Case presentation Dr Connie Haley, MD, MPH Dr Gautam Kalyatanda, MD
History of presenting illness 20 Year old woman from Nigeria who came to study at Montgomery in August 2013 About 2 weeks after arriving, she presented to student health, complaining of a cough for a week. Cough was productive with white colored sputum. She was initially given amoxcillin with very little improvement
History of presenting illness Her cough got worse and she found it hard to sleep at night Episodes of vomiting associated with bouts of cough Had an episode of hemoptysis about 4-5 weeks after these episodes began Low grade fevers more at night Occasional night sweats Weight loss
She had been having some shortness of breath for about 3 years prior to the start of these symptoms. Shortness of breath was progressively getting worse She would be Short of breath with minimal exertion Positive for pleurophasic pain
Social history Lived in Lagos 8 siblings No known exposure to anyone with active tuberculosis Worked as a primary school teacher Father passed away in 2008.
Had a chest x-ray after about 6 weeks due to persistence of these symptoms
Oct 7, 2013
Sputum AFB obtained: positive.
Would we start her on therapy
Begun on standard 4 drug antituberculous therapy: Isoniazid Rifampin Pyrazinamide Ethambutol
Nigeria WHO. Global TB Report, 2015 http://www.who.int/tb/publications/global_report/en/
Tuberculosis in Nigeria 2014 WHO Global TB Report Nigeria 4 th highest TB burden country WHO. Global TB Report, 2015 http://www.who.int/tb/publications/global_report/en/
WHO. Global TB Report, 2015 http://www.who.int/tb/publications/global_report/en/
WHO. Global TB Report, 2015 http://www.who.int/tb/publications/global_report/en/
GeneXpert result: M. tuberculosis complex with rifampin resistance (rpob mutation) Sample sent to CDC for molecular susceptibilities Patient removed from dorm, placed in hotel under isolation (quarantine) awaiting transfer to UAB for admission
What would we do now
CDC Molecular Detection of Drug Resistance (MDDR): INH: katg (Ser315Thr: complete INH resist) RIF: 2 rpob mutations not previously seen in CDC database (Asp516Glu, Ser522Leu) Oflox: gyra D94G (Asp94Gly)??? EMB: embb (Pro404Ser) 79% EMB resistant isolates have a mutation other than this one but cannot rule out if this mutation causes resistance (ie true mutation vs. polymorphism) No mutations seen in AG s (rrs, eis, tlya loci) PZA (pnca) loci examined no mutations found
Date : 10/07/13 PZA 100mcg/ml Streptomycin 20mcg/ml Streptomycin 10mcg/ml INH 2 mcg/ml INH 10mcg/ml Rif 10mcg/ml Ethambutol 50mcg/ml Kanamycin 50mcg/ml Ofloxacin 20mcg/ml Susceptibility S Possible R S Possible R Possible R Possible R Possible R S Possible R
Locus Result Interpretation Rpo B InhA( promoter) No mutation Likely rifampin resistance KatG AGC>ACC INH resistance EmbB CCG>TCG Can not rule out resistance pnca GGC>GAC Effect of this mutation on PZA unknown gyra Rrs No mutation Ofloxacin resistant Els No mutation Can not rule out resistance tya No mutation
What type of drug resistance is this?
By definition, she has multidrug resistant (MDR) TB Resistance to at least INH and Rifampin Extensively drug resistant (XDR)-TB is defined as MDR-TB plus additional resistance to a fluoroquinolone and a 2 nd line injectable (amikacin or capreomycin) Since she has one of the two XDR-TB criteria, she would be classified as pre-xdr-tb
What drugs would we use now
Began MDR-TB regimen (7 drugs): Amikacin 750mg (IV) 5 days/week Ethambutol 1200mg/daily PZA 1500mg/daily Rifabutin 300mg/daily Moxifloxacin 400mg/daily Ethionamide 750mg/daily (after ramp up) Cycloserine 250mg/daily (awaiting shipment) Vitamin B6 200mg/daily
10/21/13: AL state lab reports phenotypic high level ethambutol resistance and low level streptomycin resistance 11/14/13: CDC lab reports resistance to rifabutin Ethambutol and rifabutin discontinued and regimen modified:
Adjusted Regimen (7 Drugs) Capreomycin 750mg 5 days/wk Moxifloxacin 400mg/daily PZA 1500mg/daily Ethionamide 750mg/daily (after ramp up) Cycloserine 250mg/daily PAS 8 grams daily (after ramp up) Linezolid 600mg daily Vit B6 200mg/daily
Progress AFB smears went from numerous to 1+ in 2 weeks on MDR regimen AFB smear negative x 4 into 3rd week with (ultimately) negative cultures (initial cultures time to growth 7-10 days) Patient discharged from hospital after 1 month, placed in long term hotel Therapeutic drug monitoring (TDM): serum drug levels checked and found in range Weight increased from 112 to 125 pounds
Drug levels Drug levels in 12/13 are as follows Ethionamide 0.26 and 0.89mcg/ml Cycloserine 20 and 18. 5mcg/ml Moxifloxacin 2.63 and 3.08 mcg/ml Capreomycin 3.53 and 2.38mcg/ml Linezolid 13.46 and 9.81 mcg/ml PZA 41.72 mcg/ml PAS 12.13 and 40.97 mcg/ml Ethionamide 1.58 and 0.89 mcg/ml
CXR after 2 months of MDR-TB therapy
Initial 2 months therapy
Patient completed 5 and ½ months of capreomycin, had challenges with PICC line related to severe tape/adhesive allergy and line coming out Continuation phase 5 drugs: Moxifloxacin PZA Ethionamide Cycloserine Linezolid Completed 16 months total therapy, having 15 months of negative cultures
Closing CXR Jan 21, 2015
One month later she began to complain of a cough for which she was treated with azithromycin with immediate resolution of her symptoms
She had a chest xray done which showed consolidation of the left lung apex.
Would you start her on therapy now? TB vs Pneumonia?
Sputum was smear negative but culture positive for MTb
Repeat MDDR results (3/12/2015) Received 4/3/2015, reported 4/6/2015. Identical to initial (primary) isolate except with addition of pnca promoter mutation of uncertain significance: Effect of this mutation on PZA resistance is not known. Cannot rule out PZA resistance
Course at Shands Admitted to the hospital on 4/9/2015 Airborne isolation in negative pressure room. On admission she had no shortness of breath, cough or fever Was clinically stable on admission
GPE General examination: No cyanosis, clubbing, pallor or icterus HEENT: No posterior pharyngeal wall congestion, Sinus tenderness or lymphadenopathy CVS: Normal with no murmurs or gallops RS: PA: NAD. No hepatospleenomegaly Musculoskeletal: No joint effusions or pain Skin: No rashes or ulcers Neurological: NAD
Labs performed prior to therapy Audiology consult- Normal Ekg: Normal with no Qtc prolongation
Medications Medications started on 4/10/2015 Linezolid Capremomycin Cycloserine Pyrazinamide Vitamin B6 Imipenem
Ethionamide was started on 4/20 and sequentially increased to full dose( 500mg at night and 250mg in the morning on 4/27)
Port placed on 4/13. Had a rash at the Port site secondary to the dressing which resolved with the use of a steroid cream local application
Pyrazinamide discontinued on 4/27 after strain showed resistance
Course With an increase in her creatinine, the dose of Capreomycin was held on 5/8 and then changed to thrice weekly after 5/11.
Side effects Diziness associated with Capreomycin infusion Improved with 500ml NS infusion soon after Capreomycin infusion Intractable nausea and vomiting associated with PAS and Ethionamide( missed a few doses of her medication) Ativan was given with minimal improvement Zofran and Reglan with minimal improvement Olanzapine given but discontinued after a day with significant side effects like dry mouth and diziness
What would you do to relieve the nausea in this patient?
Marked improvement after Gtube was placed on 5/11
Was depressed, lonely and anxious Was followed by clinical psychology at Shands( felt this was acute stress reaction) Would take walks outside the hospital with Social service Daily meeting with social service Pastoral care Had problems with appetite especially since she was used to a different diet Improved and patient had a weight gain of about 4 Lbs at the end of her hospitalization
Bedaquiline started after G tube was placed on 5/12 at 400mg po daily After G tube was placed all her medications were crushed and given through her G tube except for Bedaquiline
Course complicated by Hypomagnesia and Hypokalemia for which she required K and Mag replacement Mag replaced on 4/21, 4/28, 4/29, 4/30, 5/15, 5/17, 5/18 and 5/19
Date 4/9/15 4/20/15 4/24/15 4/28/15 5/5/2015 5/8/2015 5/12/15 5/15/15 Na 139 138 140 139 139 139 138 138 K 4.1 3.5 3.4 3.1 3.6 3.7 3.3 3.5 Cl 100 98 100 100 98 99 98 98 Creat 0.74 0.67 0.86 0.83 0.77 1.03 0.76 0.69 Glu 90 141 101 123 74 101 62 80 Ca 9.8 9.5 9.5 8.7 9.5 9.1 8.8 9.3 TP 8.6 8.6 8.1 7.3 8.3 7.5 7.3 8.1 Alb 4.6 4.7 4.4 4.2 4.6 4.3 4.0 4.6 AST 24 23 23 21 27 26 29 25 ALT 12 10 10 7 12 13 13 9 T bili 0.2 0.3 0.2 0.2 0.3 0.3 0.4 0.3 Alk Phos 78 64 76 72 60 65 50 59 Mag 2.0 1.7 1.8 1.4 1.7 1.7 1.8 1.8
Date 4/9/15 4/20/15 5/5/15 5/14/15 5/18/15 Wbc 9.8 7.3 7.2 8.2 6.7 Hb 11.9 11.3 11.2 10.6 11.3 Hct 34.4 34.3 33.6 31.2 34.4 Platelet 248 270 272 220 294 Mcv 72.5 74.1 74.1 77.1 77.3 Neutr 54.6 50 47.3 59.3 44.1 Lympho 34.4 35.6 36.3 29.8 41.5 Monocytes 5.4 5.9 8.6 4.5 7.5 eosinophils 3.0 6.1 4.3 4.5 4.2
Date 5/15/2015 Free T4 1.16 TSH 2.00
Drug levels Drug Date Dose / time given Concentration Concentration normal Linezolid 4/22/201 5 600mg po daily given at 10:00 AM 32.28mcg/ml at 1200 hrs 12.37mcg/ml at 1600 hrs 12-26mcg 2 hours after oral dose/ trough 3-9mcg/ml Linezolid 5/1/2015 600mg po daily given at 11:00 AM 14.35mcg/ml at 13: 15 hrs 13.20mcg/ml at 17: 15hrs
Drug levels Drug Date Dose /time given Capreomycin 4/16/2015 1 gm IV daily/ Concentration Concentration Normal 22.14mcg/ml at 04:30am 5.73mcg/ml at 08:46 am 35-45mcg/ml
Drug levels Drug Date Dose/ time given Conentration Concentration Normal Cycloserine 4/22/2015 250mg po daily/ 23.0mcg/ml at 12:00hrs 15.1mcg/ml at 1600 hrs 20-35mcg/ml after 2 hrs PAS 5/1/2015 4gms po BID/ ETA 5/1/2015 500mg po daily (PM) 3.50mcg/ml 7.38mcg/ml 20-60mcg/ml 6 hrs after dose 1.21mcg/ml 0.57mcg/ml Peak level 1-5mcg/ml PZA 4/22/2015 1500mg po daily given at 54.20 mcg/ml at 1200 hrs 38.98mcg/ml at 1600 hrs 29-60mcg/ml 2 hours after oral dose
Discharge medications Imipenem 1gm IV BID Capreomycin 1gm three times a week Mon, Wed and Friday. Cycloserine 250mg through G tube daily Linezolid 600mg through G tube daily Bedaquiline 400mg po daily until 5/26/2015 and then 200mg po three times a week( patient needs to swallow this medicine) Ethionamide 250mg through G tube in the morning and 500mg through the G tube at night PAS 4 gms twice a day through the G tube Vit B6 200mg po daily through G tube Give 500ml NS over 60 minutes
Any role for surgery?
Denver Discussions between SNTC, Denver and Alabama Department of Health Travelled to NJH and University of Colorado saw Drs. Gwen Huitt and John Mitchell Underwent left upper lobectomy 7/29 (3 months of negative cx s) Ultimately cultures of resected lung were negative for AFB
8/24/15
8/24/15
Drug levels Although initial TDM revealed adequate serum drug levels, repeat levels are low for several drugs: Ethionamide 0.49 (1-5) Cycloserine 12.16 (20-35) PAS trace (20-60) Linezolid 6.85 (12-26) Cycloserine was increased but she was unable to tolerate increasing ethionamide dose Repeat levels are pending
4-10-15 8/24/15
Port infection- pseudomonas- required removal of port, with placement of PICC Remains in school, continues to excel academically
The biggest disease today is not leprosy or tuberculosis, but rather the feeling of being unwanted. - Mother Teresa