SBI242 - Week 10.docx

**SBI242 -- Week 10** Drugs affecting microorganisms Infection involves the invasion and multiplication of pathogenic microorganisms that cause disease either by local cellular injury, secretion of a toxin or antigen--antibody reaction. Infections can be classified primarily as [local or systemi...

**SBI242 -- Week 10** Drugs affecting microorganisms Infection involves the invasion and multiplication of pathogenic microorganisms that cause disease either by local cellular injury, secretion of a toxin or antigen--antibody reaction. Infections can be classified primarily as [local or systemic.] - *[localised infection]* involves the skin or a single internal organ but may progress to a systemic infection if the pathogen spreads. - *[system infection]* involves the whole body rather than a localised area involving blood or multiply organ systems. Antimicrobial therapy Antibiotics are natural substances derived from certain organisms (bacteria, fungi and others) that can suppress growth of or destroy microorganisms. Antibacterial drugs that are all commonly referred to as antibiotics. Other antimicrobial agents include antifungal and antiviral drugs. Once the drug has reached its site of action, it can exert either bactericidal or bacteriostatic effects, depending on its mechanism of action. - *[Bacteriostatic agents]* - inhibit bacterial growth, allowing intact and active host defence systems time to remove the invading microorganisms. - *[Bactericidal agents]* - cause bacterial cell death and lysis and eradicate the infection. Inhibitors of Bacterial Cell wall Synthesis Penicillin Mechanism of action Penicillins weaken the bacterial cell wall by binding to the Penicillin-binding proteins (PBPs), thus inhibiting the transpeptidase activity responsible for cross-linking the glycan strands; this results in cell lysis and death. Penicillins are considered to be bactericidal drugs because they kill susceptible bacteria, but their effectiveness can be influenced by the presence of, or resistance to, certain β-lactamase enzymes. Narrow-Spectrum penicillins These include penicillin G (also known as benzylpenicillin) and penicillin V. - Penicillin G and penicillin V are comparable therapeutically, but penicillin V is more stable in stomach acid and is available as an oral preparation. - In combination with ceftriaxone, benzylpenicillin is an important drug in the treatment of time-critical meningococcal infection. Penicillin G is also indicated in the treatment of rheumatic heart disease. Broad and Extended spectrum penicillin This group includes *[piperacillin, tazobactam, ticarcillin -- potassium clavulanate,]* and *[amoxicillin.]* These antibiotics have a broader spectrum of antimicrobial activity, and are effective against Gram-positive and Gram-negative pathogens, including many that produce β-lactamase. They are particularly effective against *Pseudomonas* bacteria However, only piperacillin is effective against *[Pseudomonas aeruginosa.]*  Penicillin-Adverse reaction *[Common]* - diarrhoea, nausea, vomiting, headache, sore mouth or tongue, oral and vaginal candidiasis, allergic reactions, anaphylaxis, serum sickness-type reaction (rash, joint pain and fever), hives and pruritus. *[Rare]* - cholestatic hepatitis; leucopenia or neutropenia; mental disturbances; convulsions; and interstitial nephritis. - Platelet dysfunction has been reported with piperacillin and ticarcillin, especially in people with renal impairment. *[Contraindications]* - penicillin hypersensitivity, bleeding disorders, congestive heart failure, cystic fibrosis, gastrointestinal disease and mononucleosis. Carbapenems Includes Ertapenem, imipenem and meropenem They bind to the penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. They have the broadest spectrum of activity of all the antimicrobials against Gram-positive and Gram-negative aerobic and anaerobic organisms. Generally reserved for nosocomial and life-threatening infections when other antibiotics are contraindicated or inappropriate. Meropenem is used for treating meningitis, whereas imipenem is contraindicated because of the high incidence of seizures. The half-life of imipenem is 2--3 hours, about 1 hour for meropenem and about 4 hours for ertapenem. *[Adverse reactions]* -- seizures, astric distress, diarrhoea, nausea, vomiting, allergic-type reactions, confusion, psychiatric disturbances, insomnia and raised liver enzyme levels. Cephalosporins Includes cefalexin (1st generation), cefaclor (2nd generation), ceftriaxone (3rd generation), and cefepime (4th generation). Chemical modification of the central active component, 7- aminocephalosporanic acid, and the addition of side chains, have created compounds with different and greater antimicrobial activities, classified into first, second, third and fourth generations. Mechanism of Action 1. Inhibit bacterial cell wall synthesis and are also bactericidal. 2. First and second-generation cephalosporins are primarily active against Gram- positive bacteria. The second-generation being more effective. 3. The third-generation drugs are more active against Gram-negative bacteria and β-lactamase-producing microbial strains but less effective against Gram- positive cocci. Cefepime is a fourth-generation cephalosporin with similar effects to third generation drugs but is also more resistant to some β-lactamases. Adverse reactions Cephalosporin antibiotics may be considered for patients allergic to penicillin, not on patients with serious reaction/anaphylaxis to penicillin. Use cephalosporins with caution in individuals with impaired/low vitamin K synthesis because of increased risk of bleeding. Monitoring of international normalised ratio (INR) is recommended. Because parenteral cephalosporins have high sodium contents, their use should be avoided in sodium-restricted individuals (e.g. coronary heart disease). Glycopeptides Includes [Vancomycin and teicoplanin] Both drugs inhibit bacterial wall synthesis and are primarily active against Gram-positive bacteria. Due to increasing problems with vancomycin resistance, Australia has adopted the guidelines recommended for vancomycin use by the US Centers for Disease Control Hospital Infection Control Practices Advisory Committee (See below). [Situations in which the use of vancomycin is appropriate or acceptable] Treatment of serious infections caused by β-lactam-resistant Gram- positive microorganisms and in patients who have serious allergies to β- lactam antimicrobials. - Prophylaxis in patients at high risk for endocarditis. - Prophylaxis for major surgical procedures involving implantation of prosthetic materials or devices at institutions that have a high rate of infections caused by MRSA. Pharmacokinetics Vancomycin absorption from the intestinal tract is poor; hence, it is usually administered slowly via the intravenous route and never intramuscularly. In contrast, teicoplanin is usually administered IV but can be administered IM. Parenteral vancomycin has an elimination half-life of 4--6 hours in adults and about 2-- 3 hours in children, whereas it is close to 100 hours for teicoplanin. Both are excreted primarily by the kidneys, and dosage adjustment is crucial in persons with compromised renal function. Adverse reactions - Rash - Itching - Chills - Fever Monobactams - Aztreonam is the first drug in the monobactam class of antibiotics. synthetic bactericidal antibiotic with a similar mechanism of action to that of penicillin. Mechanism of action binds to penicillin-binding proteins, resulting in inhibition of bacterial cell wall synthesis, cell lysis and death. active only against Gram-negative aerobic organisms. It is reserved for treatment of infections when other antibacterial drugs are contraindicated and for urinary tract, bronchitis, intra-abdominal, gynaecological and skin infections. Pharmacokinetics Aztreonam is not given orally, as it is not absorbed from the gastrointestinal tract. Azteonam is given as an IM injection. The half-life in adults with normal renal function is 1.4--2.2 hours, and 60--70% of the drug is eliminated in the urine within 8 hours. Adverse reactions 1. Common -- gastric distress, diarrhoea, nausea/vomiting, hypersensitivity and thrombophlebitis at site of injection 2. Rare -- Anaphylaxis, hepatitis, Jaundice, thrombocytopenia and prolonged bleeding time have been reported 3. Caution -- A low risk of allergic reaction exists in those allergic to penicillins or cephalosporins. Inhibitors of Bacterial protein synthesis Aminoglycosides Includes - the parenteral aminoglycosides *[amikacin, gentamycin]* and *[tobramycin]*; and the oral aminoglycoside *[neomycin.]* Aminoglycosides are potent bactericidal antibiotics usually reserved for serious or life- threatening infections. They are very effective against many Gram-negative bacteria but as monotherapy they have limited activity against Gram-positive bacteria. Mechanism of Action Aminoglycosides bind irreversibly to the 30S ribosomal sub-unit of susceptible bacteria, thus inhibiting protein synthesis, leading to eventual cell death. They are used with penicillins, cephalosporins or vancomycin for their synergistic effects and are especially useful for the treatment of Gram-negative infections such as those caused by Pseudomonas, E. coli, Proteus, Klebsiella, Serratia, and enterococci. Pharmacokinetics As the aminoglycosides are strongly polar molecules, they do not distribute to the central nervous system (CNS), and tissue concentrations are low. They are almost entirely eliminated by the kidneys in people with normal renal function. The plasma half-life is in the range of 2--3 hours. Monitoring aminoglycoside plasma concentrations is essential to ensuring that therapeutic concentrations are achieved without the risk of adverse reactions due to high plasma concentrations.  Chloramphenicol It is a bacteriostatic agent used for a wide variety of Gram-negative and Gram-positive organisms and anaerobes; however, because it has the potential to be seriously toxic to bone marrow (aplasia leading to aplastic anaemia and possibly death), its use has declined. It is also indicated for the treatment of Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis, as it may be bactericidal to these organisms. A broad-spectrum antibiotic that potently inhibits bacterial protein synthesis by binding to the 50S sub-unit of the bacterial ribosome. Chloramphenicol is contraindicated in people with pre-existing bone marrow suppression and/or blood dyscrasias. Lincosamides The lincosamides include *[lincomycin and clindamycin.]* Inhibits protein synthesis by binding to the bacterial 50S ribosomal sub -unit and preventing peptide bond formation. It is primarily bacteriostatic, although it may be bactericidal in high doses with selected organisms. - *[Lincomycin]* is used to treat serious streptococcal and staphylococcal infections, but clindamycin is preferred as it has better oral absorption and is more potent than lincomycin. - *[Clindamycin,]* which is a semisynthetic derivative of lincomycin, has a similar mechanism of action but is more effective. It is indicated for the treatment of bone and joint, pelvic (female), intra-abdominal, skin and soft tissue infections, bacterial septicaemia, and pneumonia caused by susceptible bacteria. Pharmacokinetics The half-life of clindamycin in adults is 2--3 hours. It reaches peak blood concentrations within 0.75--1 hour of oral administration in adults, within 1 hour in children and within 3 hours of IM injection. It is metabolised in the liver and excreted primarily in bile, with only a small proportion (6--10%) excreted as unchanged drug in urine. Adverse effects Antibiotic-associated pseudomembranous colitis - in which the normal bacterial flora within the colon are disturbed, facilitating the growth of Clostridium difficile or other bacteria. With overgrowth of the bacteria, potent bacterial toxins are released causing inflammation of the colon. Patients at risk include the elderly, those with a compromised immune system, and patients with pre-existing inflammatory bowel disease. Macrolide antibiotics Macrolides are antibiotics that contain a many-membered lactone ring that has one or more sugar molecules attached. They inhibit bacterial RNA-dependent protein synthesis by binding to the 50S ribosomal sub-unit. Macrolides are bacteriostatic: that is, they inhibit growth of microorganisms. In high concentrations with selected organisms they may be bactericidal. Include *[azithromycin, clarithromycin, erythromycin and roxithromycin.]* They have similar antimicrobial action against Gram-positive and some Gram-negative microorganisms and are used for *[respiratory, gastrointestinal, skin]* and *[soft tissue infections when β-lactam antibiotics are contraindicated because of allergy.]* Oxazolidinones The only drug available in this class is linezolid, a novel compound with a broad spectrum of activity against community and hospital-acquired Gram- positive organisms (e.g. MRSA). The site of action of linezolid is proximal to the 50S sub-unit. At that specific site, linezolid inhibits protein synthesis by interfering with the formation of a complex that is essential for protein translation. Linezolid is indicated for the treatment of serious infections due to Gram- positive organisms where other drugs are either contraindicated or not appropriate. Adverse reactions - Nausea, diarrhoea and headache. May cause thrombocytopenia, leucopenia, eosinophilia and neutropenia thus full blood count should be monitored during therapy. - Linezolid is a weak inhibitor of monoamine oxidase and hence has the potential to interact with adrenergic (e.g. adrenaline \[epinephrine\] and salbutamol) and serotonergic (e.g. SSRI) drugs. Tetracyclines Includes, doxycycline, minocycline and tetracycline. Tetracyclines are bacteriostatic towards many Gram-negative and Gram- positive organisms. They inhibit protein synthesis by reversibly blocking the 30S sub-unit of the ribosome and preventing access of tRNA to the mRNA--ribosome complex. Commonly used to treat infections such as acne vulgaris, actinomycosis, anthrax, bacterial urinary tract infections (UTIs), bronchitis and numerous systemic bacterial infections. Adverse reactions - Dizziness (minocycline), oesophagitis (doxycycline), ataxia, gastrointestinal distress, photosensitivity, discoloration of infants' or children\'s teeth (do not give to children under 8 years), skin and mucous membrane pigmentation (minocycline), dark or discoloured tongue, rectal or genital fungal overgrowth. - *[Rarely]* - hepatotoxicity, pancreatitis and benign intracranial hypertension. Inhibitors of DNA synthesis Fluoroquinolones Includes, *[ciprofloxacin, moxifloxacin, norfloxacin and ofloxacin.]* The fluoroquinolones are synthetic, broad-spectrum agents with bactericidal activity. They interfere with bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, the enzymes involved in the supercoiling of DNA that is necessary for the duplication, transcription and repair of bacterial DNA. The quinolones are effective against *[Pseudomonas aeruginosa]* and are reserved for infections when alternative drugs are either contraindicated or ineffective. These include bone and joint infection, Legionella pneumonia, epididymo- orchitis, prostatitis and complicated UTIs. Adverse effects - Common effects - dizziness, drowsiness, restlessness, stomach distress, diarrhoea, nausea, vomiting and photosensitivity. - Rare effects - CNS stimulation (psychosis, confusion, hallucinations, tremors), hypersensitivity (skin rash, redness, Stevens--Johnson syndrome, face or neck swelling, shortness of breath) and interstitial nephritis. Additionally, athletes participating in extensive training are also at risk of tendon adverse effects. These drugs should be ceased at the first sign of tendon pain or inflammation.  Miscellaneous Antibiotics Metronidazole and Tinidazole They are short-acting cytotoxic agents that interact with DNA, inhibiting bacterial synthesis and causing cell death. They are selectively toxic to many anaerobic bacteria and protozoa. Both are indicated for the treatment of amoebiasis (intestinal and extraintestinal), bone infections, brain abscesses, CNS infections, bacterial endocarditis, genitourinary tract infections, septicaemia, trichomoniasis and other infections caused by organisms susceptible to metronidazole. Adverse reactions - Dizziness, headache, gastric distress, diarrhoea, anorexia, nausea, vomiting, dry mouth, taste alterations, dark urine, peripheral neuropathy, CNS toxicity, hypersensitivity, leucopenia, thrombophlebitis, vaginal candidiasis and convulsions. Trimethoprim -- Sulfamethoxazole (co-trimoxazole) Primarily bacteriostatic. - A sulfonamide - They are structurally similar to para-aminobenzoic acid (PABA) and they competitively inhibit the bacterial enzyme dihydropteroate synthetase, necessary for incorporating PABA into dihydrofolic acid. - The blocking of dihydrofolic acid synthesis results in a decrease in tetrahydrofolic acid, which interferes with the synthesis of purines, thymidine, and DNA in the microorganism. - The combination with trimethoprim (trimethoprim--sulfamethoxazole) is synergistic, as this agent blocks a further step in the synthesis of folic acid. - Trimethoprim alone is indicated for uncomplicated UTIs, epididymo-orchitis and prostatitis. - The use of sulfonamides has declined substantially because of widespread bacterial resistance. Methenamine (hexamine) Hippurate Used to treat UTIs. - Its effectiveness depends on the release of formaldehyde, which requires an acid medium. The acids released from hippurate salts contribute to this acidity. Formaldehyde may be bactericidal or bacteriostatic and its effects are believed to be the result of denaturation of bacterial protein. - The drug is ineffective in alkaline urine as alkalinity inhibits the conversion of hexamine to formaldehyde. - It has a fairly wide bacterial spectrum, low toxicity and low incidence of resistance, is often the drug of choice in the long-term suppression of infections. - Avoid use in people with severe kidney impairment, as renal tubule concentration will be inadequate to achieve a response. Nitrofurantoin - It is a broad-spectrum bactericidal agent that can be prescribed by endorsed/authorised midwives. - Its mechanism of action is not fully understood, but it is reduced by bacteria to reactive substances that inactivate or alter cell wall synthesis, bacterial ribosomal proteins, and DNA and RNA function. - It is indicated for the treatment of acute UTIs caused by organisms such as E. coli and S. aureus, and for prophylaxis of recurrent UTIs. - Nitrofurantoin is well absorbed and has a short half-life of 20--60 minutes. About 65% of the drug is excreted, mainly as unchanged drug in the urine. Drug interactions - Antacids decreases absorption - Probenecid inhibits tubular secretion of nitrofurantoin, leading to increased plasma concentration and possible toxicity. - Combination with quinolones is contraindicated as they antagonise the bacterial action of nitrofurantoin. Adverse effects - Acute allergic pneumonitis may occur within days of initiation of treatment and presents as fever, chills, cough, dyspnoea, chest pain and often a rash. It is more common in women aged 40--50 years. - Rarely, chronic irreversible interstitial pulmonary fibrosis can occur in older patients following chronic treatment (\>6 months). - Nitrofurantoin is contraindicated in patients with nitrofurantoin hypersensitivity, peripheral neuropathy, lung disease or moderate-to-severe renal impairment. Anti-Fungal and Anti-Viral Drugs Azole Antifungals - Includes; Fluconazole, itraconazole, miconazole, Posaconazole and voriconazole. - MOA - Affects the biosynthesis of fungal ergosterols by interfering with the cytochrome P450-dependent enzyme lanosterol demethylase that catalyses ergosterol formation. - Ergosterol is a major component of the fungal cell membrane, and the azoles cause depletion of ergosterol and accumulation of 14α-methylated sterols. This results in inhibition of fungal growth, interference in nutrient transport and, ultimately, cell leakage and death. - Azole antifungals are administered orally; fluconazole and voriconazole may also be administered intravenously. Adverse effects - nausea, vomiting, stomach distress, diarrhoea, flushing, drowsiness, dizziness, headache and hypersensitivity (fever, chills and rash). - Voriconazole can cause redness, swelling or pain at the injection site. › \]Rare effects include; liver toxicity, anaemia, agranulocytosis and exfoliative skin disorders such as Stevens--Johnson syndrome (for fluconazole) and thrombocytopenia (for fluconazole and miconazole). › Voriconazole is associated with visual abnormalities, including altered visual perception, blurred vision and colour changes. Echinocandins - Includes; Anidulafungin and caspofunginnausea. - They act by inhibiting the fungal enzyme glucan synthase and hence the synthesis of glucan, a vital component of the fungal cell wall. Amphotericin B - Amphotericin B is the premier drug for the treatment of severe systemic mycoses. - It binds to ergosterol in the fungal cell membrane; this binding results in the - formation of pores or channels that alters cell permeability and results in a loss of potassium and other elements from the cell. Ergosterol is a major component of fungal cell membranes. Flucytosine - Flucytosine enters fungal cells, where it is converted to fluorouracil, an antimetabolite. It interferes with pyrimidine metabolism, thus preventing nucleic acid and protein synthesis. - Indicated for the treatment of fungal endocarditis, fungal meningitis and fungal pneumonia, septicaemia or urinary infections. Other anti-fungals include: Griseofulvin and Terbinafine -- indicated for tinea and ringworm. Anti-Virals Viral Infections - Physically, viruses are simply genetic material (DNA or RNA) contained within aprotein coating known as the capsid. This structure is known as the virus particle or virion. Viruses lack their own metabolic activity, making them true parasites. Drug therapy for viral infections - nucleoside DNA polymerase inhibitors -- Aciclovir, cidofovir, ganciclovir, penciclovir - Acts by producing an active tri- (di- for cidofovir) phosphorylated nucleoside analogue that inactivates viral DNA polymerases preventing viral DNA synthesis - non-nucleoside DNA polymerase inhibitors -- Foscarnet - It acts via the selective inhibition at the pyrophosphate binding site of viral DNA polymerase. Does not require phosphorylation as in Aciclovir. - It is indicated in cases of Aciclovir or ganciclovir resistance. Adverse reactions - Common - gastric distress, headache, dizziness, nausea, diarrhoea and vomiting. - Rarely - encephalopathic alterations such as confusion, hallucinations, convulsions, tremors and coma can occur.