2001;51:1783–8.3. Matulionyte R, Rohner P, Uc¸kay I, Lew D, Garbino J. Seculartrends of nocardia infection over 15 years in a tertiary carehospital. J Clin Pathol. 2004;57:807–12.4. Goldenberg DL, Sexton DJ. Septic arthritis in adults. UpToDate2008. Wolters Kluwer, Alphen aan den Rijn5. Kahraman S, Genctoy G, Arıcı M, C¸etinkaya Y, Altun B, Cag˘larS. Septic arthritis caused by Nocardia asteroides in a renaltransplant recipient. Transplant Proc. 2004;36:1415–8.6. Nizam I, Kohan L, Kerr D. Nocardia nova septic arthritis fol-lowing total knee replacement: a case report. J Orthop Surg(Hong Kong). 2007;15:390–2.7. Kocak Z, Hatipog˘lu CA, Ertem G, Kinikli S, Tufan A, Irmak H,Demiro¨z AP. Trimethoprim–sulfamethoxazole induced rash andfatal hematologic disorders. J Infect. 2006;52:49–52.8. Kageyama A, Poonwan N, Yazawa K, Mikami Y, Nishimura K.Nocardia beijingensis, is a pathogenic bacterium to humans: thefirst infectious cases in Thailand and Japan. Mycopathologia.2004;157:155–61.9. Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr.Clinical and laboratory features of the Nocardia spp. based oncurrent molecular taxonomy. Clin Microbiol Rev. 2006;19:259–82.10. Patti CA, Bosshard PP, Brandt ME, Clarridge JE, Feldblyum TV,Foxall P. Interpretative criteria for identification of bacteria andfungi by DNA target sequencing. Clin Lab Stand Inst.2008;28:12.11. Conville PS, Zelazny AM, Witebsky FG. Analysis of secA1 genesequences for identification of Nocardia species. J Clin Micro-biol. 2006;44:2760–6.12. Poonwan N, Mekha N, Yazawa K, Thunyaharn S, Yamanaka A,Mikami Y. Characterization of clinical isolates of pathogenicNocardia strains and related actinomycetes in Thailand from1996 to 2003. Mycopathologia. 2005;159:361–8.13. Dinulos JG, Darmstadt GL, Wilson CB, Krengel WF 3rd, BurnsJL. Nocardia asteroides septic arthritis in a healthy child. PediatrInfect Dis J. 1999;18:308–10.14. Koll BS, Brown AE, Kiehn TE, Armstrong D. DisseminatedNocardia brasiliensis infection with septic arthritis. Clin InfectDis. 1992;15:469–72.15. Asmar BI, Bashour BN. Septic arthritis due to Nocardia astero-ides. South Med J. 1991;84:933–4.412 I. Uc¸kay et al.

Posttraumatic ankle arthritis due to a novel Nocardia species

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Posttraumatic ankle arthritis due to a novel Nocardia species

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