Antimicrobials Flashcards
Empiric antimicrobial therapy
Use of antimicrobial agents before the pathogen responsible for an illness has been identified, used in cases where there is a significant risk of morbidity if a therapy is withheld until specific pathogen is detected
Steps in empiric therapy
Formulate clinical diagnosis of microbial infection, obtain specimens for lab, formulate microbiologic diagnosis, determine necessity for empiric therapy, institute treatment
Selective toxicity
The ability of a drug to injure a target cell or organism without injuring other cells or organisms that should not be injured
Methods of selective toxicity
Unique target must be present in pathogen but absent in the host OR target must be structurally different in the pathogen than in the host OR target must be more important in the pathogen than in the host
Things to consider in the selection of antibiotics
Identity and sensitivity of the organism, site of infection, safety of the agent, patient factors, the cost of therapy
Narrow spectrum antibiotics
Gram positive cocci and gram negative bacilli, gram negative aerobes, Mycobacterium tuberculosis
Gram positive cocci and gram negative bacilli
Narrow spectrum- penicillin G and V, penicillinase-resistant penicillins (nafcillin methicillin), vancomycin, erythromycin, clindamycin
Gram negative aerobes
Narrow spectrum- aminoglycosides (gentamicin), cephalosporins (2nd generation)
Mycobacterium tuberculosis
Isoniazid, rifampin, ethambutol, pyrazinamide
Broad spectrum antibiotics
Gram positive and negative organisms
Gram positive and negative organisms
Broad spectrum- broad spectrum penicillins (ampicillin), extended-spectrum penicillins (carbenicillin), cephalosporins (3rd generation), tetracyclines, imipenem, trimethoprim, sulfonamides (sulfamethoxazole), fluoroquinolones (ciprofloxacin, norfloacin)
Disruption of bacterial cell wall
Without cell walls, bacteria absorb water, swell, and burst, several families of drugs act to weaken cell wall and promote lysis of the bacteria, mammalian cells have no cell wall
Disruption of bacterial protein synthesis
Synthesis of proteins employs ribosomes, target bacterial ribosomes
Inhibition of enzymes unique to bacteria
Sulfonamides inhibit bacterial enzyme required for folic acid synthesis, bacteria cannot take up folic acid from environment, mammals do not synthesize folic acid, making it selective
Inhibition of nucleic acid
DNA gyrase
Inhibition of membrane function
Fungal membranes
Minimal inhibitory concentration (MIC)
Minimal concentration where the antimicrobial can inhibit bacterial growth
Minimal bactericidal concentration (MBC)
Minimal concentration where the antimicrobial kills bacteria
Things that determine an anti-microbial’s effectiveness against an organism
Antibiotic must bind to its target site in the bacterium, drug most occupy an adequate number of binding sites related to its concentration within the microorganism, antibiotic should remain at the binding site for a sufficient period of time to cause sufficient inhibition
Factors that may cause resistance to antibiotics
Failure of drug to reach its target, drug inactivation, target alteration
Failure of drug to reach its target
Outer membrane of a gram negative bacteria is a barrier that excludes large polar molecules from entering the cell, small polar molecules enter through porins
Mutations of porin
Can cause loss or blockage of a porin that the antibiotic used to gain access to the cell
Mutations inhibiting transport mechanisms
Can confer resistance to a drug with an intracellular target that requires active transport across the cell membrane (gentamicin)
Drug inactivation
Bacterial resistance may result from the production of enzymes that modify or destroy the antibiotic
Antibiotics affected by drug inactivation
Bacteria may develop resistance to aminoglycosides and beta-lactam antibiotics, isoniazid requires bacteria to convert prodrug to active form
Target alteration
Change in the conformation or binding sequence of the target, antibiotic can no longer bind to the target
Efflux pumps
Can transport drugs out of cells- tetracyclines, chloramphenicol, fluoroquinolones, macrolides, beta-lactam antibiotics
Which antibiotics are most likely to promote resistance
Broad-spectrum antibiotics kill off more competing organisms, are more likely to produce resistance
Superinfection
New infection that appears during the course of treatment of a primary infection, can develop due to elimination of normal flora, most common with broad-spectrum antibiotics
Factors of therapeutic objectives
Identity of the infecting organism, drug sensitivity of the infecting organism, host factors, drug of choice has greater efficacy, lower toxicity, and is narrow spectrum
Alternative agents
Should only be used when the first choice drug is inappropriate due to: allergy, inability of drug to penetrate to the site of infection, or unusual susceptibility of the patient to the toxicity of the first choice drug
Reasons for therapy with antibiotic combinations
Initial therapy of a severe infection, mixed infections, prevention of resistance, decreased toxicity, enhanced antibacterial action
Mixed infections
Caused by more than one microbe, common in brain abscesses, pelvic infections, infections from perforation of abdominal organs
Prevention of resistance
Often multiple antibiotic use is associated with promotion of resistance, combinations of drugs are used in tuberculosis
Decreased toxicity
Combination of flucytosine with amphotericin B in the treatment of fungal meningitis, can reduce dose of amphotericin B and decrease the risk of damage to the kidney
Enhanced antibacterial action
Penicillins and aminoglycosides in the treatment of enterococcal endocarditis, penicillin weakens cell wall, aminoglycoside suppresses protein synthesis
Two antibiotics used together may have different effects
Additive, potentiative (synergistic), or antagonistic
Additive response
Antimicrobial effect of the combination is equal to the sum of the effects of each drug alone
Synergistic (potentiative) interaction
Effect of the combination is greater than the sum of the effects of the individual agents, one of the two drugs must show a 4-fold increase in activity
Synergistic blockade of sequential steps in a metabolic sequence
Trimethoprim-sulfamethoxazole for folic acid production
Synergistic inhibition of enzymatic inactivation
Beta-lactams and beta-lactamase inhibitor (sulbactam)
Synergistic enhancement of antibiotic uptake
Penicillins increase uptake of aminoglycosides in staph and enterococci
Antagonism
Combination of two antibiotics may be less effective than one of the agents by itself, usually static agents are antagonistic to cidal agents
Examples of antagonism
Chloramphenicol and penicillin in treatment of pneumococcal meningitis, tetracycline and penicillin
Initial therapy of severe infection
Most common indication for use of combination is initial therapy for sever infections of unknown etiology, drug selection can be adjusted once the identity of the microbe is known
Penicillins
Amoxicillin, bind to PBP, end in “cillin”
Tetracyclines
Tetracycline, act at 30S ribosome, end in “cycline”
Aminoglycosides
Streptomycin, affects protein synthesis, “mycin” or “micin”
Quinolones
Levofloxacin, DNA gyrase inhibitors, end in “oxacin”
Cephalosporins
Cefaclor, affects protein synthesis, start with “cef” or “ceph”
Macrolides
Erythromycin, acts at 50S ribosome, end in “mycin”