Intracellular infections treatment

Ethambutol has replaced aminosalicylic acid as a first-line antitubercular drug. It is commonly included as a fourth drug, along with isoifiazid, pyrazinamide, and rifampin, in patients infected with MDR strains. It also is used in combination in the treatment of M. avium-intracellulare infection in AIDS patients. 

Intracellular infections were found to be a field of interest for drug delivery by means of nanospheres. Indeed, infected cells may constitute a reservoir for micro organisms, which are protected from antibiotics inside lysosomes. The resistance of intracellular infections to chemotherapy is often related to the low uptake of commonly used antibiotics or to their reduced activity at the acidic pH of lysosomes. To overcome these effects, the use of ampicillin, a p lactam antibiotic, bound to nanospheres was proposed as endocytozable formulation. The effectiveness of polyisohexylcyanoacrylate (PIHCA) nanospheres was tested in the treatment of two experimental intracellular infections. 

Atypical (nontuberculous) mycobacteria Nontuberculous cervical lymphadenopathy (scrofula) occurs in children infected with M. scrofidaceum or M. kansasii. Patients may demonstrate a weakly positive PPD, but diagnosis often requires biopsy. Mycobacterial infections of the skin are usually due to M. marinum. M. avium-intracellulare infects patients with chronic pulmonary disease and may become fulminant in AIDS patients. Atypical mycobacteria are treated with combination chemotherapy or in some cases, surgery. Because drug resistance is more common in nontuberculous mycobacterial infections than in TB, the susceptibility of the infectious agent must be determined early in the course of treatment. 

Fattal E, Balland O, Alphandary FI, et al. (1993). Colloidal carriers of antibiotics as an alternative approach for the treatment of intracellular infections. In Raoult D (ed.). Antimicrobial agents and intracellular pathogens. CRC Press, Boca Raton, F.L., pp. 63-72. 

Recent attention has been directed to the use of bacteriophages for bacterial infection detection and treatment (Vandenheuvel et al., 2013 Yilmaz et al., 2013 Sillankorva and Azeredo, 2014). Phages have been reported as being used as targeted drug vehicles for the eradication of S. aureus by endowing them with a targeting moiety on their surface and the antibiotic chloramphenicol (Yacoby et al., 2006 they have also been used to inhibit Chlamydia trachomatis intracellular infections (Bhattarai etal., 2012). 

Furthermore, the inability of the drug to reach the focus of the infection or to reach bacteria with intracellular location may be a common reason for the failure of antibiotic treatment. 

Recently, it has been found that NO donors inhibit HIV-1 replication in acutely infected human peripheral blood mononuclear cells (PBMCs), and have an additive inhibitory effect on HIV-1 replication in combination with 3 -azido-3 -deoxythymisylate (AZT) [139, 140]. S-nitrosothiols (RSNOs) inhibit HIV-1 replication at a step in the viral replicative cycle after reverse transcription, but before or during viral protein expression through a cGMP-independent mechanism. In the latently infected U1 cell line, NO donors and intracellular NO production stimulate HIV-1 reactivation. These studies suggest that NO both inhibits HIV-1 replication in acutely infected cells and stimulates HIV-1 reactivation in chronically infected cells. Thus, NO donors may be useful in the treatment of HIV-1 disease by inhibiting acute infection, or reactivating a latent virus. 

Adjuvants enhancing HLA class I-restricted CTL responses are especially needed for treatment or prevention of chronic viral diseases and infections linked to intracellular pathogens, and for cancer immunotherapy. Among the very few adjuvants licensed for human use, we evaluated the capacity of IRIV to enhance HLA class I-restricted CTL responses in vitro. We addressed IRIV-elicited immune responses and the induction of CTL specific to IM58 66 and Melan-A/Mart-127-35 epitopes. Proliferation assays, cytokine expression studies, and phenotypes of CD4+ T-cells demonstrated that IRIV... 

Rifabutin, a semi-synthetic derivative of rifamy-cin S, is a bactericidal antibiotic primarily used in the treatment of tuberculosis. Its effect is based on blocking the DNA-dependend RNA-polymerase of the bacteria. Rifabutin is used in the treatment of infections with Mycobacterium avium intracellulare. Rifabutin is well tolerated in patients with HIV-related tuberculosis, but patients with low CD4 cell counts have a high risk of treatment failure or relapse due to acquired rifamycin resistance. 

Viruses are obligate intracellular organisms as their replication is based on DNA and RNA dependent processes and protein synthesis of the host. Antiviral therapy can therefore not be as selective as antibacterial treatments and anti-viral agents tend to inhibit host cell function and can cause major toxicity. An other problem with antiviral therapy is the fact that active viral replication mostly takes place before symptoms become manifest. Our armamentarium against most viral infections is limited. 

Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare, and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)—drugs that also are cytochrome P450 substrates. 

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intracellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49-3). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon alfo, has been used successfully in the treatment of acyclovir-resistant HSV infections. 

Of course the corollary of preventing infectious disease is the treatment of chronic infection, and this may be where CpG ODN holds the most promise, with respect to infectious disease. There are populations throughout the world that are chronically infected with, and act as biological reservoirs for, intracellular pathogens, such as the hepatitis B and C viruses, the human immunodeficiency virus, Mycobacterium... 

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