Role of linezolid in the treatment of orthopedic infections.

Gram-positive organisms, particularly staphylococci and streptococci, are responsible for the majority of bone and joint infections. The rising incidence of antimicrobial resistance among Staphylococcus aureus, coagulase-negative staphylococci and enterococci means that novel antibiotics with unique mechanisms of antimicrobial activity are needed, especially in orthopedic infections. Linezolid is the first of the oxazolidinones, a new class of antibacterial agents particularly effective against Gram-positive infections including methicillin- and vancomycin-resistant strains. With an excellent oral bioavailability and acceptable safety profile, linezolid offers a valuable alternative to more traditional therapies, such as glycopeptides. No large randomized trials have been published on its use in patients with orthopedic infections, but early results are encouraging. Reported adverse events, especially bone marrow suppression and optic neuropathy seen with prolonged administration, mean that treatment of such patients must be undertaken with careful follow-up of laboratory tests. Until now, little resistance has been reported.

Linezolid in the treatment of Gram-positive prosthetic joint infections.

OBJECTIVES: To investigate the clinical efficacy and safety of linezolid in the treatment of Gram-positive prosthetic hip and knee infections. MATERIALS AND METHODS: A retrospective evaluation of patients hospitalized in the Department of Infectious Diseases of San Martino Hospital in Genoa with the diagnosis of Gram-positive prosthetic joint infection and treated with intravenous and/or oral linezolid. Primary end points were the patient clinical outcome at the end of treatment and at long-term follow-up (up to 12 months after the end of treatment). RESULTS: Between May 1999 and September 2003, 20 patients with prosthetic joint infection were treated with linezolid. Pathogens isolated were: methicillin-resistant Staphylococcus aureus (MRSA), 14 strains; methicillin-resistant coagulase-negative staphylococci, five strains; and Enterococcus spp., one strain. The overall duration of treatment was 7.2 +/- 2 weeks (range 6-10 weeks). Patients were given intravenous therapy for 3-7 days as inpatients, then were changed as outpatients to oral therapy under weekly laboratory testing. At long-term follow-up (1 year), we observed four cases of failure due to relapsing infections. The other 16 patients treated with linezolid did not need further surgical substitution of prosthesis or surgical joint revision. Linezolid was well tolerated, and no drug-related events leading to discontinuation of treatment were recorded. CONCLUSIONS: Our data indicate that linezolid may be an effective alternative therapy for orthopaedic infections caused by Gram-positive resistant pathogens and that a prospective and comparative evaluation of linezolid in this setting is necessary.

Pharmacokinetic interaction between chemotherapy for non-Hodgkin's lymphoma and protease inhibitors in HIV-1-infected patients.

OBJECTIVES: We have investigated whether chemotherapy for HIV-related systemic non-Hodgkin's lymphoma (NHL) affects the pharmacokinetics of protease inhibitors. PATIENTS AND METHODS: This was a prospective, open-label, non-randomized, two-way crossover trial in HIV-1-infected patients treated with highly active antiretroviral therapy and chemotherapy for NHL. Seven patients received indinavir at a dosage of 800 mg three times daily and three patients received nelfinavir at a dosage of 750 mg three times daily. Chemotherapy consisted of adriamycin, cyclophosphamide, vincristine and prednisolone (CHOP). Each patient had blood samples for protease inhibitor pharmacokinetics drawn concomitantly with or independently of the CHOP cycle. RESULTS: When indinavir was given concomitantly with CHOP, the AUC(0-8) increased by 38% (20.5 +/- 9.0 versus 14.9 +/- 9.5 mg.h/L; P=0.03), and was comparable to historical controls. By contrast, the AUC(0-8) of indinavir administered without CHOP was lower than expected. A similar trend was observed with nelfinavir. Likewise, we observed a significant number of patients with C(0) and C(8) below the IC(50) for the wild-type virus (0.1 mg/L) when the drug was administered without CHOP. CONCLUSIONS: Therapeutic drug monitoring of protease inhibitors should be part of the work-up in HIV-infected patients receiving chemotherapy for NHL.

Antimicrobial prophylaxis in solid-organ transplantation.

Solid-organ transplantation has become a widely accepted treatment modality for end-stage diseases. With the advent of newer and more potent immunosuppressive regimens, graft survival has improved, but at the expense of an increased risk for the development of infections secondary to bacterial, fungal, viral and parasitic pathogens. Prevention of such infectious complications with effective, well-tolerated and cost-effective antimicrobials would be ideal to improve the outcome of transplant patients. Cytomegalovirus is the most common cause of viral infections. Herpes simplex virus, Varicella-zoster virus, Epstein-Barr virus and others are also significant pathogens. Fungal infections are associated with the highest mortality rates. This review summarizes the most relevant data pertaining to the current understanding of infection prevention for solid-organ transplant recipients.

Successful treatment of methicillin-resistant Staphylococcus aureus endocarditis with linezolid.

We report the successful treatment with linezolid of a methicillin-resistant Staphylococcus aureus (MRSA) endocarditis in a patient with a severe allergic reaction to glycopeptides. Linezolid is a drug with well-recognised activity against S. aureus and proved to be efficacious even in the unusual site of heart valves. This drug could be a good therapeutic choice when glycopeptides treatment is not feasible.

Pharmacokinetics of amprenavir given once or twice a day when combined with atazanavir in heavily pre-treated HIV-positive patients.

We studied the pharmacokinetics of amprenavir at doses of 600 mg twice a day or 1200 mg once a day, when co-administered to HIV-positive patients with 400 mg a day of atazanavir without a ritonavir booster. Our preliminary results suggest that amprenavir and atazanavir could be coadministered and that amprenavir could be boosted by atazanavir without the need for ritonavir pharmaco-enhancement.

Gram-positive bacterial resistance: future treatment options.

Gram-positive infections are a major burden on patients and healthcare systems globally, and the need to treat these infections correctly in an empirical manner has become paramount. Further complicating this changing etiology is the emergence of resistant strains which are no longer predictably susceptible to standard first-line antimicrobials such as oxacillin or vancomycin. Thus, new agents such as linezolid have been developed to alleviate the 'guesswork' of initial empirical prescribing in infections where Gram-positive pathogens may be present. Future agents also being developed for multiresistant Gram-positive infections include evernimicin antibiotics, daptomycin, oritavancin, glycylcyclines and novel broad-spectrum cephalosporins; however, these are still in the development phase.

Fatal lactic acidosis and mimicking Guillain-Barré syndrome in an adolescent with human immunodeficiency virus infection.

We report a case of antiretroviral therapy-related fatal lactic acidosis occurring in a vertically infected HIV-positive 17-year-old patient. While receiving antiretroviral therapy with stavudine, didanosine, tenofovir and amprenavir, the patient developed severe acidosis and rapid neuromuscular and respiratory failure mimicking Guillain-Barré syndrome.

Genotypic resistance tests for the management of the HIV-infected pregnant woman.

Witness for the prosecution: Recommendations for genotypic resistance testing in HIV-infected pregnant women are the same as for non-pregnant women: acute HIV infection, virological failure or suboptimal viral suppression after initiation of antiretroviral therapy, or high likelihood of exposure to resistant virus based on community prevalence or source characteristics. All pregnant women with detectable HIV-RNA levels should perform resistance testing to maximize the response to antiretrovirals in pregnancy. Currently there are no data on the value of drug resistance testing to prevent vertical transmission. Most studies show that the most important factor in the risk of transmission is the amount of HIV-RNA at the moment of delivery. A strategy to overcome this problem would be to use of resistance testing to select a regimen, which has the greatest potential to reduce viral load at the moment of delivery. We would also like to use the same information to select the regimen that would be used to provide prophylaxis to the newborn. It is currently unknown whether zidovudine (ZDV) prevents transmission through another mechanism(s) in addition to reducing viral load, so one could argue that even if ZDV resistance has been found in the mother, it should still be included in the regimen. Witness for the defence: To reduce the risk of HIV vertical transmission, prospective controlled trials on the use of antiretroviral prophylactic treatment in different schedules during pregnancy were conducted. These studies assessed the efficacy of short- or medium-term antiretroviral therapy in reducing vertical transmission, but highlighted the concerns about the selection of resistant variants (monotherapy prophylaxis or suboptimal regimens). The availability of recent more complex multidrug regimens increased the prevalence of drug resistance among the HIV-1-infected population; so, women of childbearing age are at risk of becoming infected with resistant virus and those on treatment, living in developed countries, could harbour resistant virus before pregnancy. Therefore, there are growing concern about the role of these resistant variants in mother-to-child HIV-1 transmission. Several studies documenting HIV-resistant variants in vertical transmission form a compelling basis for recommending the use of HIV-1 genotypic drug resistance tests during pregnancy. Owing to the availability of different genotypic HIV-1 tests at variable costs, the choice of the most appropriate assay could take into account the prevalence and incidence of drug-resistant mutations, the availability of drugs and the antiretroviral experience setting, to choose the best long-term effective antiretroviral therapy for the mother and to avoid the risk of transmission to the offspring.