CNS Whipple Disease Medication
- Author: George C Bobustuc, MD; Chief Editor: Niranjan N Singh, MD, DM more...
Various antibiotics have been used with different efficacies. The most commonly used antibiotics, as reported in the literature, are tetracycline, penicillin, TMP-SMX, and chloramphenicol. Others used include demeclocycline, doxycycline, oxytetracycline, minocycline, gentamicin, streptomycin, amoxicillin, ampicillin, pefloxacin, erythromycin, profloxacin, vancomycin, ceftriaxone, cephalexin, and rifampin.
A consensus is found in the literature about using a combination of parenteral antibiotics at the initiation of therapy ("induction period") for 2-4 weeks, followed by long-term treatment (1-2 y) with an oral antibiotic. Options reported as efficacious for the induction period are a combination of parenteral antibiotics (penicillin and streptomycin) or third-generation cephalosporins such as ceftriaxone for at least 2-4 weeks.
Antibiotics for the induction period
TMP-SMX taken PO 2-3 times per day for long-term treatment (1-2 y) is the agent mostly reported as effective. An alternative reported as efficacious for long-term treatment is cefixime. Some treatment failures and acquired resistance at relapse have been reported with TMP-SMX.
Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.
For treatment of WD, induction period of 2-4 wk should be pursued, followed by long-term oral antibiotics; role of induction period has not been studied extensively; it may not be necessary, as long as good combination antibiotic regimen (ie, one with high BBB penetrance) is initiated for long-term use.
TMP-SMX inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Both sulfamethoxazole and trimethoprim diffuse into CSF.
For treatment of WD, long-term treatment (1-2 y) should be pursued
Semisynthetic third-generation cephalosporin for oral administration; can be administered in tab or susp form; chemically is (6R,7R)-7-[2-(2-Amino-4-thiazolyl) glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72(Z)-[O-(carboxymethyl)oxime]-trihydrate.
Molecular weight is 507.50 as trihydrate.
Most commonly used in treatment of bronchitis, gonorrhea, urinary tract infections, otitis media, pharyngitis, and tonsillitis. Has been reported as successful long-term treatment alternative to TMP-SMX in patients with WD.
Arguably, any antibiotic with good BBB penetrance, benign toxicity profile, and activity against gram-positive bacteria can be used in long-term treatment of CNS-WD.
Approximately 40-50% absorbed from gut whether administered with or without food. Time to maximal absorption is increased approximately 0.8 h when administered with food. Single 200-mg tab produces average peak serum concentration of approximately 2 mcg/mL (range 1-4 mcg/mL); single 400-mg tab produces average peak concentration of approximately 3.7 mcg/mL (range 1.3-7.7 mcg/mL).
PO susp produces average peak concentrations approximately 25-50% higher than tab. Area under time versus concentration curve is greater by approximately 10-25% with PO susp than with tab after doses of 100-400 mg when tested in healthy adult volunteers. Consider this increased absorption if PO susp is to be substituted for tab.
Because of lack of bioequivalence, do not substitute tab for PO susp in treatment of otitis media.
Peak serum concentrations occur 2-6 h following administration of both tab and susp. Approximately 50% of absorbed dose excreted unchanged in urine in 24 h. Also believed to be excreted in bile in excess of 10% of administered dose.
Serum protein binding is concentration independent with bound fraction of approximately 65%.
In multiple dose regimen, little accumulation in serum or urine after dosing for >14 d. Serum half-life in healthy subjects is independent of dosage form and averages 3-4 h but may range to as long as 9 h.
Average AC at steady state in elderly patients is approximately 40% higher than average AC in other healthy adults.
In subjects with moderate impairment of renal function (CrCl 20-40 mL/min), average serum half-life prolonged to 6.4 h. In severe renal impairment (CrCl 5-20 mL/min), half-life increased to average of 11.5 h. Not cleared significantly from blood by hemodialysis or peritoneal dialysis. Patients undergoing hemodialysis have similar blood profiles as subjects with CrCl of 21-60 mL/min.
No evidence of metabolism in vivo. Penetrates BBB but adequate detailed data of correlative CSF levels not available.
Various antiepileptic drugs (AEDs) and benzodiazepines reportedly have been tried to control movement abnormalities encountered in some patients with CNS-WD. Carbamazepine, phenobarbital, and lorazepam demonstrated no notable success in control of OMM and/or OSFM. Valproic acid has been reported as effective in controlling OMM and/or OSFM in some patients.
Indicated for seizures and myoclonus; chemically unrelated to other drugs that treat seizure disorders; although mechanism of action not established, activity may be related to increased brain levels of GABA or enhanced GABA action; also may potentiate postsynaptic GABA responses, affect potassium channel, or have direct membrane-stabilizing effect.
For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% every 2 wk; this reduction may start at initiation of therapy or be delayed by 1-2 wk if concern that seizures may occur with reduction; monitor patients closely during this period for increased seizure frequency.
As adjunctive therapy, divalproex sodium may be added to regimen at 10-15 mg/kg/d; may increase by 5-10 mg/kg/wk to achieve optimal clinical response; ordinarily, optimal clinical response achieved at daily doses < 60 mg/kg/d.
Has been used with some notable success for control of OMM and/or OSFM (reports exist of complete suppression of OMM and/or OSFM) once therapeutic levels were attained (75-100 mcg/mL).
Subtherapeutic levels or attempts to wean in most patients resulted in return of abnormal movements, in some patients even after completion of long-term antibiotic treatment.
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