Antimicrobial chemotherapy Flashcards
Explain the terms MIC/MBC, sensitive/resistant, bacteriocidal/bacteriostatic, synergy/ antagonism.
- MIC (Minimum Inhibitory Concentration) / MBC (Minimum Bactericidal Concentration)
MIC: The lowest concentration of an antibiotic or antimicrobial agent that inhibits the visible growth of a bacterium after a specified incubation period. It helps determine the effectiveness of an antibiotic against a specific microorganism.
MBC: The lowest concentration of an antibiotic that kills a specified percentage (usually 99.9%) of the bacteria after a specified time. It provides insight into the bactericidal properties of the antibiotic. - Sensitive / Resistant
Sensitive: Refers to bacteria that are susceptible to the effects of an antibiotic. This means that the antibiotic can effectively inhibit or kill the bacteria at achievable concentrations.
Resistant: Refers to bacteria that are not affected by an antibiotic, meaning the drug cannot inhibit their growth or kill them even at high concentrations. Resistance can be intrinsic (naturally occurring) or acquired (developed through mutation or gene transfer). - Bacteriocidal / Bacteriostatic
Bacteriocidal: Refers to antibiotics or antimicrobial agents that kill bacteria. They reduce the overall number of viable organisms. Examples include penicillins and aminoglycosides.
Bacteriostatic: Refers to agents that inhibit bacterial growth and reproduction but do not kill the bacteria outright. This allows the immune system to clear the infection. Examples include tetracyclines and sulfonamides. - Synergy / Antagonism
Synergy: Refers to a situation where two or more drugs work together in a way that enhances their overall effect, leading to greater efficacy than would be expected from their individual effects. For example, the combination of penicillin and aminoglycosides can have a synergistic effect against some bacteria.
Antagonism: Refers to a situation where two drugs work against each other, resulting in reduced effectiveness compared to when each drug is used alone. For instance, combining a bactericidal drug with a bacteriostatic drug may lead to antagonism, as the bacteriostatic drug can inhibit the action of the bactericidal drug.
Describe in outline the mechanisms of action of the major groups of antibacterial, antifungal and antiviral drugs.
- Antibacterial Drugs
Cell Wall Synthesis Inhibitors
Penicillins (e.g., penicillin G): Inhibit enzymes (penicillin-binding proteins) involved in peptidoglycan synthesis, weakening the bacterial cell wall and leading to cell lysis.
Cephalosporins: Similar mechanism to penicillins, targeting cell wall synthesis.
Protein Synthesis Inhibitors
Aminoglycosides (e.g., gentamicin): Bind to the 30S ribosomal subunit, causing misreading of mRNA and inhibiting protein synthesis.
Macrolides (e.g., erythromycin): Bind to the 50S ribosomal subunit, preventing peptide bond formation and blocking protein elongation.
Tetracyclines: Bind to the 30S ribosomal subunit, preventing the attachment of tRNA to the ribosome.
Nucleic Acid Synthesis Inhibitors
Fluoroquinolones (e.g., ciprofloxacin): Inhibit DNA gyrase and topoisomerase IV, enzymes crucial for DNA replication and repair.
Rifamycins (e.g., rifampin): Inhibit bacterial RNA polymerase, blocking RNA synthesis.
Metabolic Pathway Inhibitors
Sulfonamides: Inhibit dihydropteroate synthase, interfering with folate synthesis and ultimately DNA synthesis.
2. Antifungal Drugs
Cell Membrane Disruptors
Azoles (e.g., fluconazole): Inhibit ergosterol synthesis, a key component of fungal cell membranes, leading to membrane dysfunction.
Polyenes (e.g., amphotericin B): Bind to ergosterol, forming pores in the cell membrane and causing leakage of cellular contents.
Cell Wall Synthesis Inhibitors
Echinocandins (e.g., caspofungin): Inhibit β-(1,3)-D-glucan synthase, disrupting the synthesis of glucan in the fungal cell wall, leading to cell lysis.
Nucleic Acid Synthesis Inhibitors
Flucytosine: Converted to 5-fluorouracil in fungal cells, which interferes with DNA and RNA synthesis.
3. Antiviral Drugs
Nucleic Acid Synthesis Inhibitors
NRTIs (e.g., zidovudine): Incorporate into viral DNA during replication, causing chain termination and inhibiting further DNA synthesis.
NNRTIs (e.g., efavirenz): Bind to reverse transcriptase, inhibiting the conversion of viral RNA to DNA.
Protease Inhibitors
Protease inhibitors (e.g., ritonavir): Inhibit the viral protease enzyme, preventing the cleavage of viral proteins into functional units, essential for viral replication.
Entry Inhibitors
Fusion inhibitors (e.g., enfuvirtide): Prevent the fusion of the viral envelope with the host cell membrane, blocking entry of the virus into the cell.
CCR5 antagonists (e.g., maraviroc): Block the CCR5 co-receptor on host cells, preventing HIV entry.
Neuraminidase Inhibitors
Oseltamivir (Tamiflu): Inhibit the neuraminidase enzyme in influenza viruses, preventing the release of new virions from infected cells.
Describe the spectrum of action of commonly used drugs in these three categories (antibacterial, antifungal and antiviral drugs.)
- Antibacterial Drugs
Antibacterial drugs can be classified based on their spectrum into broad-spectrum and narrow-spectrum antibiotics.
Broad-Spectrum Antibiotics: Effective against a wide range of both Gram-positive and Gram-negative bacteria.
Examples:
Tetracyclines (e.g., doxycycline): Target various bacteria, including some Gram-positive, Gram-negative, and atypical organisms.
Amoxicillin-Clavulanate: Effective against a variety of bacteria, including those producing β-lactamases.
Narrow-Spectrum Antibiotics: Effective against specific types of bacteria.
Examples:
Penicillin G: Primarily targets Gram-positive bacteria and some anaerobes.
Vancomycin: Primarily effective against Gram-positive bacteria, particularly Staphylococcus aureus (including MRSA) and Streptococcus spp.
2. Antifungal Drugs
Antifungal agents are used to treat infections caused by fungi, and their spectrum can also be categorized.
Broad-Spectrum Antifungals: Effective against a wide range of fungal species.
Examples:
Azoles (e.g., fluconazole): Effective against many yeasts (e.g., Candida spp.) and some molds.
Echinocandins (e.g., caspofungin): Effective against Candida spp. and Aspergillus spp.
Narrow-Spectrum Antifungals: Target specific fungal pathogens.
Examples:
Amphotericin B: Primarily used for systemic fungal infections, particularly those caused by Cryptococcus neoformans and some molds.
Griseofulvin: Primarily used for dermatophyte infections, such as those caused by Trichophyton spp.
3. Antiviral Drugs
Antiviral medications target specific viruses and can also be categorized by their spectrum.
Broad-Spectrum Antivirals: Effective against multiple viruses.
Examples:
Ribavirin: Used against a variety of RNA viruses, including some strains of influenza and RSV.
Favipiravir: Investigated for activity against multiple RNA viruses, including influenza and Ebola virus.
Narrow-Spectrum Antivirals: Target specific viruses.
Examples:
Oseltamivir (Tamiflu): Specifically used for the treatment of influenza virus.
Acyclovir: Primarily effective against herpes viruses (e.g., HSV, VZV).
Antiretrovirals (e.g., zidovudine): Specifically target HIV.
Describe in outline any clinically significant resistance mechanism for particular groups of drugs.
- Antibacterial Drugs
Penicillins and Cephalosporins
β-lactamase Production: Bacteria produce enzymes (β-lactamases) that hydrolyze the β-lactam ring of penicillins and cephalosporins, rendering them ineffective.
Aminoglycosides
Enzymatic Modification: Bacteria can produce enzymes that modify aminoglycosides, preventing them from binding to the ribosomal subunit.
Macrolides
Methylation of rRNA: Modification of the 23S rRNA component of the ribosome reduces drug binding, leading to resistance.
Tetracyclines
Efflux Pumps: Bacteria can develop efflux pumps that actively transport tetracyclines out of the cell, decreasing intracellular drug concentrations.
Fluoroquinolones
Target Mutation: Mutations in DNA gyrase or topoisomerase IV reduce drug binding and effectiveness.
2. Antifungal Drugs
Azoles
Target Mutation: Mutations in the enzyme lanosterol demethylase (part of the ergosterol biosynthesis pathway) reduce azole binding and efficacy.
Overexpression of Efflux Pumps: Increased efflux pump activity can decrease azole concentrations inside the fungal cell.
Polyenes
Reduced Ergosterol Content: Fungi may alter their membrane composition to reduce ergosterol, the primary target of polyene drugs, diminishing drug efficacy.
Echinocandins
Fks1 Mutations: Mutations in the Fks1 protein, part of the β-(1,3)-D-glucan synthase complex, can lead to resistance by altering the target site of echinocandins.
3. Antiviral Drugs
NRTIs (Nucleoside Reverse Transcriptase Inhibitors)
Mutations in Reverse Transcriptase: HIV can mutate the reverse transcriptase enzyme, decreasing the binding affinity of NRTIs and conferring resistance.
NNRTIs (Non-nucleoside Reverse Transcriptase Inhibitors)
Point Mutations: Specific mutations in the reverse transcriptase enzyme can lead to resistance against NNRTIs by altering the drug-binding site.
Protease Inhibitors
Mutations in the Protease Gene: Changes in the viral protease gene can lead to structural alterations that reduce the effectiveness of protease inhibitors.
Neuraminidase Inhibitors
Mutations in Neuraminidase: Influenza viruses can develop mutations in the neuraminidase enzyme, which reduce the binding affinity of neuraminidase inhibitors like oseltamivir.
List the factors to be considered in choosing suitable antimicrobial agents to prevent or treat infection.
- Type of Infection
Determine whether the infection is bacterial, viral, fungal, or parasitic, as this influences the choice of antimicrobial agent. - Pathogen Identification
Identify the causative organism through laboratory tests (culture and sensitivity) to select the most effective agent against the specific pathogen. - Antimicrobial Spectrum
Consider whether a broad-spectrum or narrow-spectrum agent is more appropriate, based on the identified pathogen and the potential for polymicrobial infections. - Resistance Patterns
Assess local resistance patterns (antibiogram data) to ensure the chosen agent is effective against the prevalent strains in the community or healthcare setting. - Pharmacokinetics and Pharmacodynamics
Evaluate the absorption, distribution, metabolism, and excretion (ADME) of the drug, along with its mechanism of action, to ensure adequate concentrations at the site of infection. - Site of Infection
Consider the anatomical location of the infection, as some drugs may not penetrate certain tissues or barriers (e.g., CNS, bone, or abscesses) effectively. - Patient Factors
Allergies: Check for any known allergies to the selected antimicrobial agent.
Comorbidities: Consider underlying health conditions (e.g., liver or kidney function) that may affect drug metabolism and clearance.
Age: Adjustments may be necessary for pediatrics or geriatrics due to differences in pharmacokinetics. - Safety and Tolerability
Evaluate the potential side effects and toxicities of the drug, especially in patients with specific health concerns or when other medications are being taken. - Cost and Accessibility
Consider the cost of the drug and its availability, as financial constraints can impact adherence to the treatment regimen. - Duration of Therapy
Determine the appropriate length of treatment based on the type and severity of the infection, as well as patient response. - Potential for Drug Interactions
Assess possible interactions with other medications the patient is taking that could alter the effectiveness of the antimicrobial or increase the risk of adverse effects. - Guidelines and Protocols
Follow clinical guidelines and protocols established by health authorities or institutions, which are based on evidence and expert consensus for specific infections.
List the side effects commonly associated with the major groups of drugs.
- Allergic reactions, Any antimicrobial: commonly associated with the β-lactam. True penicillin hypersensitivity is rare. Approx. 10% of truly penicillin allergic patients also allergic to cephalosporins.
- Immediate hypersensitivity
Anaphylactic shock (parenteral administration of the antibiotic).
IgE mediated occurs within minutes of administration.
Itching, urticaria, nausea, vomiting, wheezing and shock.
Laryngeal oedema may prove fatal unless the airway is cleared. - Delayed hypersensitivity
Hours or days to develop:
immune complex or cell mediated mechanism. Rashes, fever, serum sickness and erythema nodosum may also occur. Rashes are usually maculopapular and restricted to the skin. The Stevens-Johnson syndrome, severe and sometimes fatal form associated with the sulphonamides (skin and mucous membranes are involved). - Gastrointestinal side effects: Nausea and vomiting are common.
Diarrhoea associated with toxin production by Clostridium difficile. C. difficile anaerobic Gram-positive bacillus asymptomatic in the GI tract, overgrow normal flora during antibiotic therapy and produces toxins. Mild form associated diarrhoea (CDAD) or infection (CDI) life threatening condition pseudomembranous colitis. Diagnosis done by detection of toxin in the stool by enzyme immunoassay (EIA). Treatment with oral metronidazole or oral vancomycin (not absorbed from the GI tract, only circumstance in which the oral form is used). Relapses are common, further courses of treatment may be required. C. difficile is a spore forming organism,
hand hygiene is particularly important for all healthcare staff.
Antibiotic policies promoting informed antibiotic prescribing.
Reduction of the 4 “C”s:
cephalosporins, ciprofloxacin, clindamycin and co-amoxiclav. - Thrush; Broad spectrum antimicrobials suppress normal flora in other parts of the body
result in overgrowth of resistant organisms. Therapy with penicillins or cephalosporins,
may be complicated by overgrowth of the yeast Candida albicans,
resulting in oral and/or vaginal candidiasis, also known as ‘thrush’. - Liver toxicity; More common in people who are pregnant. Tetracycline and the anti-tuberculous drugs isoniazid (INH)
and rifampicin have been associated with such hepatotoxicity. - Renal toxicity; The kidney is the most important route of drug excretion. Nephrotoxicity is dose related more common in patients
with pre-existing renal disease. Most common with the aminoglycoside group (e.g. gentamicin, netilmicin and amikacin) or with vancomycin. Levels of these antibiotics in the blood should be regularly monitored. Nephrotoxicity is usually reversible but may be permanent. - Neurological; Ototoxicity (aminoglycoside or vancomycin use), Optic Neuropathy (Ethambutol (an anti-tuberculous drug)),Peripheral neuropathy (Metronidazole and nitrofurantoin), Encephalopathy and convulsions (High dose penicillin and cephalosporin)
- Haematological Toxicity; Toxic effect on the bone marrow resulting in selective depression of one cell line, co-trimoxazole (sulphonamide and trimethoprim) act by competitive inhibition of folic acid synthesis in both bacteria and mammalian cells. The resulting folate deficiency lead to megaloblastic anaemia after prolonged therapy. The toxicity of some antivirals requires close monitoring of blood counts is required (e.g.: zidovudine (HIV), ganciclovir (CMV)). Anti MRSA agent linezolid also causes bone marrow suppression and may lower platelet counts.
Explain the role of the laboratory (and Clinical Microbiologists) in influencing antimicrobial usage in clinical practice.
Advice on Choice of Antimicrobial: Medical microbiologists give advice on urgent treatment of infection before an organism is isolated, identified and its antibiotic sensitivity tested. Dosage and duration of therapy to be considered in the light of the patient’s age, size, renal function,
monitoring of efficacy and toxicity.
There are two main reasons for monitoring serum levels of an antimicrobial;
1. To ensure that therapeutic levels have been achieved. Blood or serum levels may not be the same as tissue levels depending
upon the ability of the antibiotic to penetrate.
2. To ensure that levels are not so high as to be toxic.
Antibiotics most commonly measured in serum are
gentamicin (or other aminoglycosides) and vancomycin.
The simplest way to measure the
M.I.C.
(Minimum Inhibitory Concentration)
of one antibiotic against one organism is with E-test. Most diagnostic labs use automated methodology.
The growth of individual isolates is measured in the presence of different concentrations of each antibiotic and M.I.C. calculated.
What’s the difference between gram positive and negative?
Gram-positive bacteria show blue or purple after gram-staining in a laboratory test. They have thick cell walls. Gram-negative bacteria show pink or red on staining and have thin walls. They release different toxins and affect the body in different ways.
