Antimicrobial Chemotherapy

Part I

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

Antimicrobial Chemotherapypart II

Synthesis of peptidoglycan

Action of penicillins andcephalosporines

from Assembling the Peptide Cross-Links in Peptidoglycan

Action of vancomycin

Action of Tetracyclins

Action of macrolids

Action of Aminoglycosides

Action of Aminoglycosides

Amphotercin B - colistin - Imidazolen - Nystatin -

polymyxins

sulfonamides

sulfonamides

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.

Initiation Complex

Bacterial resistance

• Genetic mutations

• Acquiring resistance from other bacteria

through:

conjugation

Transformation

Transduction

trosposons

• 1. producing enzymes:

• Penicillinase

• Acetylase

• Adenylase

• Phosphorylase

• Chloramphenicol acetyl transferase

• 2. changes in permeability:

• Polymyxines

• Tetracyclins

3.Change in receptors of drug

• PBPs

• 30 S subunite of ribosome

• 50 S subunite of rifosome

• 4. change in metabolisme

• use of folic acid instead of PABA

Antibiotic Classes

• Cell Wall Active Agentsbactericidal, time dependent killing

• B-lactams- penicillins / cephalosporins /- cephamycins / carbapenems

• Glycopeptides- vancomycin / teicoplanin- gram positive agents

Structure of -lactam drugs

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.

Fourth generation cephalosporins

• Cefepime

– Marginal improvements

– Not available at the QE II

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

Mechanism of action ofTMP-SMX