3 - Antibacterial Chemotherapy

use of chemical substances to treat various aspects of disease

Chemotherapy

produced by a microorganism in small amounts to inhibit another microorganism.

Antibiotic

 special group of chemotherapeutic agents that kill microbes

Antimicrobial

agents used to kill infectious or inhibit its spread (includes antiparasitics, anthelmintics, antiprotozoal agents)

Anti-infectives

4 Major Producers of Antimicrobials

Streptomyces & Bacillus – bacteria

Penicillin & Cephalosporium – molds

Most common producer of antimicrobials

Streptomyces

Goal of antimicrobial toxicity

Selective toxicity

• For critically ill px when we are not 100% what the causative agent is but we can infer what the most likely agent it is.

• Con: prone to resistance

• Broad spectrum antimicrobial agents are used.

empiric therapy

• Identified Etiologic pathogen and susceptibility

• Narrow spectrum

• Preferred. Less resistance, less cost for px

definitive therapy

Determines the susceptibility and resistance of bacteria to a particular antibacterial agent.

Kirby-Bauer Disk Diffusion Test

• Show how susceptible a series of organisms are to different antimicrobials.

• Annual summary of local antibiotic susceptibilities

• unit specific – can vary per hospitals

Antibiogram

arrange cephalosporins according to increasing spectrum

1st generation – narrow spectrum (more + cocci)

2nd generation – intermediate spectrum (less + cocci, better – bacilli)

• H. influenzae and E. aerogenes

3rd generation – broad spectrum (good + cocci, best – bacilli)

• H. influenzae and E. aerogenes

• Some enterobacteriaceae that do not produce ampC nor extended spectrum B-lactamase

4th generation – extended-spectrum (good + cocci, best – bacilli)

• Producers of amp C and ESBL

5th generation – extended-spectrum (Methicillin resistant staph. aureus)

• E. faecalis

5D of Antimicrobial Stewardship

1. Diagnosis

2. Drug

3. Duration

4. Dose

5. De-escalation

De-escalation Strategies

• Definitive therapy 

• Switch from IV to oral

Bacteriostatic drugs

Tetracyclines

Macrolides

Clindamycin

Chloramphenicol

Ethambutol

Linezolid

Sulfonamides (-cidal at high conc)

trimethoprim

Bactericidal drugs

Penicillins

Cephalosporins

Monobactams

Carbapenems

Other cell wall synth inhibitors

Rifampicin, isoniazid, pyrazinamide

Streptogramins

Aminoglycosides

Polymyxins

Lipopeptides

Fluoroquinolones

Sulfonamides + trimethoprim (bactericidal due to additive effects)

Cell wall synthesis inhibitors

Inhibits enolpyruvate transferase (1st wall synthesis is disrupted)

moa of fosfomycin trometamol

Cell wall synthesis inhibitors

Inhibits Alanine racemase and D-alanyl-D-alanine ligase (for incorporation of alanine to tetrapeptide formation)

MOA of cycloserine

Cell wall synthesis inhibitors

Inhibits dephosphorylate by acting on the lipid carrier that transfers the peptidoglycan unit.

MOA of bacitracin

Cell wall synthesis inhibitors

Bind to D-ala-D-ala terminus to prevent further attachments to the cell wall

MOA of vancomycin

Cell wall synthesis inhibitors

Inhibits transpeptidase

MOA of penicillin and cephalosporin

Cell wall membrane function

Using Ca2+, it generates energy to bind in between the phospholipid bilayer → creating a hole in the bilayer and a channel → depolarization and ion reflux. K ions exit the cell, causing an overall destruction to the cell membrane and integrity of the cell → lysis

MOA of Daptomycin

Protein synthesis inhibitors

Bind to 50s and inhibit formation of peptide bond

MOA of Chloramphenicol

Protein synthesis inhibitors

Interfere w/ attachment of tRNA and mRNA

MOA of tetracycline

Protein synthesis inhibitors

Change shape of 30s portion → incorrect code on mRNA

MOA of streptomycin

Nucleic acid synthesis inhibitor

Disrupts RNA synthesis.  Acts on RNA polymerase → distorted mRNA

MOA of rifampin

Nucleic acid synthesis inhibitor

Disrupts DNA synthesis.  Act against folate precursors.

MOA of Trimetoprim, Sulfonamides

Nucleic acid synthesis inhibitor

Destroy bond → destroy shape/integrity of the DNA, inhibiting reproduction of nucleic acids.

MOA of metronidazole

Nucleic acid synthesis inhibitor

Inhibit topoisomerase causing supercoiling

moa of Quinolones

Antimetabolites

Inhibits dihydrofolic acid

MOA of Sulfonamide

Antimetabolites

Inhibits dihydrofolate reductase

MOA of trimetoprim

categories of cell wall synthesis inhibitors

DRUG	ACTION
Beta-Lactam Antibiotics	Contains a beta-lactam rings Penicillins, Carbapenems, Cephalosporins, Monobactams
Polypeptide Antibiotics	Bacitracin, Vancomycin
Antimycobacterials	Isoniazid, ethambutol

categories of psi

30s	50s
Buy AT 30	S(C)eL at 50s
Aminoglycosides (streptomycin, gentamicin) Tetramycin	Streptogramin Chloramphenicol Clindamycin Linezolid Macrolides (Erythromycin)

categories of nucleic acid synthesis inhibitors

CATEGORY	DRUG
DNA-Dependent RNA polymerase inhibitors	Rifamycin	Rifampicin
DNA-gyrase Inhibitors	Quinolones (-flox)	Nalidixic acid Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin Gatifloxacin

Selective and Differential Culture Media for Cultivation of Bacteria

CAUSATIVE AGENT	MEDIUM USED
Neisseria gonorrhoeae	Theyer-Martin Agar
Clostridium or Bacteroides	Thioglycollate Medium
Vibrio cholarae	Thiosulfate-citrus-bile-salts-sucrose Agar
Corynebacterium diphtheriae	Loeffler’s Medium
Helicobacter pylori	Skirrow’s Medium
Mycobacterium spp.	Lowenstein-Jensen Medium
Bordetella pertussis	Gengou Agar
Leptospira spp.	Fletcher’s Media
Haemophilus influenzae	Chocolate Agar

1st gen cephalosporins

Cephalotin	1st gen	narrow spectrum (more + cocci)
Cephapirin
Cefazolin
Cefadroxil
Cephalexin
Cephradine

2nd gen cephalosporins

Cefuroxamine	2nd gen	intermediate spectrum (less + cocci, better – bacilli)	H. influenzae
Cefaclor			E. aerogenes
Cefamandole
Cefoxitine
Cefotetan
Cefprozil

3rd gen cephalosporins

Ceftriaxone	3rd gen	broad spectrum (good + cocci, best – bacilli)	H. influenzae
Cefixime			E. aerogenes
Cefotaxime			Some enterobacteriaceae that do not produce ampC nor extended spectrum B-lactamase
Ceftazidine
Cefoperazone
Cefdinir

4th gen cephalosporins

Cefepime	4th gen	extended-spectrum (good + cocci, best – bacilli)	Enterobacteriaceae that produce ampC and ESBL
Cefpirome
Cefquinome

5th gen cephalosporins

Ceftobiprole	5th gen	extended-spectrum (Methicillin resistant staph. aureus)	E. faecalis
Ceftaroline
Ceftolozane

1st gen quinolones

Cinoxacin	1st gen	good G– bacilli activity, like enterobacteriaceae but not effective for pseudomonas
Nalidixic acid

2nd gen quinolones

Ciprofloxacin	2nd gen	additional fluorine. Better G– bacilli action including pseudomonas, good G+ cocci, good for atypical organisms
Ofloxacin
Norfloxacin
Enoxacin

3rd gen quinolones

Levoflox

3rd gen

more additional fluorine. Narrow to broad, better activity than 2nd

4th gen quinolones

Moxifloxacin	4th gen	Additional fluorine. Better G–, best G+, for anaerobic organisms
Gemifloxacin