Medical Pharmacology Topics   

Antibiotics: Other and Antiviral Agents

Agents Against Resistant Bateria

Antibiotics used primarily against resistant bacteria include the streptogramins, linezolid, mupirocin, vancomycin, teicoplanin and metronidazole.

The streptogramins, quinupristin and dalfopristin, are indicated as a mixture against nosocomial infections by vancomycin-resistant Enterococcus faecium, methicillin-resistant Staph. aureus or Staph. epidermitis, or drug resistant Strep. pneumoniae. The combination quinupristin/dalfopristine is antibacterial, and the combination 70/30 has been shown to be synergistic and may be bactericidal.These agents are extensively metabolites, and some metabolites are active. They are adequate for skin and soft tissue infections, and systemic infections. Adverse reactions include irritation at the injection site, muscle aches, general malaise (common), chest pain, arrhythmias and bloody diarrhea.

Linezolid inhibits an early stage in the formation of the ribosomal initiation complex. Resistance is rare but may be conferred by a mutation on 23s rRNA. Cross resistance may occur with lincosamides (?) and chloramphenicol. Linezolid is indicated for life-threatening infections associated with vancomycin-resistant Enterococcus faecium, and complicated infections by Staph. aureus o Strep. pyrogenes.

Linezolid is excreted 35% intact in urine, 50% metabiolized in urine and 10% metabolized in feces. It may pass into breast milk. Adverse effects include thrombocytopenia, pseudomembranous colitis, nausea, headache, vomiting and diarrhea. Liezolid has reversible MAO inhibitor activity, thus will interact with other MAO inhibitors, sympathomimetic drugs and foods rich in tyramine to increase blood pressure.

Vancomycin binds to the D-analyl-D-alanine terminus of cell wall precursors, blocking the release and incorporation of new cell wall subunits. It is bactericidal in dividing bacteria. Vancomycin is indicated against infections caused by methicillin-resistant Staph. aureus, penicillin-resistant Staph. neumoniae, Enterococcus, and Clostridum difficile (antibiotic-associated colitis).

Resistant genes to vancomycin in Enterococci are carried on plasmids. Resistance involves multiple factors, and altered enzymes for cell wall biosynthesis may be involved. Vancomycin is poorly absorbed orally, with most of the dose remaining intact in the bowel (useful to treat C. difficile). It distributes well after IV infussion and is eliminated mainly by glomerular filtration. Allergic reactions may occur, including severe rash or anaphilaxis.

Teicoplanin is chemically related to vancomycin, has similar antimicrobial actions and cross-resistance may occur. It is generally effective but may only be bacteriostatic against Enterococci. The plasma half-life of teicoplanin is around 100 hours in patients with normal renal function, mainly because these agent is highly protein bound. At therapeutic doses, adverse reactions are limited to rash.

Metronidazole has a nitro group reductivelly activated by anaerobic microorganisms into a nitro radical ion that attacks DNA and other targets. It is indicated against infections caused by protozoans such as Tritrichomonas vaginalitis, Entameoba histolytica and Giardia lamblia. It is also indicated against anaerobic bacteria such as Bacteriorides, Clostridium, Helicobacter and Colstridium difficile (colitis).

Metronidazole is well absorbed orally and distributes to most tissues, including CNS, and is eliminated by both kidney and liver. Adverse effects include CNS stimulation (headache, dizziness, convulsions), paresthesias, GI irritation, and allergic reactions. It will interact with alcohol as if taking disulfiram (ALDH inhibitior) and will increase the toxicity of lithium. Its metabolism is blocked by inhibitors of microsomal enzymes, and will interfere with anticoagulants.

Agents Against Opportunistic Infections

Infections common in immunosupressed patients include Mycobacterium tuberculosis, fungal infections (Candida, Histoplasma, Cryptococcus, Apergillus) and other opportunistic infections like Pneumocystis carinii.

A combination therapy is required against tuberculosis because resistance will develop otherwise. The standard therapy uses izoniazid, rifampin, ethambutol and pyrazinamide daily for up to 24 months. The DOTS regime uses the same drugs byt 3 times weekly for 6 months with direct observation of therapy. Izoniazid may be used alone for profilaxis only.

Izoniazid inhibits the synthesis of mycolic acids required by Mycobacterium to build their cell envelope. Resistance may occur by decreased bacterial drug uptake. Izoniazid distributes into cells except to the CNS, and will have a longer half-life in slow acetylators (3 hrs vs. 1 hr). It is excreted renally. Adverse effects include peripheral neuritis (pyridoxime deficiency) and hepatotoxicity in older patients.

Rifampin inhibits bacterial DNA-dependent RNA polymerase, and resistance occurs by altered affinity of the drug target. It enters cells, including the CNS. Adverse effects include flu-like symptoms (if doses are intermitent) , and P450 induction.

Drugs used to treat systemic fungal infections include amphoterecin B and the azole antifungals. The azole antifungals inhibit ergosterol biosynthesis annd they are indicated against Candida and Histoplasmosis local and systemic infections. Agents include ketaconazole, fluconazole and itraconazole.

Amphoterecin B binds to ergosterol in fungal membranes (a lipid similar to cholesterol). It is highly toxic when infused by itself because it is very lipid soluble and will bind to tissue with high affinity. Administratin inside liposomes or as other lipid complexes reduces toxicity greately by changing distribution. Adverse effects include hypokalemia, nephrotoxicity and hypotension, thus monitoring BUN, serum creatinine and serum potassium is required.

The combination trimethoprium/sulfamethoxazole is used against Pneumocystis carinii pneumonia. These agents block production of tetrahydropholate in bacterias, but not in mammalian cells. Adverse reactions mostly seen in AIDS patients include rash, hepattis, neutropenia, azothemia and thrombocitopenia, and about 50% of these patients must switch to another drug like pentamine or clindamycin/primaquine.

Antiviral Agents

There are no wide-acting antiviral agents but virus-specific drugs. Synthetic antiviral agents are directed at specific phases of viral reproduction. Important agents are acyclovir, indinavir, nevirapine and zidovudine.

Acyclovir is phosphorylated by Herpesvirus (HSV-1 and HSV-2) thymidine kinase. The triphosphate inhibits viral DNA polymerase as the incorporated drug causes chain termination. Adverse effects include renal insufficiency (and drug accumulation), encephalopathy (1% of patients), anorexia, diarrhea, nausea, vomiting and pain/swelling at the iinjection site. Other nephrotoxic drugs increase the risk of renal damage.

Indinavir, nevirapine and zidovudine are used in combination to treat HIV (AART therapy). This therapy will keep the virus in check but rebound will occur if the therapy is discontinued. Indinavir inhibits HIV protease, thus stopping the formation of the infectious virus. Adverse effects of indinavir include abdominal pain and nausea. Nevirapine is a non-nucleoside inhibitor of HIV reverse transcriptase, and may cause diarrhea, nausea, GI pain and a rash that may become life-ythreatening (8-17% of patients). Zidovudine (AZT) is a nucleoside analog phosphorylated by viral enzymes. The AZT trisphosphate inhibits reverse transcriptase, but may cause granulocytopenia and/or anemia in ~45% of patients, as well as headaches, seizures, and encephalopathy.

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