Pneumonia combination therapy

Cryptococcal meningitis is fatal if left untreated. Because pneumonia frequently precedes dissemination of disease and subsequent meningitis, all patients with culture-, histopathology-, or serology-proven disease should receive antifungal therapy. In patients with isolated pulmonary cryptococcosis, fluconazole is generally considered to be the therapy of choice (see Table 81-2).37 Alternatively, itraconazole or combination therapy (fluconazole plus flucytosine) has also been used with some success in patients. 

Antimicrobial combination therapy is used frequently to treat serious infections. Combination therapy may be used prior to knowing the pathogen or antibiotic susceptibility for the treatment of infections in neutropenic patients and in patients with enterococcal endocarditis or bacteremia, sepsis, or pneumonia caused by P. aeruginosa. In these cases, it is important to know whether the combination will have beneficial (or detrimental) effects on the overall antibacterial activity of the regimen. For example, the combination may result in activity that is... 

Atovaquone (mepron) has potent activity against Plasmodium species and the opportunistic pathogens Pneumocystis jirovici arul Toxoplasma gondii it is FDA approved for treatment of P. jirovici pneumonia in patients intolerant of trimethoprim-sulfamethoxazole. In patients with uncomplicated P. falciparum malaria, combination therapy with proguanil and atovaquone evoked high cure rates with few relapses and minimal toxicity. A fixed combination of atovaquone with proguanil (maiarone) is available in the U.S.for malaria prophylaxis and treatment. 

Observational studies In a study of seven patients with lupus nephritis who failed on mycophenolate mofetil monotherapy, toxicity hmited the use of combination therapy with tacrolimus - - mycophenolate mofetil [84 ]. One patient achieved complete renal remission, and three achieved partial remission with reduced proteinuria. Four of seven patients stopped taking combination therapy because of diabetic ketoacidosis (n = 1), pneumonia ( = 1) and muscle pain (n = 2). Four patients had infectious complications, pneumonia (n = 2), herpes zoster (n = l), and septic arthritis ( = 1). There were no severe nephrotoxic adverse reactions, although there was a small increase in serum creatinine in two patients. 

The more targeted use of antibiotics also could reduce overall costs, despite the expense of bronchoscopy and quantitative cultures, and minimize antibiotic-related toxicity. This is particularly true in the case of patients who have late-onset ventilator-associated pneumonia, in whom expensive combination therapy is recommended by most authorities in the field. A conservative cost analysis performed in a trauma ICU suggested that the discontinuation of antibiotics upon the return of negative bronchoscopic quantitative culture results could lead to a savings of more than 1,700 per patient suspected of VAP (98). 

Croce MA, Eabian TC, Stewart RM, Pritchard PE, Minard G, Trenthem L, Kudsk KA. Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients. J Trauma 1993 35 303-311. 

Local injection site reactions The most common adverse events associated with enfuvirtide use are local injection site reactions. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Pneumonia An increased rate of bacterial pneumonia was observed in subjects treated with enfuvirtide in the phase 3 clinical trials compared with the control arm. Hypersensitivity reactions Hypersensitivity reactions have been associated with enfuvirtide therapy and may recur on rechallenge. Hypersensitivity reactions have included individually and in combination Rash, fever, nausea and vomiting, chills. 

For parenteral therapy, nafciUin and oxacillin offer comparable efficacy and antimicrobial spectra of activity. Although both drugs undergo hepatic metabolism, only nafcillin requires dose adjustment in patients with combined hepatic and renal insufficiency. Other pharmacokinetic data for nafcillin and oxacillin appear in Table 45.1. Indications for nafcillin or oxacillin include severe staphylococcal infections like cellulitis, empyema, endocarditis, osteomyelitis, pneumonia, septic arthritis, and toxic shock syndrome. 

The starting dose as well as dose adjustment in therapy are made according to guidelines fixed in the treatment protocols. For pneumocystis carinii pneumonia prophylaxis, trimethoprim-sulfamethoxazole is administered on three consecutive days per week, with the largest possible interval in reference to the weekly methotrexate application. This is done to account for the theoretical enhancement of the antifolic activity of methotrexate by co-administered trimethoprim-sulfamethoxazole (72,73). Because several reports have suggested an improved outcome with bedtime administration, 6-MP is commonly administered in the evening hours (74,75). Also, 6-MP should not be given in combination with milk because the xanthine oxidase (XO) activity contained in milk decreases the bioavailability of 6-MP (76,77,78). 

A combination of trimethoprim-sulfamethoxazole is effective treatment for a wide variety of infections including P jiroveci pneumonia, shigellosis, systemic salmonella infections, urinary tract infections, prostatitis, and some nontuberculous mycobacterial infections. It is active against most Staphylococcus aureus strains, both methicillin-susceptible and methicillin-resistant, and against respiratory tract pathogens such as the pneumococcus, Haemophilus sp, Moraxella catarrhalis, and Klebsiella pneumoniae (but not Mycoplasma pneumoniae). However, the increasing prevalence of strains of E coli (up to 30% or more) and pneumococci that are resistant to trimethoprim-sulfamethoxazole must be considered before using this combination for empirical therapy of upper urinary tract infections or pneumonia. 

Several drugs closely related to the sulfonamides have been used effectively in the long-term treatment of leprosy. The most widely used is dapsone (diaminodiphenylsulfone). Like the sulfonamides, it inhibits folate synthesis. Resistance can emerge in large populations of M leprae, eg, in lepromatous leprosy, if very low doses are given. Therefore, the combination of dapsone, rifampin, and clofazimine is recommended for initial therapy. Dapsone may also be used to prevent and treat Pneumocystis jiroveci pneumonia in AIDS patients. 

Two other agents show promise in treatment of ocular toxoplasmosis. Atovaquone, primarily used for mild to moderate episodes of Pneumocystis carinii pneumonia, has been effective in small series of patients with toxoplasmosis. It appears to have activity against both tachy-zoites and tissue cysts. More recent studies on atovaquone in toxoplasmosis are limited to murine models, and no further reports on this drug therapy in humans have been published. Azithromycin, a macrolide antibiotic, is efficacious against T. gondii and can also kill tissue cysts. A randomized study of 46 patients compared the combinations of azithromycin plus pyrimethamine versus pyrimethamine plus sulfadiazine in treatment of ocular toxoplasmosis efficacy was similar, but the azithromycin/ pyrimethamine regimen caused less adverse effects. 

Pneumonia following influenza is often caused by Staphylococcus aureus, and best guess therapy is usually achieved by adding flucloxacillin to one of the regimens above. When staphylococcal pneumonia is proven, sodium fusidate p.o. plus flucloxacillin i.v. should be used in combination. 

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