Journal of Infection and Public Health (2016) 9, 408—414

REVIEW

Successful treatment of multi-focal XDRtuberculous osteomyelitis

Abeer N. Alshukairi a,∗, Abdulrahman A. Alrajhib,Abdulfattah W. Alamric, Adel F. Alothmand

a King Faisal Specialist Hospital and Research Centre, Department of InternalMedicine, PO BOX 40047, Jeddah 21499, Saudi Arabiab King Faisal Specialist Hospital and Research Center, Department of InternalMedicine, PO BOX 3354, Riyadh 11211, Saudi Arabiac King Abdulaziz Medical City, Department of Pathology and Lab Medicine,PO Box 9515, Jeddah 21324, Saudi Arabiad King Abdulaziz Medical City, King Abdullah International Research Center,PO Box 22490, Riyadh 11426, Saudi Arabia

Received 2 May 2015; received in revised form 12 July 2015; accepted 7 October 2015

KEYWORDSXDR tuberculosis;Osteomyelitis;Therapy

Summary We herein describe the nosocomial transmission of a pre-XDR or MDRcase of pulmonary tuberculosis in a HIV-negative health care worker in an areaendemic for MDR and XDR tuberculosis. Following inadequate therapy and non-compliance, he presented with extra-pulmonary XDR tuberculosis in the form ofmulti-focal osteomyelitis and encysted pleural effusion. He was cured after two

years of treatment with various anti-tuberculous drugs in addition to interferongamma.© 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by ElsevierLimited. All rights reserved.

Contents

Case presentation........................................Case discussion...........................................Conclusion ...............................................

Abbreviations: XDR, extensively drug resistant; MDR, multi-drug

∗ Corresponding author. Tel.: +966 505592928.E-mail addresses: abeer sh@doctor.com (A.N. Alshukairi), rajhi@k

(A.W. Alamri), othmanaf@hotmail.com (A.F. Alothman).

http://dx.doi.org/10.1016/j.jiph.2015.10.0101876-0341/© 2015 King Saud Bin Abdulaziz University for Health Scie

.....................................................409

.....................................................411..................................................... 413

resistant; MRI, magnetic resonance imaging.

fshrc.edu.sa (A.A. Alrajhi), Fatah1234@hotmail.com

nces. Published by Elsevier Limited. All rights reserved.

Successful treatment of multi-focal XDR tuberculous osteomyelitis 409

Funding ..................................................................................................... 413Competing interests...........................................................................................413Ethical approval...............................................................................................413

Acknowledgment ............................................................................................ 413References .................................................................................................. 413

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ase presentation

he case was a 30-year-old Saudi physician whotudied medicine for six years in the Ukraine from992 until 1997. He denied direct contact withatients who had extensively drug-resistant tuber-ulosis. He described having indirect contact withhese patients in January 2006. These patients wereaiting in the radiology department for chest X-

ays. In August 1996, he developed a fever andough that did not respond to one week of treat-ent with moxifloxacin. His CT chest revealed a

ight apical cavity. He was admitted to a hospitaln Riyadh and was started on isoniazid, rifampin,thambutol and pyrizinamide for smear-positiveuberculous cavitary pulmonary disease. He did notmprove after one month of therapy. Moxifloxacin,mikacin and cycloserine were therefore added.is sputum Mycobacterium tuberculosis [isolate] was sensitive to ethambutol and resistant to

soniazid, rifampin and streptomycin. Second-linerug susceptibility information was not available

Table 1). He improved clinically but his sputumultures continued to be positive for M. tubercu-osis in September and October 2006. He returned

Table 1 Tuberculosis drug susceptibilities for thethree isolates sputum and bone (R: resistant, S: sen-sitive, NP: not performed).

Tuberculosis drugsensitivities

Isolate Asputum

Isolate Bsputum

Isolate Cbone

Rifampin R R RIsoniazid R R RPyrizinamide R R REthambutol S R RStreptomycin R R RAmikacin NP R RCapreomycin NP R RKanamycin NP NP REthionamide NP R ROfloxacin NP R RMoxifloxacin NP NP RLinezolid NP S SPAS NP NP RCycloserine NP S NPClarithromycin NP NP NPClofazimine NP S NP

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o the Ukraine in November 2006 and continuedn isoniazid, rifampin, ethambutol, pyrizinamide,oxifloxacin and cycloserine for six months. He

topped his therapy in April 2007 and developed recurrent fever and cough in May 2007. Heraduated in July 2007 and returned to Saudirabia to be admitted for pleura-pulmonary tuber-ulosis. His sputum was smear-positive and hisleural effusion was also positive for M. tuber-ulosis. His tuberculous empyema required chestube drainage. He was re-started on isoniazid,ifampin, pyrizinamide, ethambutol, moxifloxacin,ycloserine and amikacin. In July 2007, second-ine drug susceptibility testing was performedy the National Tuberculosis Reference Labora-ory, London, UK. His sputum M. tuberculosisisolate B] was resistant to isoniazid (high levelesistance), rifampin, ethambutol, pyrazinamide,floxacin, streptomycin, amikacin, capreomycinnd ethionamide. It was only sensitive to line-olid, clofazimine and cycloserine (Table 1). Head no medical follow-up from September 2007ntil July 2008. He sought a second opinion in Jor-an. He felt better on alternative medicine and hisespiratory symptoms improved. He was receivingoxifloxacin, ethambutol and cycloserine in August

008 when he experienced left ankle pain, swellingnd limitation of movement. MRI confirmed leftnkle osteomyelitis (Fig. 1) and he underwentebridement. Bone histopathology showed caseat-ng granuloma with negative acid-fast bacilli. Aissue sample from the ankle bone was emulsifiedn sterile normal saline using a sterile mortar andistol. Both samples were inoculated in BACTEC-GIT TB liquid culture tubes (BD Biosciences,parks, MD) and incubated in the BACTEC-MEGIT60 instrument (BD Biosciences) until there wasositive detection by the machine. The isolateas confirmed to be M. tuberculosis by PCR using

he gene GeneXpert MTB/RIF (Cepheid, Sunny-ale, CA). Sensitivity testing to isoniazid, rifampin,thambutol and streptomycin were performed on

MEGIT 960 instrument (BD Biosciences) accordingo manufacturer’s instructions. The drug concen-

rations were as follows: isoniazid 0.4 mg/ml,ifampin 1 mg/ml, ethambutol 5 mg/ml and strep-omycin 4.0 mg/ml. The organism was resistanto all first-line drugs. The sample was referred

410 A.N. Alshukairi et al.

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samhlbSstarted after six months of therapy when thelinezolid and amikacin were stopped. It was con-tinued for six months with no adverse effects.After two years of therapy, the patient is clinically

Figure 1 The first MRI of the left ankle showingosteomyelitis of the left fibula.

to the National Tuberculosis Reference Labora-tory, London, UK for second-line sensitivity testing.The bone tissue M. tuberculosis strain [isolate C]was resistant to isoniazid, rifampin, pyrizinamide,ethambutol, streptomycin, amikacin, capreomycin,kanamycin, ethionamide, para-aminosalicylic acid(PAS), ofloxacin and moxifloxacin. It was only sen-sitive to linezolid. The sensitivity to cycloserine,clofazimine and clarithromycin was not exam-ined (Table 1). Within two weeks, the patientdeveloped left elbow and knee pain, swellingand limitation of movement, which were con-firmed by MRI as left elbow and knee osteomyelitis(Figs. 2 and 3). His chest CT showed right encystedpleural effusion with no cavitary pulmonary dis-ease. At this stage, it was realized that this patienthad serious XDR tuberculosis in the form of multi-focal osteomyelitis and encysted pleural effusion.We used a combination of clofazimine, linezolid,meropenem, ampicillin-clavulanate, cycloserine,PAS, capreomycin daily, moxifloxacin and clar-ithromycin for two months. Subsequently, hewas continued on PAS, cycloserine, moxifloxacin,azithromycin, clofazimine, linezolid and amikacinevery other day (the capreomycin was stopped) forfour months. Finally, he received PAS, cycloserine,moxifloxacin, clofazimine and azithromycin for 18months. He developed intolerable gastro-intestinalupset related to clarithromycin, meropenem andampicillin-clavulanate and they were stopped after

two months of treatment. He developed linezolid-associated axonal neuropathy confirmed by nerveconduction studies, so the linezolid was stoppedafter six months of therapy. Capreomycin was

Fo

igure 2 The first MRI of the left elbow showingsteomyelitis of the left humerus.

topped after two months because it was notvailable. He was continued on amikacin for fouronths only in view of its ototoxicity. In summary,

e received a total of six months of second-ine injectable agents. Pyrizinamide was not givenecause of the patient’s severe polyarthritis.ubcutaneous interferon gamma injections were

igure 3 The first MRI of the left knee showingsteomyelitis of the left femur.

Successful treatment of multi-focal XDR tuberculous osteomyelitis 411

Figure 4 A follow-up MRI of the left ankle after1o

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Figure 5 A follow-up MRI of the left elbow after12 months of treatment showing improvement of theosteomyelitis in the left humerus.

Figure 6 A follow-up MRI of the left knee after1o

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2 months of treatment showing improvement of thesteomyelitis in the left fibula.

symptomatic with no residual joint pain, swellingr limitation of movement. His HIV serology isegative. His CRP and ESR, as well as his com-lete blood count and renal and liver functionests are normal. After one year of therapy,

follow-up MRI of his left ankle, elbow andnee showed 80% improvement of the osteomyeli-is (Figs. 4—6) and his CT chest revealed 50%esolution of his encysted pleural effusion. After8 months of therapy, his left knee MRI showedesolution of the osteomyelitis (Fig. 7). He haseen asymptomatic since the discontinuation of hisnti-tuberculous medication in March 2011. As hes doing postgraduate studies outside Saudi Ara-ia at this time, follow-up imaging could not beerformed.

ase discussion

ur case illustrates the nosocomial transmission ofDR tuberculosis to a health care worker in an areandemic for resistant tuberculosis. The nosocomialransmission of MDR tuberculosis is a real concernn resource-poor settings. It has been estimatedhat the application of nosocomial infection controltrategies could prevent half of XDR tuberculosisases [1].

It was difficult to determine whether our case

as initially an MDR tuberculosis stain or an XDR

tain due to the lack of second-line drug sus-eptibility testing on specimen A. However, the

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2 months of treatment showing improvement of thesteomyelitis in the left femur.

evelopment of secondary ethambutol resistancen specimen B is an indicator of the propagationf resistance. Our case demonstrates the vari-us risk factors for the progression of tuberculosisrom MDR to XDR strains. First, our patient was

on-compliant with his therapy and did not con-inue his medical follow-up. In MDR tuberculosisatients with baseline resistance to second-line

412

Figure 7 A follow-up MRI of the left knee showing res-

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In our case, with the limited options available

olution of the osteomyelitis in the left femur after 18months of therapy.

drugs, it was shown that the risk of XDR tuber-culosis increased from 1.4% to 15.9% in directlyobserved therapy programs, whereas it increasedfrom 3.4% to 60.9% in indirectly observed ther-apy programs [2]. Second, our case illustrates thatthe presence of cavitary pulmonary disease is animportant risk factor for the amplification of sec-ondary resistance among MDR and XDR tuberculousbacilli. It was previously found that 25% of resectedpulmonary cavity XDR tuberculosis cases had addi-tional drug resistance compared to preoperativesputum tuberculous cultures [3]. Third, the extentof resistance to second-line drugs was initiallyunknown in our MDR tuberculosis case, leadingto inadequate therapy and a complicated out-come. It was shown that 2.4% of MDR tuberculosispatients with no baseline second-line drug resis-tance developed acquired XDR tuberculosis, while44.1% of those with resistance to three second-line drugs developed acquired XDR tuberculosis[2].

The resistance of our case was confirmed bydirect susceptibility testing of sputum and bonetuberculous cultures. The diagnosis of XDR tuber-culosis osteomyelitis is challenging. The diseaseis paucibacillary and requires invasive procedures.The genotype line probe assays for rifampin,second-line injectable agents and fluoroquinolones

are promising in respiratory specimens but requirefurther evaluation in non-respiratory specimens[4]. Because they are dependent on the gold

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A.N. Alshukairi et al.

tandard, slow, direct susceptibility testing, theiagnosis and initiation of effective therapy areelayed for several weeks in cases of XDRuberculosis osteomyelitis. In addition, follow-uppecimens to assess the disease response were lack-ng in our case, although we clearly demonstratedhe radiological improvement of osteomyelitis afterdequate therapy in addition to the patient’s clini-al response.

The optimal treatment for MDR and XDR extra-ulmonary tuberculosis is difficult to determine andas not been clearly demonstrated. The guidelinesor the management of MDR and XDR extra-ulmonary tuberculosis were adopted from thereatment guidelines for MDR and XDR pulmonaryuberculosis. The WHO guidelines for XDR tuber-ulosis therapy suggested six medications in thenduction phase for eight months and four med-cations in the maintenance phase for 12 months5].

In our case, we could not adopt the WHO guide-ines. The treatment was challenging for severaleasons. First, the strain was only sensitive to line-olid and clofazimine and might have been sensitiveo cycloserine (the patient was previously exposedo cycloserine). Second, the patient had an inter-upted exposure to cycloserine, moxifloxacin andmikacin, which made it more difficult to build anffective drug regimen for him. Third, several med-cations were not available in Saudi Arabia, suchs PAS and capreomycin, and were purchased usingersonnel efforts and communications. Fourth,he best drug combination to provide effectiveone penetration is not known. Fifth, the treat-ent plan was modified because of drug toxicity

nd intolerance (pyrizinamide, linezolid, amikacin,larithromycin, clavulanate and meropenem). Weiscussed our case with several international XDRuberculosis experts and we agreed that the ther-py should be tailored for the above reasons. Theifficulty in building our regimen relied on combin-ng medications with limited benefit to which theatient had not been exposed (meropenem, clavu-anate, clarithromycin, clofazimine and linezolid)nd adding medications with proven benefit butith known resistance, to which the patient wasxposed (cycloserine, moxifloxacin and amikacin).he induction phase was shortened to six months

n view of drug toxicity (linezolid and amikacin)nd drug intolerance (meropenem, clavulanate,nd clarithromycin) with a sequential reduction ofedication from nine drugs to five drugs.

or sensitive drugs, resistant drugs such as mox-floxacin, PAS, amikacin and capreomycin weresed. Despite the bacteria being resistant, the

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uccessful treatment of multi-focal XDR tuberculou

se of moxifloxacin is recommended in XDR tuber-ulosis to improve the treatment outcome [5,6].t is not known whether the use of other resis-ant medications, such as second-line injectablerugs, will lead to a similar outcome. The syner-istic effects of resistant anti-tuberculous agentsre unknown and need to be evaluated. In addi-ion, with the availability of new drugs for resistantuberculosis, the best combination therapy withhe lowest pill burden and shortest effective ther-py needs to be determined in future studies. Inhe French cohort study that evaluated the effi-acy of bedaquiline, 19 out of 35 patients had XDRuberculosis and one case was osteoarticular tuber-ulosis. After six months of therapy, all but one ofhe patients had culture conversion. This cohorttudy also showed that bedaquiline had a favor-ble outcome when combined with moxifloxacin,ven though the tuberculous strains were resistanto fluoroquinolones [7].

The role of immune modulation and the use ofnterferon gamma in XDR tuberculosis are contro-ersial and poorly studied [8]. We used interferonamma injections in our case when our patienteveloped adverse effects related to linezolid andmikacin and the number of drugs in the induc-ion phase was reduced. Further clinical studies areeeded to evaluate its efficacy against XDR tubercu-osis. At present it may be considered in refractoryases of XDR tuberculosis despite optimal ther-py and in the presence of medication-related sideffects.

Our case is unique in the literature in that it is case of multifocal XDR tuberculous osteomyelitisith a successful outcome. The literature describ-

ng MDR and XDR tuberculous osteomyelitis isimited to a few case reports [9—12]. All of the pre-ious cases reviewed were MDR tuberculosis and notDR tuberculosis. A systematic review summarized3 case reports, and indicated that six patientsad spinal disease and seven patients had extra-pinal disease. All of them had a good outcome withedical therapy. Eight of them required surgical

ntervention [11].

onclusion

he diagnosis and management of extra-pulmonaryDR tuberculosis remains challenging, particularlyecause it is endemic in resource-limited countries.ith the lack of rapid diagnostics and effective

herapy, preventive strategies are crucial. Reli-ble molecular testing and low-burden treatmentsre areas that should be addressed in futureesearch.

teomyelitis 413

unding

o funding sources.

ompeting interests

one declared.

thical approval

ot required.

cknowledgment

A would like to thank:

Mohamad Ashmawi, Khalid Albogami, Dr. Habashy,Dr. Aftab and Dr. Abdulhakeem Althagafi for pro-viding us with the non-formulary medications.Dr. Altaf Zahid and Dr. Abdulkader Alkinawi forproviding us with the MRI figures.Professor Mickel Iseman for his expert opinionregarding the management of the case.Dr. Haneen Alshukairi for editing the manuscript.

eferences

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[2] Cegielski JP, Dalton T, Yagui M, Wattanaamornkiet W,Volchenkov GV, Via LE, et al. Extensive drug resistanceacquired during treatment of multidrug resistant tubercu-losis. Clin Infect Dis 2014;59(8):1049—63.

[3] Kempker RR, Rabin AS, Nikolaishvili K. Additional drug resis-tance in Mycobacterium tuberculosis isolates from resectedCavities among patients with multidrug-resistant or exten-sively drug-resistant pulmonary tuberculosis. Clin Infect Dis2012;54(6):e51—4.

[4] Hillemann D, Rusch-Gerdes S, Boehme C, Richter E. Rapidmolecular detection of extrapulmonary tuberculosis by theautomated GeneXpert MTB/RIF system. J Clin Microbiol2011;49(April (4)):1202—5.

[5] , Treatment strategies for MDR-TB and XDR-TB: 76-96.www.who.int/tb/publications/pmdt companionhandbook/en/Languages:English. ISBN: 978 92 4 154880 9. WHOReference number: WHO/HTM/TB/2014.11 Companionhandbook to the WHO guidelines for the programmaticmanagement of drug resistant tuberculosis; 2014.

[6] Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, MurrayMB. Treatment outcomes among patients with extensivelydrug resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis 2010;51(1):6—14.

[7] Gugliemetti L, Le Du D, Jachym M, Henry B, Martin D,

Caumes E, et al. Compassionate use of bedaquiline for thetreatment of multidrug resistant and extensively drug resis-tant tuberculosis: interim analysis of a French cohort. ClinInfect dis 2015;60(2):188—94.

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[9] Leela Rani H, Belwadi S. Tubercular osteomyelitis. Rare pre-

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[10] Lynn MM, Khukanesen JR, Khan AW. Troublesometuberculosis: a case report on multifocal tuberculous

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osteomyelitis in an immunocompetent patient. J Clin MedRes 2012;4(1):73—6.

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