Antibiotics

ANTIBIOTICS

SELECTIVE TOXICITYAction on a structure or pathway not present in human cells

•Inhibition of Cell wall synthesis: B lactams , Vancomycin

•Inhibition of Protein synthesis: * 30S ribosomal subunit: Aminoglycosides & Tetracyclines * 50S ribosomal subunit: Macrolides &Chloramphenicol

•Inhibition of Nucleic acid synthesis:

SELECTIVE TOXICITYInhibition of Nucleic acid synthesis:

• Quinolones (Topoisomerase inhibitors) –DNA synthesis; DNA coiling

• Rifampicin (– DNA dependent RNA polymerase) inhibits transcription

• Sulphonamides (PABA analogues block folic acid synthesis) block C transfer needed for Thymidine & purine synthesis

• TMP & pyrimethamine (folate antagonists) block reduction of FH2

BACTERIAL RESISTANCEto Antibiotics

Chromosomal:

Mutation (1:10^-7 –1:10^-12) alteration of structural receptor

Plasmid- mediated: (extra chr. DNA)

R factors usually code for enzymes eg B-lactamases (esp of G-ve bacteria) & acetyl-transferase (chloramphenicol)


SPREAD OF RESISTANCE*Generational

*Selection pressure

*Plasmid transfer



*Selection pressure

*Plasmid transfer



*Selection pressure

*Plasmid transfer

R


Staphylococci & penicillin then methicillin

PNEUMOCOCCI:

•The most common bacterial pathogens in children (acute OM, sinusitis, pneumonia, sepsis& meningitis)

•Till 1980 >90% of isolates were highly sensitive to penicillin

•Currently, 25-50% of isolates have intermediate or high penicillin resistance due to altered PBP


*Other B lactams &/or increased dose can be effective esp in non-CNS infections

*10% of isolates are multiresistant

Increased tendency to Vancomycin use has resulted in the increasing problem of Vancomycin-Resistant enterococci

Is a post-antibiotic era the anticipated future?

Factors favouring the development of antibiotic resistance

•Prolonged / repeated antibiotic courses

•Incomplete eradication of the organism

•Prolonged sub-therapeutic antibiotic levels

•Induction of resistance by drugs

•Hospital-based spread of resistant organisms

When?

Which?

How much?

How long?

When?

Which?

How much?

How long?

•Proven bacterial infection

•Suspected bacterial infection

•Prevention of bacterial infection

Barden et al.(1998) have found the self-reported rate of antibiotic prescriptions which could have been omitted without impairing patient care was

10-50%

Suggested targets for economising antibiotic use:•Non-specific URTI (essentially viral)

•Non-streptococcal pharyngitis (GABHS are the only common bacterial cause representing <15% of cases)

•Acute ‘cough illness’

•Asthma (antibiotics rarely alter the course of acute episodes)

•Secretory otitis media

•Diarrhoeal diseases

Possible reasons for antibiotic overuse:DIAGNOSTIC DIFFICULTY:

*Clinical

*Lack of rapid reliable tests

*Reluctance to use diagnostic tests (parent stress, cost, time,etc)

AVOID DELAY IN STARTING THERAPY:

*Awaiting test results

*2ry bacterial infection in known viral illnesses

PARENT REQUESTS

‘IT WON’T HARM’

When?

Which?

How much?

How long?

The main antibiotic groups

B lactam group•Penicillins

•Cephalosporins

•Monobactams

•Carbapenems

*Contain B-lactam ring

*Inhibit cell wall synthesis osmotic lysis

*Low toxicity (?CNS stimulation?)

*Allergy is rare but may be serious

*Elimination primarily renal (exceptions)

•Penicillins

*Benzyl penicillin

*Procaine penicillin &Benzathine penicillin

*Phenoxymethyl penicillin

*Broad – spectrum Ampicillin & Amoxycillin

*Penicillinase Resistant Methicillin & Flucloxacillin

* AntiPseudomonal Carbenicillin & Piperacillin

B lactam group•Penicillins PENICILLINASE INHIBITORS

•Sulbactam / Ampicillin•Clavulinate / Amoxycillin .

•Used to overcome resistance due to Penicillinase production: Staph, some Gm-ve(H.influenza, Moraxella, E.coli, Kleb. ) and anaerobes(B.fragilis)

•Tazobactam / Piperacillin


•Cephalosporins

B lactam ring is more protected less sensitive to B lactamases

Oral forms more palatable


•Cephalosporins+B.fragilis

H.influenza incl penicillinase producers (less with cephamandol)

++CSF penetr by Cefuroxime not Cefamandol


•Cephalosporins

*less G+ esp Staph

*NOT for enterococci &Listeria

*++G- bacilli including some aminoglycoside R

*Variable: Pseudomon &Bacteroides

Dual Excr

CNS

ACQUIRED RESISTANCE TO ONE INVOLVES THE WHOLE GROUP


•Cephalosporins

•Monobactams

•Carbapenems


•Cephalosporins

•Monobactams

•Carbapenems

Aztreonam


•Cephalosporins

•Monobactams

•Carbapenems

Imipenem/ Cilastatin*Now approved for neonates

*CNS irrit esp with meningitis

*Renal elim blocked by Cilastatin

Meropenem

AMINOGLYCOSIDES

*Irreversible binding to 30S -- ptn synthesis

*Active against Gm –ve bacilli

*Anaerobes, streptococci & pneumococci are RESISTANT

*Synergism with B-lactams if given 1-2h after them

*Gram –ve resistance due to inactivating enz varies within the group

*Ototoxicity nephrotoxicity

*Cleared exclusively by Glomerular filtration

MACROLIDES*Prevent peptide bond formation by blocking the action of peptidyl-transferase at 50S

*Concentrated in tissues esp. Azithromycin & Clarithromycin

*Azithromycin has good GIT tolerance & no hepatic interactions

*Broad spectrum includes most G+ve , atypical pathogens: ( intracellular , no cell wall) Chlamydia , Mycoplasma & Legionella

CHLORAMPHENICOL

*Irreversible binding to 30S -- ptn synthesis

*Active against Anaerobes

Atypicals

Gm +ve

. Gm –ve but not Pseudomonas

*Excellent CSF penetration

*Toxicity limits its use esp in neonates

*Thiamphenicol may be less toxic

VANCOMYCIN

*Glycopeptide which blocks formation of the peptide portion of peptidoglycan

*Most Gm +ve including:

MRSA

Pneumococci including multiresistant

Clostridia including Cl difficile

Enterococci ( resistance escalating)

*Ototoxic , Nephrotoxic , Red Man Syndrome

SULPHONAMIDE + TMP

Co-Trimexazole*Combination is bactericidal

*Effective in Gm –ve

QUINOLONES*Concern about joint damage not confirmed in humans

*Covers most Gm –ve & some Staph & Strept

*CNS: dizziness , confusion

IDENTIFY ORGANISM

•Culture & sensitivity

•Common pathogens by disease & age

•Common pathogen by Procedure & place

DRAWBACKS OF C/S

*Delay in results

*Financial factors

*Inaccuracy

-Contamination (pt or lab)

-Antibiotic ttt

-Incomplete testing for all AB

-Anaerobes & fungi

*Don’t change a clinically effective ttt

*Don’t step-up unless sensitivity is higher

Antibiotics

Documents

common bacterial pathogens

onlycommon bacterial

selection pressure

b lactams

postantibiotic era

vancomycin use

plasmid transferr

s ribosomalsubunit