antimicrobial medications
DESCRIPTION
Antimicrobial Medications. Antibiotics. Antimicrobial drugs naturally produced by microorganisms Penicillium species: Penicillins Cephalosporium specis : cephalosporins Streptomyces species: lincosamides , aminoglycosides , tetracyclines , chloramphenicol. - PowerPoint PPT PresentationTRANSCRIPT
Antimicrobial Medications
Antibiotics• Antimicrobial drugs naturally
produced by microorganisms– Penicillium species: Penicillins– Cephalosporium specis:
cephalosporins– Streptomyces species:• lincosamides, aminoglycosides,
tetracyclines, chloramphenicol
Features of antimicrobial drugs• Selective toxicity
– Therapeutic index• Antimicrobial action
– Bactericidal– Bacteristatic
• Spectrum of activity– Broad spectrum– Narrow spectrum
• Combination effects– Antogonistic– Synergistic– Additive
Pharmacokinetics: what happens to the drug in the body?
• Absorption• Tissue distribution• Metabolism• Route of excretion• Rate of elimination
Adverse effects• Adverse drug reaction• Toxic effects• Suppression of normal
microbiota
Mechanisms of antimicrobial drugs
• Inhibition of cell wall synthesis• Inhibition of protein synthesis• Inhibition of nucleic acid synthesis• Inhibition of biosynthetic pathways • Disruption of cell membrane integrity
Targets of Cell Wall Synthesis
Penicillin
• Inhibits formation of tetrapeptide side chains
How organisms degrade penicillins
Family of Penicillins
• Natural penicillins• Penicillinase-resistant penicillins• Broad-spectrum penicillins• Extended-spectrum penicillins• Penicillins plus beta-lactamase inhibitors
Family tree of penicillins
β-lactams
• Penicillins• Cephalosporins• Carbapenems• Vancomycin• Bacitracin
Cephalosporins
• Derived from fungus, Acremonium cephalosporium
• Chemical structure makes them resistant to beta-lactamase: low affinity for penicillin binding proteins
• Grouped into first, second, third, and fourth generation cephalosporins
Vancomycin
• Binds to the terminal amino acids of the peptide chain of NAM molecules, blocks peptidoglycan formation
Antibiotics that inhibit protein synthesis
Oxazolidinones
• Reversibly bind to the 50S subunit, interfere with initiation of protein synthesis
• Used for treating gram positive infections resistant to Beta-lactam drugs and Vancomycin
• Ex: Linezolid
Aminoglycosides
• Bactericidal • Irreversibly bind to 30S ribosome, cause
misreading of the mRNA• Transported into cells that actively respire (not
effective against ananerobes, streptococci, enterococci)
• Ex: streptomycin, gentamicin, tobramycin
Tetracyclines & Glycylcyclines
• Bind reversibly to 30S, block attachment of the tRNA to ribosome
• Actively transported into bacterial cells• Effective against gram positive and gram
negative• Resistance: due to decrease in uptake or
increase in excretion• Ex: Doxycycline
Macrolides
• Reversibly bind to the 50S, prevent continuation of protein synthesis
• Drug of choice for patients allergic to penicillins
• Not good for Enterobacteriaceae• Ex: Erythromycin, Azithromycin• Resistance: enzymes that alter drug,
decreased uptake
Inhibition of protein synthesis: Chloramphenicol
• Rare side effect = irreversible bone marrow suppression
• Banned in food animals• Making a come-back in companion animal
medicine due to effectiveness against multi-drug resistant staphylococci
Antibiotics that inhibit nucleic acid synthesis
• Fluoroquinolones– Interferes with function of topoisomerase
• Rifamycins– Blocks prokaryotic RNA polymerase from initiating
transcription
Antibiotics that inhibit biosynthetic pathways
• Sulfonamides• Trimethoprims
Sulfonamides (sulfa drugs)
• First synthetic drugs to treat microbial infections
• Used to treat urinary tract infections (UTIs)• Combination of trimethoprim and
sulfamethoxazole (TMP-SMZ) example of synergism
Drugs used together inhibit folic acid synthesis
Tests for microbial susceptibility
• Kirby-Bauer (disk diffusion method)
Tests for microbial susceptibility
• Minimum Inhibitory Concentration: MIC– Grow bacteria in a serial dilution of the
antimicrobial being tested– Fixed concentration of bacterial cells– Observation of turbidity after 16 hrs-24 hrs of
growth– Lowest concentration of drug that inhibits growth
= MIC
Minimum Inhibitory Concentration
• Manual broth dilution method• Automated broth dilution method• E-test
Determining the Minimum Inhibitory Concentration (MIC)
Automated MIC
E-test for MIC
Zone size & MIC values
• Raw data• Meaningless without interpretation• Correlation of in vitro results with achievable
levels of drug concentration in a live patient• Correlation with actual clinical outcome
What resistance looks like…
Mutant Prevention Concentration?
Mechanisms of acquired drug resistance
• Destruction or inactivation of the drug: drug inactivation enzymes
• Alteration of target molecule (mutation)
• Decreased uptake: alteration of porins
• Increased elimination: efflux pumps
Acquiring resistance
• Spontaneous mutation• Gene transfer– R plasmids
Emerging antimicrobial resistance
Streptococcus pneumoniae
• Altered penicillin binding proteins– DNA-mediated transformation
Enterococcus species
• Gram positive enteric cocci; facultative anaerobes; formerly classified as Group D streptococcus
• Common cause of nosocomial infections– Enterococcus faecalis,
Enterococcus faecium• Intrinsic resistance:• Acquired resistance
Mycobacterium tuberculosis
• Multidrug-resistant M. tuberculosis– Resistance to isoniazid
& rifampin• Extensively drug-
resistant M. tuberculosis– Resistance to isoniazid
& rifampin + 3 or more of the 2nd line drugs
Enterococcus species: intrinsic resistance
• Low affinity of penicillin binding proteins for many β-lactam antibiotics, esp. cephalosporins
• Resistance to potentiated sulfonamides (i.e., trimethoprim-sulfa): able to utilize external sources of folate
• Low permeability for aminoglycosides– Treatment with a cell-wall active drug such as
ampicillin is synergistic (allows the drug to get into the cell) UNLESS high-level gentamicin resistance is present
Enterococcus species: acquired resistance
• High-level gentamicin-resistance: plasmid-encoded inactivating enzymes
• Tetracycine resistance: efflux pumps, ribosomal protection
• Macrolide resistance: efflux pumps• Vancomycin resistance: altered drug binding
site on cell wall
Enterobacteriaceae• Gram negative enteric
rods• Intrinsic resistance to
many drugs due to outer membrane
• β-lactamases: enzymatic inactivation of the lactam ring
• Extended spectrum β-lactamases (ESBL+)
• Carbapenem-resistance: enzymatic inactivation
Staphylococcus species
• Staph aureus• Staph pseudintermedius• Staph schleiferi• Methicillin-resistant staph: penicillinase +
altered penicillin-binding proteins with low affinity for β-lactam drugs (mecA gene on R plasmid)
• Vancomycin-resistant staph
Methicillin-resistant staphylococci• MRSA: methicillin-resistant Staph aureus– drug resistance + increased pathgenicity
• MRSP: methicillin-resistant Staph pseudintermedius– Acquisition of drug resistance is not associated
with acquisition of new virulence factors• MRSS: methicillin-resistant Staph scheiferi– Drug resistance/no new virulence factors
• Coagulase-negative MRS
Coagulase test
• Tests for coagulase enzyme = virulence factor produced by Staphylococcus aureus, Staph. pseudintermedius and Staph. schleiferi subspecies coagulans
• Important in differentiating potentially pathogenic from non-pathogenic species of staphylococci
Coagulase enzymes
• Bound coagulase (“clumping factor”) – attached to bacterial cell wall– Coagulase enzyme + fibrinogen in plasma → fibrin
clot surrounding bacteria: prevents antibody and complement binding, prevents phagocytosis, protects from NETs
• Free coagulase – secreted enzyme– Coagulase enzyme + CRF → conversion of
prothrombin to thrombin and fibrinogen to fibrin
Coagulase slide test
• Rabbit plasma + bacteria: agglutination within 1-2 minutes = positive result– Detects only bound coagulase– False negatives or equivocal results are common– Negative or equivocal tests have to be confirmed
with tube test
Coagulase tube test
• Rabbit plasma + bacteria: coagulation of the plasma = thickening OR formation of fibrin clumps or threads– Standard practice = read at 4 hrs, if negative
recheck at 24 hrs• Tests not read at 4 hrs that are negative at > 4 hrs will
have to be repeated because early positive results may revert to a negative result
Coagulase negative staph
• Common isolates from skin cultures• Non-pathogenic commensuals• Rarely part of mixed population in deep skin/
wound infections (furuncles)• Rarely cause bacteremia or other systemic
infections in immune-compromised individuals
• Commonly carry plasmids with mecA gene
MRS: colonization vs. infection
• Sharing of plasmids + high antimicrobial use• Selecting for MRS population• Increasing % of staphylococcal isolates from
non-lesional skin and nasal mucosa are methicillin resistant
Responsible drug use
• Use vs misuse of antimicrobial drugs• Responsibilities of health care professionals?• Responsibilities of patients?• Responsibilities of pet owners?• Public education• Over the counter antimicrobial drugs– Developing countries– US feed stores
Antimicrobial Stewardship
• Increasing drug resistance• Fewer drugs in development• Drugs being developed don’t have novel
targets• Drugs being developed are broad spectrum• “Bad Bugs, No Drugs” task force 10x20
initiative
Antimicrobial Stewardship
• 4 D’s of antimicrobial therapy– Right Drug, – Right Dose, – De-escelation to pathogen directed therapy – Right Duration of therapy
• Prevent overuse, misuse and abuse• Minimize the development of resistance