Antimicrobial Chemotherapy
• Use of drugs to combat infectious agents
• Antibacterial
• Antiviral
• Antifungal
• Antiparasitic
Antimicrobial Chemotherapy
• Differential(selective) toxicity: based on the concept that the drug is more toxic to the infecting organism than to the host
• Majority of antibiotics are based on naturally occurring compounds
• or may be semi-synthetic or synthetic
What is the ideal antibiotic
• Have the appropriate spectrum of activity for the clinical
setting.
• Have no toxicity to the host, be well tolerated.
• Low propensity for development of resistance.
• Not induce hypersensitivies in the host.
What is the ideal antibiotic
• Have rapid and extensive tissue distribution
• Have a relatively long half-life.
• Be free of interactions with other drugs.
• Be convenient for administration.
• Be relatively inexpensive
Principles / Definitions
• Spectrum of Activity: Narrow spectrum - drug is effective against a limited number of species
Broad spectrum - drug is effective against a wide variety of species
• Gram negative agentGram positive agentAnti-anaerobic activity
Principles / Definitions
• Minimum Inhibitory Concentration (MIC)- minimum concentration of antibiotic required to inhibit the growth of the test organism.
• Minimum Bactericidal Concentration (MBC)- minimum concentration of antibiotic required to kill the test organism.
• Bacteriostatic
• Bactericidal
• Time dependent killing
• Concentration dependent killing
Principles / Definitions
• Treatment & prophylaxis
• Prophylaxis - antimicrobial agents are administered to prevent infection
• Treatment - antimicrobial agents are administered to cure existing or suspected infection
Combination Therapy
• To prevent the emergence of resistance- M.tuberculosis
• To treat polymicrobial infections
• Initial empiric therapy
• Synergy
Combination Therapy
• Why not use 2 antibiotics all the time?• Antagonism
• Cost
• Increased risk of side effects
• May actually enhance development of resistanceinducible resistance
• Interactions between drugs of different classes
• Often unnecessary for maximal efficacy
What influences the choice of antibiotic?
• Activity of agent against proven or suspected organism
• Site of infection
• Mode of administration
• Metabolism and excretion
– renal and hepatic function
• Duration of treatment / frequency of dose
• Toxicity / cost
• Local rates of resistance
How do antimicrobial agents work
• must bind or interfere with an essential target
• may inhibit or interfere with essential metabolic
process
• may cause irreparable damage to cell
Targets of antibacterial agents
• Inhibit cell wall production- penicillin binding proteins
• Inhibit protein synthesis- bind 30s or 50s ribosomal subunits
• Inhibit nucleic acid synthesis- binding topoisomerases / RNA polymerase
• Block biosynthetic pathways- interfere with folate metabolism
• Disrupt bacterial membranes- polymixins
Antimicrobial resistance
• Resistance: the inability to kill or inhibit the organism with clinically achievable drug concentrations
• Resistance may be innate (naturally resistant)
• Resistance may be acquired- mutation- acquisition of foreign DNA
Antimicrobial resistance
• Factors which may accelerate the development of
resistance
- inadequate levels of antibiotics at the site of infection
- duration of treatment too short
- overwhelming numbers of organisms
- overuse / misuse of antibiotics
Antimicrobial resistance
General mechanisms of resistance
Altered permeability
Inactivation / destruction of antibiotic
Altered binding site
Novel (new) binding sites
Efflux (pumps) mechanisms
Bypass of metabolic pathways
Action of bacterial enzyme
• Without the antibiotic binding to a bacterial enzyme, the activate site of the enzyme is able to react with its substrate.
Action of antibiotics on enzyme
• When an antibiotic binds to a bacterial enzyme, it may alter the activate site of the enzyme and prevent it from reacting with its substrate.
Action of oxazolidones
• The oxazolidinones (linezolid) bind to the 50S ribosomal subunit and interfere with its binding to the initiation complex.
• Genetic mutations
• Acquiring resistance from other bacteria
through:
conjugation
Transformation
Transduction
trosposons
• 1. producing enzymes:
• Penicillinase
• Acetylase
• Adenylase
• Phosphorylase
• Chloramphenicol acetyl transferase
Antibiotic Classes
• Cell Wall Active Agentsbactericidal, time dependent killing
• B-lactams- penicillins / cephalosporins /- cephamycins / carbapenems
• Glycopeptides- vancomycin / teicoplanin- gram positive agents
Penicillins
• Penicillin G / V - good gram positive (not Staph)-moderate anaerobic activity
• Synthetic penicillins (Ampicillin)- good gram positive (not Staph)- moderate gram negative (not Pseudomonas)
• Anti-staphylococcal penicillins- Cloxacillin
• Anti-pseudomonal penicillins- Piperacillin
Cell Wall Active Agents
• B-lactams bind to “penicillin binding proteins” (PBP)-PBP are essential enzymes involved in cell wall synthesis-weakened / distorted cell wall leading to cell lysis and death
• Glycopeptides bind to the terminal D-ala of nascent cell wall peptides and prevents cross-linking of these peptide to form mature peptidoglycan
Vancomycin: Mechanism of Action
• Inhibit peptidoglycan synthesis in bacterial cell wall by complexing with the D-alanyl-D-alanyl portion of the cell wall precurser
2L-ala
2D-ala
D-ala-D-ala
UDP-L-ala-D-glu-L-lys
UDP-L-ala-D-glu-L-lys-D-ala-D-ala
pentapeptide--
racemase
ligase (ddl)
adding enzyme
--L-ala-D-glu-L-lys--D-ala-D-ala
vancomycin
-L-ala-D-glu-L-lys-D-ala-D-alatransglycosidase
-L-ala-D-glu-L-lys-D-ala-D-ala
-L-ala-D-glu-L-lys-D-ala-D-ala
transpeptidase
-L-ala-D-glu-L-lys-D-ala-D-alacarboxypeptidase
Cell Wall Active Agents
• B-lactam resistance1. Production of a B-lactamase (most common)2. Altered PBP (S.pneumoniae)3. Novel PBP (MRSA)4. Altered permeability
• Glycopeptide resistance- primary concern is Enterococcus / S.aureus- altered target- bacteria substitutes D-lac for D-ala- vancomycin can no longer bind
Cephalosporins
• History– Discovered in sewage in Sardinia in the
mid 1940s.
– Cephalosporium sp was recovered and proved a source of cephalosporin.
– Subsequently, four generations of cephalosporins have emerged.
Cephalosporins
• 1st generation- mainly gram pos, some gram neg(cefazolin)
2nd generation- weaker gram pos, better gram neg(cefuroxime)
3rd generation - excellent gram neg, some gram pos(ceftriaxone)
4th generation - excellent gram neg, good gram pos(cefepime)
First-Generation Cephalosporins: What do they cover?
• Cefazolin (Kefzol) and cephalexin (Keflex)
– Activity includes:
• Methicillin susceptible staphylococci
• Streptococci excluding enterococci
• E. coli, Klebsiella sp., and P. mirabilis
• Many anaerobes excluding B. fragilis
Where do you think they should beused?
• Simple mixed aerobic infections.
• In penicillin allergic (not immediate) patients.
• Surgical prophylaxis.
• Convenience drug for S. aureus and streptococci?
What about second generationcephalosporins?
• Cefuroxime– Think Haemophilus in
addition to 1st generation specturm
– A respiratory drug
• Cefoxitin/cefotetan
– 1st generation plus-anaerobes
– A mixed, non-serious infection surgeon drug
– Think cefazolin/metro which is what we would use
Third-Generation Cephalosporins
• Cefotaxime, ceftriaxone (IV)
– Enhanced activity against Enterobacteriaceae
– Enhanced activity against streptococci, including penicillin resistant S. pneumoniae.
– Long half life favors ceftriaxone
– Less diarrhea favors cefotaxime
• Ceftazidime (IV)
– Active against P. aeruginosa.
– Decreased activity against gram positive cocci.
Carbapenems:What don’t they get?
• Everything except:
– MRSA and MRSE
– Enterococcus faecium
– Stenotrophomonas maltophilia
– Burkholderia cepacia
When to use carbapenems?
• Life threatening polymicrobial infections
– Intra abdominal sepsis in ICU espnosocomial in origin
– Gram negative/ nosocomial pneumonia in intubated patient
• Monotherapy of febrile neutropenia (high risk patients)
What are the beta-lactamase inhibitors?
• Clavulanate (with amoxicillin or ticarcillin)
• Tazobactam (with piperacillin)
What additional bugs do they cover?
• S. aureus
• H. influenzae
• Neisseria sp.
• Bacteroides fragilis
• E. coli and Klebsiella
• Not better for Pseudomonas or Enterobacter
Inhibitors of protein synthesis
• Ribosomes are the site of protein synthesis
• many classes of antibiotics inhibit protein synthesis by binding to the ribosome
• binding may be reversible or irreversible
• Macrolides, ketolides, lincosamides, streptograminsTetracyclinesAminoglycosides
Inhibitors of protein synthesis
• Macrolides (erythromycin, clarithromycin, azithromycin)- primarily gram positive, mycoplasma, chlamydia- bacteriostatic, time dependent killing
Lincosamides (clindamycin)- gram positive, anaerobic activity
• Resistance (acquisition of a gene)- M phenotype: macrolides only
efflux- MLSB phenotype:
macrolides, lincosamides, streptograminstarget site modificationconstitutive, inducible
Inhibitors of protein synthesis
• Aminoglycosides: gentamicin, tobramycin, amikacin- excellent gram negative, moderate gram positive- bactericidal, concentration dependent
• ResistancePrimarily due to aminoglycoside modifying enzymes
Inhibitors of nucleic acid synthesis
• Fluoroquinolones (ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin)
- bactericidal, concentration dependent- bind to 2 essential enzymes required for DNA replication- DNA gyrase and topoisomerase IV- gram pos and gram neg- atypical bacteria, some have anaerobic activity
• Resistance- altered permeability (porin channels)- altered target site- efflux
Inhibitors of metabolic pathways
• Trimethoprim/sulfamethoxazole (Septra, TMP/SMX)- good gram negative, some gram positive
• block folic acid synthesis at two different pointsTMP and SMX act synergistically
• Resistance may arise if the organism can “bypass” the pathway making it redundant