Drug Resistant Tuberculosis

Transcription

1 Drug Resistant Tuberculosis Michael Lauzardo, MD MSc Director, Southeastern National Tuberculosis Center Chief, Division of Infectious Diseases and Global Medicine University of Florida

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8 Section 1 Epidemiology of Drug Resistant Tuberculosis

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12 Epidemiology of MDR-TB Globally There were an estimated 390,000 to 510,000 cases of MDR TB globally in 2014 Twenty-seven countries account for 86% of these cases Four highest: China 100,000 India 100,000 Russia 40,000 South Africa 15,000 Almost all countries with the capability to diagnose XDR-TB have had at least one case of XDR-TB

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14 MDR TB in the United States-2014 Overall, the percentage of MDR TB cases decreased slightly from 1.4% (96 cases) in 2013 to 1.3% (91 cases) in 2014.** Of the total number of reported MDR TB cases, the proportion occurring among foreign-born persons increased from 31% (149 of 484) in 1993 to 88% (80 of 91) in The percentage of MDR TB cases among persons without a previous history of TB (1.0%) and the percentage of MDR TB cases among persons with a previous history of TB (3.4%) were lower in 2012 than in 2011.

15 Question List three reasons why Multi-drug resistant tuberculosis in the United States is low? What are some barriers that prevent us from lowering it even further?

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17 Section 2 Pathogenesis and Transmission of Drug Resistant Tuberculosis

18 Multi-Drug Resistant (MDR) TB Defined as resistance to isoniazid and rifampin Created by poorly managed TB programs Non-adherence to therapy Poor quality drugs or supply Leads to bad outcomes Longer treatment (go from 6-24 months) Toxic regimens Cost increases fold High death rates Disastrous outcomes in HIV settings

19 Mutations and TB Drug Resistance Nature Genetics 45, (2013)

20 Spontaneous mutations develop as bacilli proliferate to >10 8 Drug Mutation Rate Rifampin 10-8 Isoniazid 10-6 Pyrazinamide

21 Drug-resistant mutants in large bacterial population Multidrug therapy: No bacteria resistant to all 3 drugs INH RIF PZA INH Monotherapy: INHresistant bacteria proliferate 21

22 INH resistant bacteria multiply to large numbers INH Spontaneous mutations develop as bacilli proliferate to >10 8 INH RIF INH mono-resist. mutants killed, RIF-resist. mutants proliferate MDR TB 22

23 Question Are drug resistant strains as transmissible as drug-susceptible strains?

24 Are drug resistant strains as transmissible as drugsusceptible strains? A case-control study by Snider et al. demonstrating that contacts of patients with drug-resistant and drugsusceptible incident cases of TB had an equal prevalence of positive tuberculin skin test results suggests that infectivity was not diminished by drug resistance. In contrast, animal studies have shown that isoniazidresistant strains caused significantly less disease in guinea pigs than drug-susceptible strains. Snider et al Am Rev Respir Dis 1985; 132:125 32, Middlebrook Am Rev Tuberc 1954; 69:471 2, Riley Am Rev Respir Dis 1962; 85:

25 Question Are drug resistant strains likely to progress to active disease once infection is established?

26 Are drug resistant strains likely to progress to active disease once infection is established? In the context of an effective TB program in San Francisco, Burgos et al found that strains that were resistant to isoniazid either alone or in combination with other drugs were less likely to result in secondary cases than were drugsusceptible strains. In this setting, isoniazid-resistant and MDR TB cases were not likely to produce new, incident drug-resistant TB cases. This presumed reduced pathogenicity may be related to mutations in the katg gene.

27 Are drug resistant strains likely to progress to active disease once infection is established? It will depend on various factors: Pathogen related Undefined virulence factors Variability in virulence between genotypes Size of the infecting inoculum Host related Presence of immunosuppression Ethnic susceptibility to various strains

28 Genetic Diversity and MDRTB Epistasis occurs when phenotypic effect of a mutation changes depending on other mutations. Can either increase or decrease the fitness cost of mutations and can lead to increased prevalence of certain strains. Borrell and Gagneux, CMI 2011 Beijing strain

29 Section 3 Diagnosis of Drug Resistant Tuberculosis

30 Diagnosis of Active TB Disease Key: THINK TB

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32 Diagnosis of Drug Resistance Clinical Characteristics Previous treatment for TB disease (*recent? Selfadministered?) History of exposure to an individual with MDR-TB Recent emigration from a geographic region with a high prevalence of resistance to tuberculosis therapy (former USSR, China, Korea, Honduras, Peru) Progressive clinical and/or radiographic findings while on TB therapy

33 Diagnosis of Drug Resistance Clinical Characteristics Lack of sputum culture conversion to negative after 2 months of therapy for TB Travel to a region with high rates of drug resistant TB Residence or work in an institution or setting in which drug-resistant TB is documented HIV

34 Diagnosis of Drug Resistance Limits of Clinical History and Epidemiology Retrospective, case control study to identify risk factors for MDR-TB and analyze impact of testing for rifampin resistance by rpob gene mutation identification Of 42 confirmed MDR-TB cases that were evaluated almost half (43%) of patients did not have any of the conventionally recognized risk factors for MDR O Riordan P. et al PLoS September 2008

35 Agar Proportion Method Plate bacteria on media containing No drugs Critical concentrations of a drug Incubate for 3 weeks Count colonies Isolate is resistant if the number of colonies on drugcontaining media is >1% of the colonies on drug-free media 35

36 Critical Concentration The lowest concentration of a drug that Inhibits growth of all susceptible strains AND Allows growth of all resistant strains 36

37 Critical Concentration Ethambutol 37 S.J. Kim Eur Respir J 25:564.

38 Group Activity The patient is a 35 year old engineer from India who developed symptoms compatible with TB 18 months after arriving in the US. He was diagnosed with TB started on four drug therapy and responded well initially but his susceptibility report came back showing MDR. His physician put him on an MDR regimen and sent for confirmatory results at a different lab. Review the results below and come up with five reasons why the results are what they are. Drug Tested Lab 1 Lab 2 Lab 3 INH R R S Rifampin R S S PZA S S N/A Ethambutol S S S Strep R R R

39 Reasons for Discordant DST Results Bacterial population (isolate vs. subculture) Differential growth kinetics Different inoculation methods (size, clumps) Different methods or media Cross-contamination Transcription, labeling errors Problem strains and drugs MIC critical concentration 39

40 Diagnosis of Drug Resistance Conventional methods: (indirect/proportion method?) Molecular Beacon Testing: Real-time PCR test Performed directly on AFB+ smears or on growth on solid media or MGIT tube INH resistance: katg, inha (85%) RIF resistance: rpob core region (>95%)

41 Diagnosis of Drug Resistance Line Probe Assays commercially available in Europe not cleared yet by FDA Hain: detects presence of TB complex and gene mutations associated with Rifampin resistance (rpob ) and INH resistance (kat G and inha) In smear positive specimens: Rifampin resitance: Sensitivity (98.9%) Specificity (99%) INH resistance: Sensitivity (94%) Specificity (99%) Turnaround times: 1-2 days

42 Molecular Detection of Resistance Sensitivity and Specificity of MTB/RIF test for Detection of Rif and MDR as compared to Phenotypic Drug-Susceptibility Testing Boemhme et al, NEJM 2010

43 Missed Rifampin Resistance with Liquid Media Phenotypic drug susceptibility testing (DST) methods for TB are assumed to be the gold standard for identifying rifampin (RMP) resistance. However, previous results indicated that low-level, yet probably clinically relevant, RMP resistance linked to specific rpob mutations is easily missed by some growth-based methods. OBJECTIVE: To compare the level of resistance detected on Löwenstein- Jensen (LJ) medium with resistance detected by the Bactec MGIT 960 automated DST (MGIT-DST) system for various rpob mutants. RESULTS: Full agreement between LJ and MGIT-DST was observed for mutations located at codons 513 (Lys or Pro) and 531 (Leu, Trp), which were always resistant by both methods. For mutations 511Pro, 516Tyr, 533Pro, 572Phe, and several 526 mutations, LJ and MGIT results were highly discordant, with MGIT-DST failing to give a result or declaring the strains susceptible. J Clin Microbiol Aug;51(8):

44 Missed Rifampin Resistance with CONCLUSIONS: Liquid Media Phenotypic RMP resistance testing of M. tuberculosis is not a binary phenomenon for some rpob mutations and that the widely used automated MGIT 960 system is prone to miss some RMP resistance-conferring mutations, while careful DST on LJ missed hardly any. Given the association of these mutations with poor clinical outcome, our findings suggest that the gold standard for rifampin resistance should be reconsidered, in order to address the present confusion caused by discrepancies between phenotypic and genotypic results. The impacts of these mutations will depend on the frequency of their occurrence, which may vary from one setting to another.

45 Section 4 Treatment of Drug Resistant Tuberculosis

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47 Bonus Questions What is the infectious process that led to the x-ray appearance below? What is the patient s sister s favorite color? Hint: Answers must be in French

48 General Principles of Chemotherapy for TB Disease Existence of mutant bacilli with innate resistance to antibiotic action

49 General Principles of Chemotherapy for TB Disease Existence of mutant bacilli with innate resistance to antibiotic action Slow or intermittent growth of mycobacterium which permits the persistence of viable organisms despite prolonged antibiotic treatment, because only actively replicating organisms are killed by antibiotics

50 Treatment of active TB disease FIRST TWO MONTHS FOUR MONTHS POST CONVERSION INH 300 MG/D PO 300 MG/D RIF 600 MG/D PO 600 MG/D PZA EMB STM MG/KG/D PO MG/KG/D PO 1 GM/D IM

51 DOT Therapy Works! 95% of patients with TB will be cured by DOT Decreases morbidity and mortality and cost (~ $1500/pt) Decreases spread of disease Average patient with TB infects 30 other individuals Decreases resistance MDR costs ~ $250,000 to cure with only ~ 80% success 5% of patients with active TB will be unable to complete therapy; requiring legal interventions and facilities to cure them In S.F. one non-compliant patient with MDR-TB was responsible for 40 other cases

52 Causes of Inadequate Response to Therapy Non-adherence!!!!!!!!!!!!!!!!! DOT Involuntary detention Increased drug resistance/incorrect sensitivities Malabsorption/increased metabolism Inability of drugs to penetrate effected tissues

53 Case Question A 48 year old man from Mexico who has lived in the United States for more than 20 years was evaluated by his primary care physician because of a cough of six weeks duration. The work up included the chest x-ray below. He was started on four drugs and after six weeks susceptibility tests came back showing low level INH resistance. What treatment regimen would you continue and why? How long would you treat?

54 Isoniazid Mono-resistant Disease Among patients with INH mono-resistant TB, outcomes were improved with longer duration of RIF and PZA, use of daily treatment (not intermittent treatment) and with greater numbers of effective drugs. Studies in the United States have reported relapse rates of 2 to 5% using 3- to 4-drug regimens administered for 6 or more months. However, a large proportion (26-59%) of patients had treatment discontinued or the duration of treatment extended because of drug-related adverse reactions, usually associated with PZA. Treatment outcomes do not differ based on whether the isolate has low- or high-level INH resistance in vitro

55 Rifampin Mono-Resistant TB Include Isoniazid, ethambutol, fluorquinolone, supplemented with PZA for the first two months. Consider using an injectable for the first two months in patients with extensive disease. Duration of therapy is months In a BRMC trial, daily and thrice weekly therapy with isoniazid, PZA, and streptomycin given for 9 months was effective. Not sure if ethambutol will be interchangeable with streptomycin in this regimen

56 Group Case Activity The patient is a 19 year old student from Peru who was seen in the Emergency Department because of worsening cough, weight loss, and now hemoptysis. He is immediately isolated, sputum specimens are obtained for AFB and he is started empirically on RIPE therapy. He initially responds well but after six weeks his susceptibilities come back and he is found to be resistant to isoniazid and rifampin. He has no other medical problems. His initial films are below.

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59 Group Case Activity With your small group develop an action plan about next steps that addresses the following: 1. Treatment regimen 2. Baseline Laboratory monitoring and other studies before starting new drugs 3. Further testing if any on the isolate 4. Contact Investigation

60 Guiding Principles for Treating MDR-TB A single new drug should never be added to a failing regimen. When initiating or revising therapy, always attempt to employ at least three previously unused drugs to which there is in vitro susceptibility. One of these should be an injectable agent. Do not limit the regimen to three agents if other previously unused drugs that are likely to be active are available. Patients should receive either hospital-based or domiciliary DOT. The implications of treatment failure and further acquired resistance are such that these cases should receive highest priority for DOT. Intermittent therapy should not be used in treating tuberculosis caused by drug-resistant organisms, except perhaps for injectable agents after an initial period (usually 2--3 months) of daily therapy.

61 Guiding Principles for Treating MDR- TB The use of drugs to which there is demonstrated in vitro resistance is not encouraged because there is little or no efficacy of these drugs assuming the test results are accurate. It should be noted that the use of INH was associated with better survival rates in patients with the strain-w variety of MDR M. tuberculosis that was susceptible to higher concentrations of INH. Resistance to RIF is associated in nearly all instances with cross-resistance to rifabutin and rifapentine.

62 Case Question A 53 year old woman from Ukraine with a history of macular degeneration is diagnosed with pulmonary and renal tuberculosis and she is started on appropriate four drug therapy. After three weeks of therapy she develops a severe rash as seen in the photo below. After sequential re-introduction it is determined that the cause is rifampin and. Which of the following in fact she developed questionable angioedema options is the best option? 1.Treat with Benadryl or Atarax and continue treatment 2. Treat with INH, PZA, and EMB for 9 months 3. Treat with INH and PZA for 18 months 4. Admit to a hospital and desensitize to rifampin 5. Treat with four drugs but use rifabutin instead of rifampin

63 Guiding Principles for Treating MDR-TB There is no cross-resistance between SM and the other injectable agents: amikacin, kanamycin, and capreomycin (although resistance to all may occur as independent events); however, cross-resistance between amikacin and kanamycin is universal. Simultaneous use of two injectable agents is not recommended due to the absence of proof of efficacy and potential amplification of drug toxicity. However, resistance to PZA is uncommon in the absence of resistance to other first-line drugs.

64 Second-line Drugs for Drug Resistant TB Isoniazid Rifamycins Pyrazinamide Ethambutol Aminoglycosides Capreomycin Quinolones Thioamides Cycloserine PAS Need lab testing and or epi information on prevalent resistant strains 4-6 drugs for 2 years Less effective <80% cure rate $3500 to $5000 cost for drugs No clinical trials to support

65 Step 1 Begin with any First line agents to Which the isolate is Susceptible Add a Fluoroquinolone And an injectable Drug based on susceptibilities Use any available First-line drugs Pyrazinamide Ethambutol PLUS One of these Fluoroquinolones Levofloxacin Moxifloxacin PLUS One of these Injectable agents Amikacin Capreomycin Streptomycin Kanamycin 65 BS

66 Step 1 Begin with any First line agents to Which the isolate is Susceptible Use any available First-line drugs PLUS One of these Fluoroquinolones PLUS One of these Injectable agents Add a Fluoroquinolone And an injectable Drug based on susceptibilities Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Amikacin Capreomycin Streptomycin Kanamycin Step 2 Add 2 nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS 66

67 Step 1 Begin with any First line agents to Which the isolate is Susceptible Use any available First-line drugs PLUS One of these Fluoroquinolones PLUS One of these Injectable agents Add a Fluoroquinolone And an injectable Drug based on susceptibilities Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Amikacin Capreomycin Streptomycin Kanamycin Step 2 Add 2 nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) Step 3 Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS Consider use of these If there are not 4-6 drugs available consider 3 rd line in consult with MDRTB experts Third line drugs Imipenem Linezolid Macrolides Amoxicillin/Clavulanate 67 BS

68 Bangladesh Regimen for MDR TB DESIGN: Prospective, observational study of a gatifloxacin (GFX) based directly observed regimen, mainly with initial hospitalization. The 4-month intensive phase was extended until sputum smear conversion. Patients were monitored using culture for up to 2 years after treatment completion. RESULTS: Of the 515 patients who met the study inclusion criteria and were successively enrolled from 2005 to 2011, 84.4% had a bacteriologically favorable outcome. Only half of the patients completed treatment within 9 months; however, 95% were able to complete treatment within 12 months. Eleven patients failed or relapsed, and 93.1% of the 435 patients who were successfully treated completed at least 12 months post-treatment followup. Int J Tuberc Lung Dis Oct;18(10):

69 Bangladesh Regimen for MDR TB The strongest risk factor for a bacteriologically unfavorable outcome was high-level fluoroquinolone (FQ) resistance, particularly when compounded by initial pyrazinamide (PZA) resistance. Low-level FQ resistance had no unfavorable effect on treatment outcome. Amplification of drug resistance occurred only once, in a patient strain that was initially only susceptible to kanamycin and clofazimine. CONCLUSION: The excellent outcome of the Bangladesh regimen was largely maintained. Bacteriological treatment failures and relapses were rare, except among patients with high-level GFX resistance, notably in the presence of PZA resistance. Int J Tuberc Lung Dis Oct;18(10):

70 Role of Surgery in MDR and XDR TB Estimated pooled treatment success rate of pulmonary resection for patients with MDR- TB of 84%, with 92% achieving early success (30 days post-operative) and 87% long-term success. Patients who had surgical resection were twice as likely to have a favorable outcome as those who received chemotherapy alone and they were less likely to die. Predictors of good outcomes across the studies included surgical resection, body mass index (BMI) 18.5, and use of 4 effective drugs in the treatment of MDR/XDR- TB. Perioperative morbidity and mortality has ranged between 0-39% (median 23%) and 0-5% (median 1.3%), respectively. There is an even larger treatment effect related to surgery in XDR patients.

71 Section 5 Monitoring of Therapy in Patients with Drug Resistant Tuberculosis

72 Guidelines for Treatment Monitoring General principles Counsel every patient beginning any TB therapy to anticipate toxicity. Even patients taking INH monotherapy frequently feel poorly in the first few weeks of therapy. If patients do not anticipate this reaction and are not reassured that it will improve, they may stop the therapy. Monitor patients for general toxicities and drug-specific toxicity at every healthcare visit (including during DOT encounters). Patients with drug-resistant TB may experience more toxicity than patients treated for drug-susceptible disease. Most of the second-line TB drugs are associated with significant side effects.

73 Guidelines for Treatment Monitoring Take measures to minimize toxicity and to help patients tolerate the toxicity rather than losing the drug in the regimen. In many cases, there are no alternative drugs for replacement. Supplemental ancillary medication can be helpful in addressing some common side effects. Non-pharmaceutical approaches should also be considered. Examples might include: Change the timing of the dose to minimize toxicity (e.g., dose at bedtime). Dose some medicines with food (have patient try different foods to find something palatable). Relaxation techniques can sometimes be helpful

74 Routine Toxicity Monitoring in MDR TB Patients For patients with MDR-TB or XDR-TB, routine monitoring for drug toxicity frequently includes the following: Bone marrow suppression: Complete blood counts intermittently as clinically indicated; monthly for patients on linezolid (LZD). Renal function: Creatinine at least monthly for patients receiving aminoglycosides or CM. Baseline creatinine clearance should be documented in persons with serum creatinine elevation, diabetes, or elderly patients

75 Routine Toxicity Monitoring in MDR TB Patients Liver function: Liver function tests (LFTs) monthly (AST, ALT, total bilirubin) for patients taking pyrazinamide (PZA), ethionamide (ETA), or paraaminosalicylate (PAS). Serum electrolytes: Potassium, calcium, and magnesium monthly for patients on CM and aminoglycosides. Hypothyroidism: Thyroid function (TSH) every 3 months for patients receiving ETA or PAS.

76 Question A patient on treatment for MDR TB gets progressively withdrawn. He is becoming increasingly hopeless and isolated emotionally. He is no longer infectious but stays in his home and says that he is afraid to be outside and infect others. You are not only worried about depression but you worry about suicidal ideation. List five things that the team needs to do?

77 Routine Toxicity Monitoring in MDR TB Patients Hearing loss and vestibulopathy. Assess audiometry and vestibular function monthly for patients receiving aminoglycosides or CM Visual changes: Screen monthly for visual acuity and color discrimination for patients on ethambutol (EMB), LZD, and CFZ. Refer a patient for further evaluation if changes in vision (acuity or color) or complaint of eye pain is noted. Watch for evidence of uveitis for patients on rifabutin (RFB). EKG at least 2, 12 and 24 weeks into treatment for patients on BDQ, or weekly if BDQ is combined with other medications that may prolong the QT interval.

78 Routine Toxicity Monitoring in MDR TB Patients Peripheral neuropathy: Monitor for peripheral neuropathy monthly while patient is on LZD and as clinically indicated for patients on fluoroquinolones (or high-dose INH). Depression, agitation, and psychosis: Monitor for depression and mood changes (including agitation) monthly for patients taking cycloserine (CS).

79 Section 6 Outcomes of Therapy in Patients Treated for Drug Resistant Tuberculosis

80 Treatment Outcomes

81 Treatment Outcomes-Survival A long-term observational study conducted in Russia looking at survival between cohorts of non-mdrtb and MDRTB among civilian and prisoner populations and a civilian XDRTB cohort In the region where the study was conducted MDRTB and XDRTB rates of 54.8% and 11.1% respectively were identified in the region 71% of non-mdrtb patients were alive at 5 years as opposed to 58% of MDRTB patients at 5 years Previous treatment and MDR were risk factors for death Balbalanova, PLoS one 2011

82 Treatment Outcomes- Survival Balbalanova, PLoS one 2011

83 Section 7 Nosocomial Drug Resistant Tuberculosis

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87 Reducing Nosocomial Risk of MDR Nardell et al IJTLD 2010

88 The microbe is nothing the terrain is everything LOUIS PASTEUR