eMedicine Specialties > Neurology > Neurological Infections
Tuberculous Meningitis: Treatment & Medication
Updated: Dec 4, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
The duration of chemotherapy for TBM is unclear, and the benefits of adjuvant corticosteroids remain in doubt. Death may occur as a result of missed diagnoses and delayed treatment.
- The best antimicrobial agents in the treatment of TBM include isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and streptomycin (SM), all of which enter CSF readily in the presence of meningeal inflammation. Ethambutol is less effective in meningeal disease unless used in high doses. The second-line drugs include ethionamide, cycloserine, ofloxacin, and para -amino salicylic acid (PAS). INH, RIF, and PZA are bactericidal. RIF and SM achieve optimal CSF levels only when the meninges are inflamed. Usually, intrathecal drugs are not necessary. Treatment is best started with INH, RIF, and PZA. The addition of a fourth drug is left to the choice of the local physicians and their experience, with little evidence to support the use of one over the other.
- Evidence concerning the duration of treatment is conflicting. The duration of conventional therapy is 6-9 months, although some investigators still recommend as many as 24 months of therapy. No guidelines exist as to the components and duration of treatment in the case of multidrug-resistant TBM.
- Studies have shown that young children with TBM can be treated safely for 6 months with high doses of anti-TB agents without overt hepatotoxicity and with a low risk of relapse. Children must be treated for 12 months with combination antibiotic therapy and adjunctive corticosteroids. Twelve months is probably a conservative estimate of the time required for bacterial cure. The rationale behind the use of adjuvant corticosteroids lies in reducing the harmful effects of inflammation as the antibiotics kill the organisms. The use of corticosteroids in adults is controversial; they may be indicated in the presence of increased intracranial pressure, altered consciousness, focal neurological findings, spinal block, and tuberculous encephalopathy. Treatment of tuberculoma consists of high-dose steroids and continuation of antituberculous therapy, often for a prolonged course.
- Hyaluronidase has been used in spinal arachnoiditis with good results. Gourie-Devi and Satish Chandra recommend the use of hyaluronidase administered intrathecally in cases of arachnoiditis complicating TBM.18
- In 2006, Walker et al report that BCG vaccination is partially protective against TB meningitis; therefore, a history of BCG vaccination or the presence of a BCG vaccination scar affords some degree of reassurance when considering a diagnosis of TBM (grade C).19 In patients in whom TBM is suspected clinically, the diagnosis must be rigorously investigated; a history of BCG vaccination does not rule out the diagnosis (grade C). In 2005, Kumar et al report that children with TBM who have been vaccinated with BCG appear to maintain better mentation and have superior outcomes. They believe this may be explained, in part, by the better immune response to infection, as is reflected in the higher CSF cell counts in their patient group.20
- In TBM, despite adequate treatment of hydrocephalus and various other complications, patients commonly fail to improve. This poor outcome is often associated with the extensive tuberculous exudate in the subarachnoid cisterns of the brain, which affects cerebral vessels and induces ischemia. Hence, treatment modalities should include optimizing physiologic variables to preserve cerebral perfusion.21
- The hypercoagulable state in childhood TBM is comparable to that described in adults with pulmonary tuberculosis and may further increase the risk for infarction. Therapeutic measures that reduce the risk for thrombosis could therefore be potentially beneficial in childhood TBM.22
- To ascertain the immediate and underlying causes of death in adults who died in hospital with a premortem diagnosis of tuberculosis, Martinson et al, in their autopsy studies, demonstrated disseminated, extensive tuberculosis associated with advanced HIV disease.23 Severe bacterial infections, including salmonellosis, were the leading comorbidity, suggesting that hospitalized HIV-infected adults in whom tuberculosis is suspected may benefit from broad-spectrum antibiotic therapy.
- Since uveitis is often treated with immunosuppressive and corticosteroid therapy, such treatment may have catastrophic consequences if patients with tuberculous granulomatous uveitis were not properly diagnosed and managed.
Surgical Care
- In patients with evidence of obstructive hydrocephalus and neurological deterioration who are undergoing treatment for TBM, placement of a ventricular drain or ventriculoperitoneal or ventriculoatrial shunt should not be delayed.
- Studies suggest that prompt ventriculoatrial or ventriculoperitoneal shunting improves outcome, particularly in patients presenting with minimal neurological deficit.
- Unless a mass effect is compromising vital structures, surgical intervention is rarely required in the treatment of tuberculomas.
Medication
First-line therapy includes INH, RIF, PZA, SM, and ethambutol. Second-line therapy includes ethionamide, cycloserine, PAS, aminoglycosides, capreomycin, and thiacetazone.
Potential new agents include oxazolidinone and isepamicin. Fluoroquinolones useful in the treatment of TBM include ciprofloxacin, ofloxacin, and levofloxacin. A new rifamycin called rifapentine has been developed.
Trials for novel agents for the treatment of TB are under way. Long-acting rifamycin derivatives and potent fluoroquinolone antibiotics have been studied, and they lead the way for improved regimens against active and latent TB. The recent rapid increase in knowledge of mycobacterial pathogenesis is likely to lead to the advent of potent new drugs in latent disease and against the phenomenon of persistence. Without a doubt, sustained and increased funding for basic research plays a key role in eradicating this global epidemic altogether.
Finally, because of the intensity of the inflammatory and fibrotic reactions at the meningeal site, adjunctive corticosteroids, in addition to standard antituberculous therapy, is recommended in TM.
Studies have confirmed the benefit of adjunctive corticosteroid therapy on survival and intellectual outcome in children with TBM, with enhanced resolution of basal exudates but no effect on intracranial pressure or the incidence of basal ganglia infarction.24
Wasay, in his 2006 editorial, discusses at length CNS TB and the paradoxical response. The paradoxical response to antituberculous therapy is well known; it usually develops after approximately 2 weeks of treatment. It is characterized by the clinical or radiological worsening of preexisting tuberculous lesions or the development of new lesions not attributable to the normal course of disease in a patient who initially improved with antituberculous therapy. Up to 10% of patients with CNS TB report the paradoxical response, and this number may be as high as 30% in HIV-infected patients.25,26
The paradoxical response has been attributed as a component of immune reconstitution inflammatory syndrome or immune restoration syndrome, which results from an exuberant inflammatory response toward incubating opportunistic pathogens.27 An increase in the incidence and severity of the paradoxical response is noted in HIV-infected patients on highly active antiretroviral therapy.28 Patients demonstrating a paradoxical response are more likely to have lower baseline lymphocyte counts, followed by a surge.29
Antitubercular agents
Any regimen must contain multiple drugs to which the mycoplasma is susceptible. In addition, the therapy must be taken regularly and continued for a sufficient period.
Capreomycin (Capastat)
Second-line drug for concomitant use with other appropriate anti-TB drugs when first-line drugs are ineffective or cannot be used because of toxicity.
Adult
1 g/d IM for 60-120 d, followed by 1 g IM 2-3 times/wk up to 18-24 mo; not to exceed 15-20 mg/kg/d
Adjust dose in presence of renal impairment (based on CrCl)
Pediatric
Not established
Aminoglycosides may increase risk of ototoxicity, respiratory paralysis, and renal dysfunction; cisplatin and vancomycin increase risk of nephrotoxicity and ototoxicity; colistin increases risk of nephrotoxicity
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Exclude renal impairment when given with other anti-TB drugs; use caution in pregnancy, breastfeeding, children, ototoxicity, and hypokalemia
Adverse reactions may include toxic nephritis and electrolyte disturbances resembling Bartter syndrome; in addition to hearing loss, tinnitus, vertigo, hepatic impairment, leukocytosis or leukopenia, and urticaria may occur; maculopapular skin rashes can occur, associated (in some cases) with febrile reactions, pain, induration, and excessive bleeding at injection site; occasionally, sterile abscesses also may develop
Cycloserine (Seromycin)
Second-line anti-TB drug effective against M tuberculosis. Competitive antagonist of racemase enzyme involved in bacterial cell wall synthesis. Also active against other mycobacteria such as Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium malmoense. Indicated in TB resistant to first-line drugs, in combination with other drugs.
Adult
250 mg PO q12h for 2 wk, gradually increase to maximum 500 mg q12h; not to exceed 30 mg/L
Pediatric
10 mg/kg/d PO; adjust according to blood concentration and response
May increase plasma concentration of phenytoin (ie, risk of toxicity); alcohol increases potential risk of convulsions; INH and ethionamide increase potential for CNS toxicity
Documented hypersensitivity; severe renal impairment; porphyria; depression; epilepsy; severe anxiety; psychotic reactions; alcohol dependence
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Discontinue or reduce dose if allergic skin reaction or CNS toxicity occurs; reduce dose in renal impairment (avoid if severe); monitor hematologic, renal, and hepatic functions; use caution in pregnancy and breastfeeding; monitor blood concentration, especially in renal impairment, if dose >500 mg/d or if signs of toxicity become evident
Adverse effects include convulsions (dose related), headache, dizziness, vertigo, drowsiness, tremor, psychosis, depression, rashes, megaloblastic anemia, and changes in LFT results
Ethambutol (Myambutol)
Bactericidal at 25 mg/kg at pH between neutral and alkaline. Bacteriostatic at 15 mg/kg. Site of action is extracellular. Acts on rapidly growing pathogens in cavity walls. Also effective in slow-growing pathogens. Indicated as first-line anti-TB drug.
Adult
15-25 mg/kg/d PO, up to 50 mg/kg intermittently 2-3 times/wk
Pediatric
10-15 mg/kg/d PO
Aluminum hydroxide delays or reduces absorption; works in synergy with other anti-TB agents
Documented hypersensitivity; optic neuritis; severe renal failure; epilepsy; neonates
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal failure, elderly persons, and pregnancy; may cause optic neuritis, resulting in decreased visual acuity or other vision changes
False-positive screening test result for pheochromocytoma could occur
Adverse reactions include retrobulbar neuritis with decreased visual acuity, constriction of visual field, central or peripheral scotoma, green-red color blindness, reduced renal clearance of urates (gout), GI disturbances, rash, headache, dizziness, and anorexia
Ethionamide (Trecator)
Bacteriostatic against M tuberculosis. Also active against atypical mycobacteria such as M kansasii, some strains of M avium complex, and Mycobacterium leprae. Indicated as second-line anti-TB agent.
Adult
15-20 mg/kg PO qd; not to exceed 1 g/d
Pediatric
Administer as in adults
Cycloserine has caused convulsions; may increase adverse reactions due to other anti-TB drugs
Documented hypersensitivity; severe liver damage
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hepatitis occurs more often in patients with diabetes mellitus (monitor serum transaminases every 2-4 wk during therapy); caution in patients with psychiatric illness, pregnant women, and breastfeeding mothers; may interfere with estimation of dehydrogenase and phosphate
Adverse reactions include GI effects (common), peripheral neuropathy, optic neuritis, psychiatric disturbances (eg, depression), postural hypotension, jaundice, hepatitis, thrombocytopenia, and rashes
Glycemic control may be difficult in diabetic patients
Isoniazid (Laniazid, Nydrazid)
Bactericidal against actively dividing pathogens but bacteriostatic against nondividing organisms. Highly effective against M tuberculosis. Indicated for treatment of all forms of TB. Usually, preventive therapy with INH delayed in pregnant women until delivery unless patient likely to have been infected recently.
Adult
300 mg PO qd; may be doubled in miliary or meningeal forms; alternative is 900 mg 2-3 times/wk; not to exceed 15 mg/kg in each dose
Prophylaxis: 300 mg/d
Patients on dialysis: 5 mg/kg PO 3 times/wk recommended, but some believe this may be less effective than 300 mg/d with pyridoxine
Pediatric
5-10 mg/kg/d PO; higher doses may be given; intermittent therapy 2-3 times/wk at dose of 10 mg/kg; slow-release forms providing 35 mg/kg for slow acetylators and 50 mg/kg for rapid acetylators have been well tolerated
Prophylaxis: 5-10 mg/kg PO for 6-12 mo
Increases effects of phenytoin and its toxicity; alcohol may cause hyperpyrexia or tremor; RIF may cause hepatitis; increases effects of carbamazepine; prednisolone causes significant decrease in levels; antagonizes hypoglycemic action of insulin; pyridoxine antagonizes effects
Documented hypersensitivity; previous INH-associated hepatic injury or other severe adverse reactions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use special precautions in renal impairment, pregnancy, and breastfeeding
Adverse reactions include hepatitis (rare), peripheral neuritis, nausea, vomiting, epigastric distress, visual disturbances, hepatitis, fever, rash, pyridoxine deficiency, hyperglycemia, and hepatotoxicity (enhanced by RIF); high-carbohydrate diet reduces absorption and bioavailability; cheese reaction observed with certain foods such as cheese, red wine, some fish, and others
Prothionamide
Thionamide derivative, active against M tuberculosis. Action similar to that of ethionamide, with which it is considered interchangeable. Resistance develops quickly if used alone. Better tolerated than ethionamide. Indicated as second-line anti-TB drug. Not available in the United States.
Adult
15-20 mg/kg PO qd; not to exceed 1 g/d
Pediatric
Administer as in adults
RIF potentiates hepatotoxic effects; increases serum concentration of INH by inhibiting metabolism
Documented hypersensitivity; severe hepatic damage
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use special precautions in pregnant women, breastfeeding mothers, and children; monitor LFT results; combination with RIF should be avoided
Adverse reactions include severe hepatic damage (although better tolerated than ethionamide), liver dysfunction, GI upset, headache, insomnia, sleepiness, paresthesia, depression, cutaneous acneiform lesions, facial pruritus, and excessive salivation
Pyrazinamide (Tebrazid)
Has bactericidal action against M tuberculosis in acidic environment present in macrophages and inflamed tissue; works both intracellularly and extracellularly. Together with RIF, provides greatest sterilizing action with reduction in replace rate. Reduces tubular secretion of uric acid. Indicated as part of multidrug regimens during first 2 mo; may be continued if necessary.
Adult
20-35 mg/kg/d PO qd; not to exceed 3 g/d
Intermittent therapy: 50 mg/kg PO 3 times/wk or 75 mg/kg 2 times/wk
Pediatric
15-30 mg/kg PO qd; not to exceed 2 g/d
Significantly reduces serum INH concentration
Documented hypersensitivity; pregnancy; existing liver disease; gout
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use caution in patients with diabetes and renal failure because interferes with control of diabetes and with urinary ketone estimations; caution in children and breastfeeding mothers
May cause severe liver damage and fulminant hepatitis, hepatotoxicity (hepatomegaly, splenomegaly, and jaundice may develop and, in rare cases, fulminating acute yellow atrophy and death may occur)
Other adverse effects include anorexia, nausea, vomiting, arthralgia, malaise, fever, hyperuricemia, abnormal LFT results, raised plasma fibrinogen level, and photosensitivity associated with rashes (rare)
Rifampin (Rifadin, Rimactane)
Bactericidal action against wide range of organisms, including intracellular organisms and semidormant or persistent ones. Generally, reserved for treatment of TB and leprosy and opportunistic atypical mycobacterial infections such as those in patients with AIDS or HIV infection. Inhibits DNA-dependent RNA polymerase enzyme, resulting in suppression of nucleic acid synthesis. Indicated as part of multidrug anti-TB regimens.
Adult
450 or 600 mg/d PO for first 2 mo and then 10-15 mg/kg 3 times/wk for further 4-6 mo; not to exceed 900 mg/d
Pediatric
10-20 mg/kg/d PO; not to exceed 600 mg/d
Phenobarbital and phenytoin lower blood levels; probenecid increases blood levels; decreases effects of tolbutamide, clofibrate, warfarin anticoagulants, diazepam, and oral contraceptives; reduces levels of metoprolol, norethisterone, and quinidine; INH reduces vitamin D blood levels and can cause severe hepatitis; reduces efficacy of corticosteroids in Addison disease, which can induce addisonian crisis; also can cause liver enzyme induction, affecting metabolism of chloramphenicol, corticosteroids, clofibrate, cyclosporine, dapsone, digoxin, hexobarbitone, ketoconazole, quinidine, and verapamil
Documented hypersensitivity; jaundice; biliary obstruction; severe hepatic disease
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in impaired hepatic/renal function (may cause fatalities in patients with liver disorders)' caution in elderly, malnourished, or very young patients and in pregnancy and breastfeeding
Adverse reactions include shocklike syndrome (can also occur with intermittent use only), GI disturbances, pseudomembranous colitis (rare), abnormalities of liver function, influenzalike symptoms, skin reactions, eosinophilia, transient leukopenia or thrombocytopenia, shock, drowsiness, headache, ataxia, visual disturbances, and menstrual irregularities
Urine and tears are reddish colored; interferes with colorimetric tests, including bromsulfophthalein tests of liver function and assays of bilirubin; erroneous low readings of vitamin B-12 and folate levels may be recorded; food may delay absorption
Streptomycin sulfate
Has bactericidal action, inhibits bacterial protein synthesis. Susceptible organisms include M tuberculosis, Pasteurella pestis, Pasteurella tularensis, Haemophilus influenzae, Haemophilus ducreyi, donovanosis (granuloma inguinale), Brucella species, Klebsiella pneumonia, Escherichia coli, Proteus species, Aerobacter species, Enterococcus faecalis, and Streptococcus viridans (in endocarditis, with penicillin). Always given as part of total anti-TB regimen.
Adult
0.75-1 g/d IM for first 2 mo
Intermittent therapy: 3 times/wk for 2-6 mo
Pediatric
15-20 mg/kg/d IM for first 2 mo
Intermittent therapy: 3 times/wk for 2-6 mo
Potentiates nephrotoxicity induced by other aminoglycosides, vancomycin, and some cephalosporins; also potentiates ototoxicity produced by other aminoglycosides, ethacrynic acid, and furosemide; indomethacin can increase plasma levels; H1-receptor blockers may mask early signs of ototoxicity; incompatible with acids and alkalis; works synergistically with benzylpenicillin
Documented hypersensitivity; ear disease; pregnancy; myasthenia gravis
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in renal impairment and lactation; adverse reactions include anaphylactic shock, aplastic anemia, agranulocytosis, giddiness, vertigo, tinnitus, ataxia, hypersensitivity reactions, ototoxicity, and nephrotoxicity
Para-aminosalicylic acid (Sodium PAS)
Weak bacteriostatic agent available as enteric-coated granule designed for gradual drug release. Believed to competitively inhibit conversion of aminobenzoic acid to dihydrofolic acid and/or to inhibit iron uptake. In treatment of clinical TB, should not be given alone.
Adult
10-12 g/kg/d PO divided bid/qid
Usually, given as 4 g (1 packet) tid by sprinkling on applesauce or yogurt or by mixing with an acidic drink such as tomato or orange juice (glass should be swirled to suspend granules in liquid)
Pediatric
8-12 g/d PO or correspondingly smaller doses than for adults if sprinkled on applesauce or yogurt or mixed with an acidic drink such as tomato or orange juice
Reduces rate of acetylation of INH, however, effect not clinically significant; reduces vitamin B-12 absorption by approximately 50% with significant erythrocyte abnormalities developing; after depletion (ie, after receiving PAS for 1 mo), vitamin B-12 maintenance is consideration
Documented hypersensitivity; severe renal disease
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adverse GI effects include nausea, vomiting, diarrhea, and abdominal pain; hypersensitivity reaction includes rash, including exfoliative dermatitis, followed by fever, and, much less frequently, anorexia, nausea, and diarrhea; hepatitis has been reported in 0.5% of patients receiving rapidly absorbed preparations; other rare adverse effects include hypoprothrombinemia, agranulocytosis, thrombocytopenia, Coombs-positive hemolytic anemia, goiter, and lupuslike syndrome
Thiacetazone
Although not available in United States, used in many developing countries because inexpensive. Although related to INH biochemically, is bacteriostatic and more toxic than INH. Commonly combined in single tab containing 300-400 mg of INH and 150 mg of thiacetazone.
Adult
150 mg/d PO
Pediatric
Not established
May potentiate vestibular toxicity of SM; severe liver damage has been reported in patients receiving with concurrent INH, although roles of individual agents not clear
Documented hypersensitivity; HIV infection
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
GI upset, including nausea and vomiting, occurs in as many as 10% of patients; less frequent adverse effects include jaundice ( <1%), reversible bone marrow suppression (0.2%), and rashes (3.9%); cutaneous reactions may be severe and, if drug is not stopped, exfoliative dermatitis or Stevens-Johnson syndrome may occur (these reactions are frequent, especially in persons with HIV infection)
Geographic variation in adverse effects has been observed, with patients in East Africa tolerating drug better than those in Asia
Rifapentine (Priftin)
In vitro activity superior to that of RIF against isolates of M tuberculosis and M avium complex. Both rifapentine and its metabolite are protein bound.
Adult
4 tab (600 mg) qwk for intensive phase of short-term therapy, followed by 600 mg qwk for 4 mo in combination with INH or appropriate agent for susceptible organism
Pediatric
Not established
Induces cytochrome P-4503A4 and P-4502C8/9, thereby decreasing levels of other drugs that are metabolized by these enzymes
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Adverse effects include serious hepatic events, including hepatitis and liver failure, Clostridium difficile -associated colitis, hyperbilirubinemia, urticaria, thrombocytopenia, hyperkalemia, fatigue, and gout; may cause red-orange discoloration of body fluids (eg, tears, urine, sweat, CSF)
Kanamycin (Kantrex)
Aminoglycoside containing 1 or 2 amino sugars linked to aminocyclitol nucleus. Nucleus is 2-deoxystreptamine. Bactericidal and believed to inhibit protein synthesis by binding to 30S ribosomal subunit. Effective against extracellular mycobacteria.
Injectable agent available as 75-mg, 500-mg, and 1-g vials.
Adult
15-30 mg/kg/d IM 5 times/wk; not to exceed 1 g/d
Solution for IV use prepared by adding contents of 0.5-g vial to 100 mL sterile diluent (eg, isotonic saline, 5% dextrose in water); total IV single daily dose also is 15 mg/kg, given over 30 min
Average peak serum concentration (Cmax) is 21 mcg/mL, 1 h after IM administration of 7.5 mg/kg single dose
Pediatric
Not established
Avoid other agents with nephrotoxic potential
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Auditory toxicity more common with kanamycin than with SM and capreomycin; monthly audiometric testing recommended during treatment; vestibular toxicity rare; renal toxicity occurs at frequency similar to that of capreomycin; regular monitoring of serum creatinine recommended
Amikacin (Amikin)
Aminoglycoside containing 1 or 2 amino sugars linked to aminocyclitol nucleus. Nucleus is 2-deoxystreptamine. Highly bactericidal against M tuberculosis in vitro.
Adult
MIC approximately 4-8 mcg/mL for wide range of strains of M tuberculosis
Pediatric
Not established
Coadministration with other aminoglycosides, cephalosporins, and amphotericin B increases nephrotoxicity; enhances effects of neuromuscular blocking agents; causes respiratory depression; concurrent loop diuretics may cause irreversible hearing loss
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Major adverse effect is nephrotoxicity; adjust dose or administration frequency if renal insufficiency develops; monitor BUN and creatinine levels weekly or biweekly and, if elevated, evaluate CrCl
Other adverse effects include vestibular dysfunction, hearing loss, chemical imbalance (calcium, potassium, magnesium levels should be monitored weekly or biweekly for decreases), circumoral numbness, and minor dizziness
Perform baseline audiogram prior to treatment and monthly thereafter if patient receiving 1 injectable drug, twice monthly if receiving 2 injectable drugs
In case of similar susceptibility to capreomycin and amikacin, use capreomycin if patient aged 60 y or older because older patients seem to experience greater renal and CN VIII toxicity with amikacin than with capreomycin
Appears to have advantages of being less ototoxic than kanamycin and less painful on IM administration
Fluoroquinolones
Several fluoroquinolones have shown in vitro activity against M tuberculosis. The target of the quinolones is the enzyme DNA gyrase. Ofloxacin and ciprofloxacin are compounds of this family that are licensed for use in the United States. However, neither of these drugs is licensed for treatment of TB.
The minimal inhibitory concentration of ofloxacin and ciprofloxacin is approximately 1 mcg/mL for a wide range of strains of M tuberculosis, compared with a peak serum concentration of 4.3 mcg/mL 1-2 h after a 750-mg dose of ciprofloxacin, and a 4.6 mcg/mL peak serum concentration after multiple 400-mg doses of ofloxacin. One study showed a similar minimal inhibitory concentration for ofloxacin in the macrophage model, and minimal bactericidal concentration was found to be 2 mcg/mL; however, the bactericidal activity of ofloxacin was less than that of RIF. Another study found identical minimal bactericidal concentration levels of 2 mcg/mL for both ciprofloxacin and ofloxacin in 7H12 broth medium. In general, quinolones are well tolerated.
The quinolones are cleared primarily by renal excretion; adjust dosage for those with CrCl less than 50 mL/min. Few long-term studies have been preformed on the use of quinolones, but one review found that toxicity is dependent more on dose than on duration of therapy.
Data on the use of these agents for the treatment of TB are limited. A study from Japan reported patients who had chronic cavitary lung TB were excreting bacilli resistant to various anti-TB agents. Of 17 patients who received ofloxacin in combination with other anti-TB agents as single doses of 300 mg/d for 6-8 months, 14 patients showed a decrease in culture positivity and 5 had a negative conversion. No adverse effects were observed.
Another study of ofloxacin reported 22 patients receiving 300 or 800 mg of ofloxacin in a single daily dose for 9 mo to 1 y. All patients tolerated the drug well, and indications were noted of higher efficacy at higher doses.
Ciprofloxacin (Cipro)
Shown to have in vitro activity in M tuberculosis, but data on clinical use of these agents in TB limited. Not approved in United States for treatment of TB. Probably greater efficacy at higher doses. Target is enzyme DNA gyrase.
Generally well tolerated. Toxicity related more to duration of therapy than to dose.
Cleared primarily by renal excretion; adjust dosage for CrCl <50 mL/min.
Adult
Severe respiratory tract infections
750 mg PO bid
Pediatric
Not recommended
May prolong half-life of theophylline, increase serum levels of theophylline, and increase risk of adverse effects caused by theophylline; antacids (eg, aluminum, magnesium) and calcium and ferrous sulfate may interfere with absorption
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Because quinolones have been shown to cause arthropathies in studies with immature animals, these drugs should be used during pregnancy or in children only after carefully weighing risk to the fetus or child against potential benefits of therapy with these drugs
Changes in laboratory parameters that may be associated with adverse effects include elevations of AST, ALT, and serum creatinine, eosinophilia, and leukopenia; GI symptoms, dizziness, and hypersensitivity are most commonly reported adverse effects
Ofloxacin (Floxin)
Broad-spectrum fluoroquinolone that inhibits DNA gyrase. Good gram-positive coverage and excellent gram-negative coverage but poor anaerobic coverage.
Adult
Severe respiratory tract infections
400 mg PO bid
Pediatric
Not established
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations
May increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy
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Further Reading
Keywords
tuberculous meningitis, TBM, TB, Mycobacterium tuberculosis, M tuberculosis, tuberculosis, Rich foci, extrapulmonary tuberculosis, tuberculous spinal meningitis, tuberculous spondylitis, tuberculous radiculomyelitis, TBRM, tuberculous meningitis, CNS infection, Pott disease, spinal caries, skeletal tuberculosis
