Puneet Arora

13/07/2011

Puneet Arora

13/07/2011

Renal Tuberculosis: Diagnosis & Management

Renal Tuberculosis: Diagnosis & Management

TB's HistoryProof of TB has been found in 4

000 year old mummies.

Corpus Hippocraticum

Great white plagueConsumptionScrofula (king’s evil)PhtisisRomantic disease

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

.

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)

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

Epidemiology1993 – the WHO declared TB a global

emergency

2 billion people latently infected

7-8 million cases of active TB

Surge due to HIV Infection

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

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 bladderTransplant recipient

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.

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.

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 glomeruliThese 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

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.

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.

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

Pathology: Gross

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

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)

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

kidney.

Caseating granuloma

Bilateral microscopic renal involvement is the rule.

Pathology: Microscopic

Necrotizing granulomas fungal infectionswegener's granulomatosis. Non-caseating granulomassarcoidosisleprosy, and brucellosis. Foreign body type granulomasamyloidruptured tubulesmyeloma protein, and therapeutic embolization

Differential diagnosis

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

close contact with sputum positive individualsvagrancy,social deprivation,neglect,immunosuppression,HIV infection,diabetes mellitusrenal failureelderlypatients with TB elsewhere

Risk factors

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

ProteinuriaMild Proteinuria (<1gm/day in 50% cases)>1gm/day in 15% patientsRarely 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

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)

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.

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:

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

Glomerular DiseasesRare association with

-dense deposit diseaseHariprasad et al. New york state journal of medicine, 1979

-Mesangio-capillary glomerulonephritisAmyloidosis 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 TuberculosisDue to increased synthesis of calcitriol by granulomas.

Paces R et al. Nephron 1987

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.

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

DiagnosisUrine 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

Sterile PyuriaTuberculosis 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 growthWBC from outside urinary tract, e.g. from foreskin or

vulva Renal parenchymal causes as acute tubulointerstitial

nephritis, glomerular disease

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.

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

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

· Gold standard

· positive in 80% to 90% of cases

· Decontamination of sediment.

· main problems:

-COST

-AVAILABILITY

-DELAYS

Culture

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

High dose IVU – traditional gold standardCT – new standardPyelography (ante/retrograde) – limited usePlain radiographs – important CXR,spine X-Ray,X-Ray KUBUS – limited valueNuclear Perfusion Scan – functionMRI,Arteriography – little application

Imaging

X-RaysPlain 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

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

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.

Sonogram of left kidney shows 1.5-cm hypoechoic nodule (arrowhead) in cortex

USG-initial investigation of choice

CavitiesObstruction

Early findings may be missed

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

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

When ureters are involved, usually the upper or lower third (more common) Beading (sawtooth ureter)Corkscrew ureterPipe stem ureter

Bladder involvement rarely leads to calcification of wall (think schistosomiasis) Reflux, thickening of bladder wall (thimble bladder),

fistula formation

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.

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

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.

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.

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

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.

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-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.

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).

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

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-

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.

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

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.

Cystoscopy

Two goals

Clinical Management

conservation of tissue and function

antimycobacterial cure.

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

Genito-urinary T.B. -- Cat I

(HRZE)2 + (HR)4

Drug Daily Dose Intr. DoseIsoniazid 5mg/kg 10mg/kgRifampicin 10mg/kg 10mg/kgPyrizinamide 25mg/kg 35mg/kgEthambutol 15mg/kg 25mg/kgStreptomycin 15mg/kg 15mg/kg daily

Streptomycin- max. dose 750 mg in pts. <40 yrs age

RNTCP- DOTS Therapy

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

Longer courses of ATT

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?

INHRifampicin 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

Important side-effects of first-line anti-tuberculosis drugs

DrugIsoniazid

Side-effectsHepatitisperipheral neuropathy psychosisConvulsionsdisulfiram-like reaction

Rifampicin Flu-like symptomsred-orange discoloration of secretions and contact lensesHepatitisCholestasisThrombocytopeniarenal failure

Drug Side-effect

Pyrazinamide Hepatotoxicityasymptomatic hyperuricemia

joint pains

Ethambutol Retrobulbar optic neuritisperipheral neuropathy

Streptomycin Vestibular dysfunctionhearing loss

non-oliguric renal failure

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

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

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?

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.

Women during Pregnancy and Lactation

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

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

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

Transplant patients

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

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

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.

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

Not so rare, as thought….

Long latent period

Clinical symptoms not very prominent

The Great Pretender

Urine analysis still most time-trusted investigation

DOTS best regimen

Take Home Message

Thank you

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.

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%,

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 cases—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

As urine contains contaminating microorganisms which may overgrow the culture medium, deposits for culture must first be ‘decontaminated’, usually by treating the deposits with dilute sulfuric or oxalic acid, neutralizing and recentrifuging before inoculating the medium. Alternatively, a ‘cocktail’ 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.

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