Seminar on renal tuberculosis

Seminar prepared by Dr. Puneet Arora, DM resident in Nephrology, IPGMER Kolkata

1. Puneet Arora 13/07/2011 Renal Tuberculosis: Diagnosis & Management

2. TB's History Proof of TB has been found in 4 000 year old mummies. Corpus Hippocraticum Great white plague Consumption Scrofula (king’s evil) Phtisis Romantic disease

3. Indian History Rigveda Calls the disease : yaksma Atharvaveda calls it another name:  balasa . first description of  scrofula  is given. The  Sushruta Samhita , written around 600 BCE, recommends that the disease be treated with breast milk, various meats, alcohol and rest. The  Yajurveda  advises sufferers to move to higher altitudes. The  Manu Smriti , written around 1500 BCE, states that sufferers of  yaksma  are impure and prohibits  Brahmins  from marrying any women that has a family history of the disease .

4. Robert Koch discovered in 1882 that TB was caused by a bacteria. 1920 – BCG vaccine 1944 – Streptomycin. 1970 – first outbreak of MDR-TB in USA. 2005- XDR-TB (KwaZulu-Natal, South Africa)

5. Etiology Genus Mycobacterium Weakly gram+ive,Acid fast Non- motile,non sporing,strictly aerobic,straight or slightly curved rod 2 to 4 µm in length with a diameter of 0.3 to 0.6 µm

6. Epidemiology 1993 – the WHO declared TB a global emergency 2 billion people latently infected 7-8 million cases of active TB Surge due to HIV Infection

7. Disease of young to middle-aged adults. M/F ratio= 5:3(In contrast to other forms of non-pulmonary TB) Uncommon in children and seen today almost exclusively in the rare child with miliary disease. Approximately 20-30% of extra-pulmonary infection(second most frequent form of non pulmonary TB) Seen in approximately 4% to 8% of non-HIV infected individuals with pulmonary tuberculosis. Renal tuberculosis

8. Renal tuberculosis Hematogenous spread Observed in two clinical settings: commonly, as a late manifestation of earlier clinical or subclinical pulmonary infection and rarely, as part of the multiorgan infection ( miliary tuberculosis) Rarely primary one— BCG Tt for Ca bladder Transplant recipient

9. 25% of the patients with genitourinary tuberculosis have a history of diagnosed tuberculosis. In an additional 25% to 50% of patients, changes compatible with old pulmonary tuberculosis can be found on chest x-ray films.

10. Considerable lapse of time between the onset of pulmonary infection and the diagnosis of active genitourinary tuberculosis. Time lapse of 16 to 25 years from primary tuberculous infection (i.e., erythema nodosum, pleurisy, or hilar adenopathy) If one looks at patients with reactivation pulmonary tuberculosis, then the time lapse is usually about 4 to 8 years It may be as long as several decades.

11. The small silent renal granulomas resulting from silent hematogenous dissemination are typically found bilaterally in the renal cortex Arise from capillaries within and adjacent to glomeruli These cortical granulomas remain dormant until unknown factors permit the bacilli to proliferate. If enlarging granuloma rupture, delivers organisms into the proximal tubule. Pathogenesis caseation fibrosis

12. Bacilli in the nephron are trapped at the level of loop of henle,where they multiply and survive well possibly on account of impaired phagocytosis in the hypertonic environment. Clinically important renal tuberculosis, therefore, is usually initially localized to the medulla and is usually unilateral.

13. Progressive destruction with cavity formation Papillary necrosis tuberculous pyonephrosis ( caseocavernous renal tuberculosis) are common in advanced disease . Communication with the collecting system usually is responsible for the spread of bacilli to the renal pelvis, ureters & bladder Lymphatic spread to contiguous structures also occurs. Direct hematogenous seeding of pelvic genital organs with clinical sparing of the kidney can occur occasionally.

14. Fibrosis accompanies the granulomatous process infundibular strictures and renal pelvic kinking obstructive uropathy The end-stage kidney is nonfunctional ( autonephrectomy ) and destroyed by the combined necrotizing and obstructive processes

15. Pathology: Gross Renal tuberculosis. Photograph of a cut gross specimen shows multiple, predominantly peripheral, white tuberculous granulomas throughout the kidney.

16. Photographs of a cut gross specimen show the early necrosis of the medullary tip (black spot in a ). Once devitalized, the papilla sloughs off, leaving a defect (cavity in b )

17. Calcification in advanced lesions is common and may be focal or generalized, which produces a putty or cement kidney.

18. Caseating granuloma Bilateral microscopic renal involvement is the rule. Pathology: Microscopic

19. Necrotizing granulomas fungal infections wegener's granulomatosis . Non- caseating granulomas sarcoidosis leprosy, and brucellosis. Foreign body type granulomas amyloid ruptured tubules myeloma protein, and therapeutic embolization Differential diagnosis

20. Insidious mode of presentation, with approximately 20% of cases diagnosed unexpectedly at operation or autopsy. A high index of suspicion enables early diagnosis One measure of the frequently occult nature of urinary tract tuberculosis comes from Lattimer's report in which 18 of 25 physicians with renal tuberculosis being diagnosed only after far-advanced cavitary disease had developed . Lattimer JK. Renal tuberculosis. N Engl J Med 1965;273:208 . Clinical Features

21. close contact with sputum positive individuals vagrancy, social deprivation, neglect, immunosuppression , HIV infection, diabetes mellitus renal failure elderly patients with TB elsewhere R isk factors

22. Approximately 75% of patients present with symptoms suggesting urinary tract inflammation. - Dysuria -Mild or moderately severe back or flank pain - Recurrent bouts of painless gross hematuria - Nocturia (due to conc. Defect) - Pyuria (esp. episodic) -Renal colic– up to 10% cases

23. Proteinuria Mild Proteinuria (<1gm/day in 50% cases) >1gm/day in 15% patients Rarely nephrotic range proteinuria Bladder symptoms in advanced cases (urgency, frequency) Paucity of constitutional symptoms usually associated with tuberculosis such as fever, weight loss, night sweats, and anorexia . Constitutional symptoms should lead to a search for other foci of tuberculosis

24. patients with renal tuberculosis may be subject to dehydration because of a concentrating defect, a tendency to lose salt Rarely NDI Always think of concomitant tuberculous adrenal disease (Addison's disease)

25. complete renal function loss owing to parenchymatous infection and destruction Strictures, can result in hydronephrosis and loss of renal function. Obstruction and hydronephrosis can develop during therapy because such sclerotic strictures are frequently part of the healing process .

26. Tubercular interstitial nephritis In some patients with pulmonary or disseminated tuberculosis there is evidence of renal failure without typical miliary involvement or localized genitourinary lesions In these cases biopsy has shown interstitial nephritis, usually, but not in all cases, with granulomata The evidence that the renal malfunction is due to a combination of infection and immunological renal damage is the recovery of function with a combination of antituberculosis treatment and corticosteroids Rare presentations:

27. The incidence of urinary tract tuberculosis as a cause of endstage renal disease is probably being underestimated as, although many individuals with classical urinary tract tuberculosis are identified, the interstitial form is easily overlooked. Hence, it is important that the diagnosis is considered in all patients with equal-sized smooth kidneys without a clear-cut renal diagnosis, especially in high-risk groups In such patients renal biopsy should always be considered. Mallinson et al. Quarterly Journal of Medicine 1981 Tubercular interstitial nephritis

28. Glomerular Diseases Rare association with -dense deposit disease Hariprasad et al. New york state journal of medicine, 1979 - Mesangio -capillary glomerulonephritis Amyloidosis Chronic tuberculosis sometimes leads to amyloidosis and in India is a not uncommon cause of renal amyloid and renal failure Chugh et al. 1981 Hypercalcemia in Tuberculosis Due to increased synthesis of calcitriol by granulomas . Paces R et al. Nephron 1987

29. Three other major complications of renal tuberculosis: hypertension (RAS axis mediated) super-infection (12 to 50%) nephrolithiasis (7 to 18%) In 1940, Nesbit and Ratliff reported that hypertension could be cured by the removal of a tuberculous kidney, More recent data, however, suggest that this is an uncommon event. Nesbit RM, Ratliff RK. Hypertension associated with unilateral nephropathy. J Urol 1940;43:427.

30. Descending infection to bladder Healing small, contracted bladder with greatly thickened walls (thimble bladder) three functional consequences - small bladder capacity -incomplete emptying with sec. bacterial infection - vesicoureteral reflux

31. Diagnosis Urine analysis Essentially every patient with established urinary tract tuberculosis has an abnormal urinalysis with pyuria , hematuria, or both. Acid-Sterile pyuria — the old clinical teaching that the asymptomatic patient with pyuria , particularly with an acid urine and a urine culture that fails to reveal conventional bacterial pathogens, must be considered as having tuberculosis until proved otherwise remains true today Another indicator is failure of the patient's symptoms to respond to conventional antibacterial treatment

32. S terile Pyuria Tuberculosis of the urinary tract Chlamydia trachomatis , Mycoplasma , or Ureaplasma infection Chemically induced cystitis Renal calculi, prostatitis Coliform (or other pathogen) urinary tract infection but antibiotic inhibiting growth WBC from outside urinary tract, e.g. from foreskin or vulva Renal parenchymal causes as acute tubulointerstitial nephritis, glomerular disease

33. Early-morning urine specimens are preferred Sterile container three to five daily specimens Preferably immediate examination, if delay unavoidable sample must be refrigerated, not freezed.

34. concentrated by centrifugation. Smears prepared from sediment Z-N staining. Problem of E.M.s( Mycobacteria Smegmatis ) G.U.T.B. should never be diagnosed solely on the basis of microscopy

35. Hot 1% carbol-fuchsin for five minutes. 3 % HCl or 20% sulphuric acid Ethanol counterstained with 0.1% methylene blue for 30 sec. Fluorescence methods : Auramine O- Bright yellow Auramine O-Rhodamine B- Yellow orange. ZN staining

36. Gold standard positive in 80% to 90% of cases Decontamination of sediment. main problems: -COST -AVAILABILITY - DELAYS Culture

37. newer commercial media (BACTEC..) -faster (about 10 days) -but expensive++, -technical demanding -not useful for control in high prevalence . Role of PCR .PPD Any role in India??????? False negative results in uraemia

38. High dose IVU – traditional gold standard CT – new standard Pyelography (ante/retrograde) – limited use Plain radiographs – important CXR,spine X- Ray,X -Ray KUB US – limited value Nuclear Perfusion Scan – function MRI,Arteriography – little application I maging

39. X-Rays Plain films of the abdomen- -genitourinary calcifications (present in up to 50%) as well as other extrapulmonary foci of mycobacterial disease (vertebral, mesenteric lymph node, adrenal glands) may be present (approximately 10%) Chest radiographs show evidence of tuberculosis in 50% to 75% of patients with active renal disease Radiology

40. Plain radiograph of the abdomen demonstrates extensive calcification in the left kidney, which was nonfunctional (the putty kidney), consistent with autonephrectomy from tuberculosis .

41. Genitourinary tract tuberculosis. Plain radiograph of the abdomen in a patient with calcified seminal vesicles due to tuberculosis. Note the amorphous and speckled calcification in the right kidney.

42. Sonogram of left kidney shows 1.5-cm hypoechoic nodule ( arrowhead ) in cortex USG -initial investigation of choice Cavities Obstruction Early findings may be missed

43. Intravenous urography - most useful because of its ability to detect calcification, to provide images of detailed anatomy and to show the commonly occurring multiple lesions Affected kidney may contrast-enhance on CT Renal calcification is common (24-44%) Stones, focal or extensive globular calcification, ring-like calcifications of papillary necrosis Cortical scarring "Smudged" papillae (moth-eaten) –irregular due to inflammation and  necrosis Several cysts surrounding a calyx with cortical thinning Intravenous pyelography & CT urogram findings

44. Hicked -up pelvis (Kerr kink sign) Infundibular strictures Hydrocalyces without dilatation of renal pelvis, or Hydronephrosis "Putty kidney" – sacs of casseous , necrotic material Autonephrectomy – small, shrunken kidney with dystrophic calcification Bilateral, but frequently asymmetric About 75% unilateral radiologically

45. When ureters are involved, usually the upper or lower third (more common) Beading (sawtooth ureter) Corkscrew ureter Pipe stem ureter Bladder involvement rarely leads to calcification of wall (think schistosomiasis) Reflux, thickening of bladder wall (thimble bladder), fistula formation

46. IVP of 32-year-old woman. A , left renal parenchymal mass (arrows) and left hydroureter due to left distal ureteral stricture (arrowheads). B , magnification of left kidney shows irregular caliceal contour as moth-eaten appearance (arrows) of upper calix and multiple cavities (arrowheads) of lower pole.

47. Genitourinary tract tuberculosis. Lobar calcification in a large destroyed right kidney in a patient with renal tuberculosis. Note the involvement of the right ureter .

48. IVP of 45-year-old woman demonstrates tubercular autonephrectomy and calcifications (white arrowheads) of small right kidney (white arrows). Amputated infundibulum (black arrowhead) of left kidney and left distal ureteral stricture (black arrow) are also visible .

49. IVP film-The lower end of the right ureter demonstrates an irregular caliber with an irregular stricture at the right vesico-ureteric junction. Note the asymmetric contraction of the urinary bladder, with marked irregularity due to edema and ulceration .

50. Genitourinary tract tuberculosis. Intravenous urography series in a man with renal tuberculosis shows marked irregularity of the bladder lumen due to mucosal edema and ulceration

51. Renal Tuberculosis. Coronal reformatted non-enhanced CT scan of the abdomen and pelvis demonstrates a small, left kidney containing globular calcifications (white circle) pathognomonic for renal tuberculosis.

52. A, Contrast-enhanced CT scan obtained at level of right renal hilum shows wedge-shaped hypoperfused areas ( arrowheads ). B, CT scan obtained at level 2.5 cm caudad to A shows hypoperfused areas ( arrowheads ) and focal caliectasis ( arrows)

53. 53-year-old man with tuberculosis involving collecting system. Contrast-enhanced CT scan of left kidney shows uneven caliectasis caused by varying degrees of stricture at various sites.

54. A, CT urogram shows severe nonuniform caliectasis and multifocal strictures ( arrowheads ) involving renal pelvis and ureter.Calcification ( arrow ) is noted in left distal ureter . B, Contrast-enhanced CT scan shows wall thickening and enhancement of left ureter ( arrowhead ).

55. 50-year-old woman with putty kidney. CT scan shows dense calcification replacing right kidney, so-called “putty kidney.”

56. May be normal in patients with early genitourinary tuberculosis. Calcification may occur in patients with Diabetes mellitus and schistosomiasis. Brucellosis also may mimic tuberculosis. A congenital megacalyx and focal papillary necrosis may mimic renal tuberculosis radiologically. Limitations-

57. Genitourinary tract tuberculosis. Lateral view of the abdomen in a patient with schistosomiasis shows tubular calcification of the ureters in contrast to the speckled calcification in tuberculosis.

58. Radiograph of the pelvis in a patient with schistosomiasis shows fine linear calcifications of the bladder wall with normal volume. In tuberculosis, the bladder is contracted and demonstrates speckled calcification

59. Cystoscopy under general anaesthesia with adequate muscle relaxation helps to visualize the mucosal lesions,golf hole ureteric orifice.or the reflux of toothpaste like caseous material Biopsy during acute stage is avoided for fear of dissemination of T.B Aspirated pus and caseous material generally contain few viable mycobacteria so it is more rewarding to examine biopsies of the surrounding tissue. C ystoscopy

60. Two goals Clinical Management conservation of tissue and function antimycobacterial cure.

61. It is a common practice for clinicians to treat GUTB for periods longer than six months. DOTS is the most effective way Standard Category I regimen is effective for the treatment of patients with GUTB Antimicrobial cure

62. Genito-urinary T.B. -- Cat I (HRZE)2 + (HR)4 Drug Daily Dose Intr. Dose Isoniazid 5mg/kg 10mg/kg Rifampicin 10mg/kg 10mg/kg Pyrizinamide 25mg/kg 35mg/kg Ethambutol 15mg/kg 25mg/kg Streptomycin 15mg/kg 15mg/kg daily Streptomycin- max. dose 750 mg in pts. <40 yrs age RNTCP- DOTS Therapy

63. Longer courses of ATT ranging from 9 months to 2 years are useful in patients: Who do not tolerate Pyrazinamide Those responding slowly to standard regimen Those with miliary and CNS disease Children with multiple site involvement L onger courses of ATT

64. Intermittent regimens have been compared head-to-head with daily treatment in several RCTs and have been shown to be as effective as the latter. Evidence from animal models suggests that intermittent treatment is in fact more efficacious that daily treatment. The reason for this might lie in post-antibiotic effect (PAE). PAE is the continued suppression of bacterial multiplication even after the level of the drug has fallen below the therapeutic concentration. drug-induced hepatotoxicity occurs less commonly in patients treated with intermittent regimens. Daily or intermittent?

65. INH Rifampicin no adjustment Pyrazinamide Drug Cr. Clearance Dose interval Ethambutol 10-50 ml/min 24-36 hrs <10 ml/min 48 hrs Streptomycin 10-50 ml/min 24-72 hrs <10 ml/min 72-96 hrs or avoid Dose modification in renal failure

66. Important side-effects of first-line anti-tuberculosis drugs Drug Isoniazid Side-effects Hepatitis peripheral neuropathy psychosis Convulsions disulfiram-like reaction Rifampicin Flu-like symptoms red-orange discoloration of secretions and contact lenses Hepatitis Cholestasis Thrombocytopenia renal failure

67. Drug Side-effect Pyrazinamide Hepatotoxicity asymptomatic hyperuricemia joint pains Ethambutol Retrobulbar optic neuritis peripheral neuropathy Streptomycin Vestibular dysfunction hearing loss non-oliguric renal failure

68. RNTCP guidelines- silent . After 2 month of therapy- 3 urine cultures If negative- continue therapy At the end of therapy 3 consecutive negative samples Repeated after 3 months and at 1 year. Treatment monitoring

69. IVP -at the end of 2 months -and at the completion of Tt . In case of renal calcification- yearly 3 urine examinations up to 10 years. Treatment monitoring

70. Another area of controversy in the treatment of GUTB is the utility of corticosteroids in the prevention of complications such as ureteric stricture/fibrosis Lack of RCTs on this issue it seems unlikely that corticosteroids would be able to reduce the development of complications such as ureteric obstruction in patients with GUTB. This issue is worth investigating What is the role of corticosteroids?

71. Most ATDs are safe during pregnancy except Streptomycin No contraindication during breast feeding and not necessary to isolate the baby from mother Baby should receive BCG immunization and Isoniazide prophylaxis Women taking OCPs should be advised to take higher doses or use alternative methods. W omen during Pregnancy and Lactation

72. The kidney is often involved in the disseminated tuberculosis but only a minority of patients have clinical features Marques et al. 1996 In a study in India, 17 of 35 patients dying of AIDS were found to have tuberculous lesions in their kidneys, with this disease being more common than fungal infections (five cases) and CMV (two cases) Lanjewar et al. 1999 Tuberculosis and HIV positivity

73. In India, about 5.2% of patients with TB have underlying HIV co-infection Extrapulmonary involvement occurs more commonly among HIV co-infected patients. All patients should therefore be offered voluntary counseling and testing services for detecting HIV co-infection. (NACO guidelines) HIV screening

74. Tuberculosis should always be considered when a renal transplant patient develops fever, especially when the patient is from a high-risk group One of the patients acquired tuberculosis from the transplanted kidney (Peters et al. 1984). Tuberculosis preventive therapy-no consensus T ransplant patients

75. European Best Practice Guidelines for Renal Transplantation (2002) recommend that all renal transplant candidates and recipients considered to have latent tuberculosis be treated with isoniazid 300 mg daily for 9 months. Such patients are defined as those with one or more of the following: induration after Mantoux testing of 5 mm (transplant recipients) or 10 mm (transplant candidates on dialysis); a history of inadequately treated tuberculosis; a chest X-ray suggestive of old tuberculosis; and close contact with a person with tuberculosis. tuberculin-negative patients who receive a kidney from a tuberculin-positive donor Transplant patients-Prophylaxis

76. In the prechemotherapy era, surgical ablation of infected foci was the only therapy available for renal tuberculosis Today the primary form of surgical intervention is in the relief of strictures, particularly those of the ureters, which can result from the scarring process. Thus, ureteral dilatations, ureteral reimplantations, and in some cases, relief of intrarenal obstruction to urine flow are important aspects of the modern function-conserving approach to urinary tract tuberculosis Surgical Management

77. Less commonly, patients whose bladders have been badly scarred by the tuberculosis process have such poor bladder function that bladder augmentation or even urinary diversion may be necessary to deal with unbearable urinary frequency, inadequate emptying, or both.

78. Rare event now a days End-stage tuberculous kidneys with complications -conventional bacterial sepsis -Hemorrhage -Intractable pain -Newly developed severe hypertension -Inability to sterilize the urine because of patient unreliability -Drug resistance nephrectomy

79. Not so rare, as thought…. Long latent period Clinical symptoms not very prominent The G reat P retender Urine analysis still most time-trusted investigation DOTS best regimen T ake Home Message

80. Thank you

81. Tuberculosis can be a difficult therapeutic problem in patients with renal failure. Rifampicin (Fabre et al. 1983) and isoniazid (Gold et al. 1976) can be given in the usual dosage. Neither is cleared significantly by dialysis. Pyridoxine should be given with isoniazid to prevent peripheral neuropathy (Cuss et al. 1986). The plasma half-life of ethambutol is, however, prolonged in renal impairment (Andrew 1980; Lee et al. 1980). If the GFR is less than 30 ml/min, the dose should be 10–15 mg/kg per day with a further reduction to 4 mg/kg daily if the GFR is less than 10 ml/min. Although 10 mg/kg daily has been used at these levels of GFR, cases of optic atrophy have been reported (Andrew 1980). Ethambutol is not dialysed to any significant extent. Pyrazinamide should be given at reduced dose (10–15 mg/kg) (Cuss et al. 1986). Capreomycin (Lehmann et al. 1988), a second-line drug, can be used in isoniazid or streptomycin resistance but is itself nephrotoxic and ototoxic but can be given in a single dose of 500 mg. With repeated transplant patients on cyclosporin , rifampicin cannot be used as it reduces the concentration of cyclosporin very substantially as a result of hepatic enzyme induction (Allen et al. 1985). The necessity to use more than three agents will be dictated by the nature and severity of the infection. Treatment may need to be prolonged to between 9 and 12 months in uraemic or immunosuppressed patients, in contrast to the shorter courses that are preferred in patients with normal renal function.

82. 75% of male patients with tuberculous epididymoorchitis already have evidence of urinary tract involvement. Epididymitis can present decades after apparently adequate therapy for renal tuberculosis While the incidence of renal disease in women with genital tuberculosis is less than 5%,

83. In the male, genital tuberculosis is acquired by seeding from infected urine or via the bloodstream. The most common manifestation is epididymo-orchitis ; less common is tuberculous prostatitis . Tuberculosis of the urethra and penis are much less common but, like tuberculous prostatitis ( O'Flynn 1970; Symes and Blandy 1973), can present with papulonecrotic skin lesions, fistulae, and genital ulceration. Although infection usually results from direct seeding from infected urine, penile tuberculosis can be acquired by direct inoculation from contaminated surgical instruments or clothing following ritual circumcision ( Annobil et al. 1990). The urinary tract should be fully investigated in any patient found to have genital tuberculosis since 75 per cent of patients with epididymo-orchitis or prostatitis have evidence of urinary tract involvement (Ferric and Rundle 1983). Tuberculosis of the female genital tract is accompanied by urinary tract tuberculosis in less than 5 per cent of casesâ €”far less commonly than in the male. Presumably, this is because the genital and urinary tracts in the female are separate so avoiding the possibility of direct infection of the genital tract from the urine. Thus tuberculosis of the female genital tract is probably almost always the result of haematogenous spread ( Pasternack and Rubin 1993). Tuberculosis of the genital tract

84. As urine contains contaminating microorganisms which may overgrow the culture medium, deposits for culture must first be ‘ decontaminatedâ €™, usually by treating the deposits with dilute sulfuric or oxalic acid, neutralizing and recentrifuging before inoculating the medium. Alternatively, a ‘ cocktailâ €™ of antibiotics that kill virtually all microorganisms other than mycobacteria can be added to the medium. Aspirated pus and caseous material generally contain few viable mycobacteria so it is more rewarding to examine biopsies of the surrounding tissue.

85. In cases of multidrug resistance, other agents including ethionamide , prothionamide , thiacetazone , cycloserine , capreomycin , p-amino salicylic acid, fluoroquinolones , such as ofloxacin and sparfloxacin , and the newer macrolides including clarithromycin and azithromycin are used. Limited evidence indicates that the antileprosy drug clofazimine and combinations of aminopenicillins and β-lactamase inhibitors, such as amoxycillin with sulbactam , are also of use. These drugs are generally more toxic, more expensive and less active than the first-line drugs and treatment is often prolonged and costly. Such therapy should, whenever possible, be guided by rigorously controlled drug susceptibility testing and single drugs should never be added blindly to failing treatment regimens