Meningitis drug combinations

High-dose penicillin G traditionally has been the drug of choice for the treatment of pneumococcal meningitis. However, due to increases in pneumococcal resistance, the preferred empirical treatment now includes a third-generation cephalosporin in combination with vancomycin.13 All CSF isolates should be tested for penicillin and cephalosporin resistance by methods endorsed by the CLSI. Once in vitro sensitivity results are known, therapy may be tailored (Table 67-3). Patients with a history of type I penicillin allergy or cephalosporin allergy may be treated with vancomycin. Treatment should be continued for 10 to 14 days, after which no further maintenance therapy is required. Antimicrobial prophylaxis is not indicated for close contacts. 

Amphotericin B is the drug of choice for treatment of acute C. neoformans meningitis. Amphotericin B, 0.5 to 1 mg/kg/day, combined with flucytosine, 100 mg/kg/day, is more effective than amphotericin alone. In the acquired immune deficiency syndrome (AIDS) population, flucytosine is often poorly tolerated, causing bone marrow suppression and GI distress. 

Before moving on, you should understand that not all drug interactions are bad. Sometimes we use them to our advantage. For example, it s common practice to combine antibiotics that attack bacteria in different ways when treating serious infections like pneumonia or meningitis. The two antibiotics work together to kill... 

Resistance to a combination of trimethoprim-sulfamethoxazole is always less frequent than when any of these drugs is used separately. This combination of drugs, which is known by the commercial names cotrimoxazole, bactrim, biseptol, sulfatrim, and many others, is used for treating infections of the respiratory tract, infections of the urinary tract, gastric infections, surgical infections, enteritis, meningitis, and other diseases. 

Combinations of amphotericin-B with flucytosine are sometimes used to reduce the occurrence of resistance. Amphotericin-B is not absorbed from the gastrointestinal tract which necessitates intravenous administration. It is 90% protein bound and widely distributed, except for the CNS. For the treatment of fungal meningitis therefore only intrathecal drug administrations can be effective. Amphotericin-B is eliminated very slowly in urine, mainly in an inactive form, with an elimination half-life of about 24 hours which can increase to up to 15 days with repeated doses. 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

To decrease dose-related toxicity by using reduced doses of one or more components of the drug regimen. The use of flucytosine in combination with amphotericin for the treatment of cryptococcal meningitis in non-HIV-infected patients allows for a reduction in amphotericin dosage with decreased amphotericin -induced nephrotoxicity. 

Ethambutol [e THAM byoo tole] is bacteriostatic and specific for most strains of M- tuberculosis and M- kansasii. Resistance is not a serious problem if the drug is employed with other antituberculous agents. Ethambutol can be used in combination with pyrazinamide, isoniazid, and rifampin to treat tuberculosis. Absorbed on oral administration, ethambutol is well distributed throughout the body. Penetration into the central nervous system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion. The most important adverse effect is optic neuritis, which results in... 

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is weU absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t) 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis). 

Pharmacokinetic studies have not been performed in horses however, i.v. doses of 0.7-1.Img/kg three times a day have been suggested as being suitable for use in small animals. Imipenem has to be administered i.v. because it is not absorbed following p.o. administration. Imipenem has been shown to penetrate inflamed meninges. It is metabolized extensively by the renal tubules to a potentially toxic compound. Therefore, it is usually combined with cilastatin, a drug that inhibits the renal tubular enzymes. The combined product produces high urine concentrations of active antibiotic and avoids renal toxicity. In the presence of cilastatin, 70% of a dose of imipenem is excreted unchanged in the urine. The half-life of imipenem in the dog is 30-45 nrin. 

The current approach is to treat tuberculosis in two phases an initial phase where a combination of three drugs is used to reduce the bacterial level as rapidly as possible, and a continuation phase in which a combination of two drugs is employed. Front-line drugs are isoniazid, rifampicin, streptomycin and ethambutol. Pyrazinamide, which has good meningeal penetration, and is thus particularly useful in tubercular meningitis, may be used in the initial phase to produce a highly bactericidal response. 

Ceftriaxone and vancomycin are the agents of choice to treat presumed pneumococcal meningitis empirically until the susceptibility is known. Penicillin may be used for drug-susceptible isolates with MICs of 0.06 mg/L or less, but for intermediate isolates, ceftriaxone is used, and for highly drug resistant isolates, a combination of ceftriaxone and vancomycin should be used. Vancomycin should not be used as monotherapy. In especially severe cases, therapeutic drug monitoring of the CSF and possibly even direct antibiotic instillation may be necessary. 

Flucytosine is converted via fungal cytosine deaminase to the antimetabolite fluorouracil, which causes inhibition of thymidylate synthase. Flucytosine enters the cerebrospinal fluid and has been used in combination with amphotericin B in cryptococcal meningitis. The drug has a narrow spectrum of antifungal activity and is not effective in esophageal candidiasis. The answer is (A). 

Emergency situations In severe infections (eg, sepsis, meningitis), combinations of antimicrobial drugs are used empirically to suppress all of tbe most likely pathogens. 

Combinations of antimicrobial drugs are not always synergistic. In the treatment of bacterial meningitis, two drugs may not be better than one. For example, the combination of penicillin eind a tetracycline cures fewer patients with pneumococcal meningitis than the same dose of penicillin used alone. The aaswer is (C). 

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