Applied Sciences Lecture Course

Antibiotics
Dr Cathy Armstrong
SpR In Anaesthesia & Clinical Fellow in Undergraduate Medical Education
Manchester Royal Infirmary

March 2011

Objectives
Understand the classification of bacteria Discuss the broad mechanisms of action of antibiotics Consider important features of the main classes of antibiotic Understand penicillin allergy Understand the definitions of SIRS, sepsis & septic shock Be aware of some prescribing strategies & where to access help / information

Definitions
Antibiotic
Molecules that kills or stop the growth of microorganisms

Bactericidal
Antibiotics that kill bacteria

Bacteriostatic
Antibiotics that stop the growth of bacteria

Bacteria

Pili

Ribosome Flagella DNA

Classification bacteria
Gram positive
Retain the original blue colour of Gram stain

Gram negative
Original blue colour washed away by acetone, counterstained red

Classification of bacteria
Gram Positive
Peptidoglycan cell wall
Plasma membrane

outer membrane

Gram negative

Peptidoglycan cell wall Periplasmic space Plasma membrane

Classification of bacteria
Bacteria

Aerobic

Anaerobic

Gram +ive
Cocci Bacilli

Gram -ive
Cocci Bacilli

Gram +ive
Cocci

Gram -ive Bacilli

Bacilli

Gram positive bacteria

Aerobic
Strep pneumoniae
CAP, septic shock, meningitis

Staph aureus
Cellulitis, septic shock, endocarditis

Strep A
pharyngitis

Anaerobic
Clostridium
Tetanus Abdominal sepsis

Gram negative bacteria

Aerobic
E. Coli
UTI, septic shock

Klebsiella
UTI, septic shock, pneumonia

Pseudomonas
UTI, pneumonia, septic shock

Anaerobic
Bacteroides
Abdo sepsis

Classification of antibiotics
Class by coverage
Gram negative Vs. Gram Positive Anaerobic vs aerobic atypical

Class by group
Beta lactams
penicillins Cephalosporins Carbapenems

Glycopeptides Aminoglycosides Macrolides Quinilones Sulphonamides tetracyclines

Classification of antibiotics
Class by mechanism of action
Inhibit cell wall synthesis

Inhibit protein synthesis

Inhibit nucleic acid synthesis

Inhibition of cell wall synthesis

Beta lactams
Penicillins Cephalosporins Carbapenems

Glycopeptides

Which of these is the safest option in penicillin allergy?

1. 2. 3. 4. 5. 6. Co-amoxiclav teicoplanin flucloxacillin Tazocin Cefuroxime Meropenem
16% 16% 16% 16% 16% 16%

Beta lactam antibiotics

Single largest group
Penicillins, Cephalosporins, Carbapenems, Monobactams

All contain a beta lactam ring in chemical structure Target penicillin binding proteins (PBPs)
Peptidoglycan Cell wall synthesizing enzymes found in plasma membrane Not present in mammalian cells

Bacteriocidal Synergistic action

Beta lactam resistance

Enzymatic destruction of -lactam (-lacatamase or penicillinase) Bacterial modification of PDP target (MRSA) Impermeability of cell membrane to -lactam Active excretion by bacteria (mainly Gram neg)

Penicillins
Narrow spectrum
Benzylpencillin
Most Gram pos, anaerobes, some Gram neg Most S. Aureus resistant (-lactamase)

Flucloxacillin
Unaffected by staphylococcal -lactamase

Classically given together in cellulitis

(staph / strep infections)

Penicillins
Broad Spectrum
Amoxicillin
Gram pos & some Gram neg -lactamase resistance common

Piperacillin
Similar to amoxicillin + pseudomonas cover Destroyed by -lactamase

Combined with -lactamase inhibitors

Amoxicillin + clavulanic acid = co-amoxiclav Piperacillin + Tazobactam = Tazocin

What is the incidence of penicillin allergy resulting in anaphylaxis?

1. 2. 3. 4. 0.0005% 0.05% 5% 15%
25% 25% 25% 25%

Penicillin allergy
Anaphylactic reactions are rare (0.05%) BUT - fatal in up to 10% of cases General hypersensitivity reaction (e.g. rashes) occurs in 1-10% of exposed patients Patients who have vague symptoms or GI upset are probably not allergic

Cephalosporins
Classified in generations 1st generation mainly Gram positive cover, successive generations increasing potency against Gram negative E.g.
1st - cephalexin 2nd - cefuroxime 3rd - cefotaxime / ceftriaxone Cefotaxime & ceftriaxone readily cross BBB - used in meningitis

Can cephalosporins be given in penicillin allergy?

Traditionally 10% cross-reactivity stated
Based on 1975 study

Historically contraindicated in patients with severe immediate allergic reaction to penicillin (urticaria / anaphylaxis) Recent epidemiological studies
Suggest for 2nd generation - cross reactivity much less

BNF 61 (March 2011)

The principal side-effect of the cephalosporins is hypersensitivity and about 0.5-6.5% of penicillinsensitive patients will also be allergic to the cephalosporins. Patients with a history of immediate hypersensitivity to penicillin should not receive a cephalosporin. If a cephalosporin is essential in these patients because a suitable alternative antibacterial is not available, then cefixime, cefotaxime, ceftazidime, ceftriaxone, or cefuroxime can be used with caution; cefaclor, cefadroxil, cefalexin, and cefradine should be avoided.

Carbapenems
Similar mode of action to other -lactams Greater affinity for PBP-2
Faster bacterial death

Extremely broad spectrum E.g. imipenem / meropenem Used for severe hospital acquired infections

Glycopeptides
Prevent bacterial cell wall synthesis
Bind to amino acids in cell wall

Active against Gram positive bacteria.

Dont penetrate outer membrane of Gram neg bacteria (polar molecules)

E.g. Teicoplanin, vancomycin Used in severe Gram pos infection Vancomycin

Needs levels monitoring (after 3-4 doses in normal renal function) red man syndrome

Inhibit protein synthesis

Affect 30s ribosome unit (bactericidal)
Aminoglycosides
gentamicin

Tetracyclines

Affect 50s ribosome unit (bacteriostatic)

Macrolides
Clarithromycin, erythromycin

Chloramphenicol

Aminoglycosides
Gentamicin
Good Gram neg cover, some Gram pos cover Used for serious Gram neg infections Synergistic action with -lactams Side effects
Nephrotoxic & ototoxic Toxicity directly related to plasma levels once daily dosing Caution in renal failure

Inhibit nucleic acid synthesis

Affect DNA
Quinolones
ciprofloxacin

Nitro-imidazoles (metronidazole) Trimethoprim Inhibit folate synthesis Sulphonamides

Affect RNA
Rifampicin

Side effects
Common
GI disturbances

Less common
Anaphylaxis / hypersensitivity reactions Thrombocytopenia ARF Hepatotoxicity Photosensitivity

Drug interactions
OCP

Which of the following is most likely to cause C. Diff?

1. 2. 3. 4. Clindamycin Metronidazole Benylpenicillin Vancomycin
25% 25% 25% 25%

When to Prescribe
Prophylaxis
Surgery Endocarditis

Treat infection

Which of the following is NOT considered as part of the criteria for SIRS?
1. RR > 20/min 2. Heart rate < 60 3. Temp <360C or >380C 4. PaCO2 < 32mmHg
25% 25% 25% 25%

SIRS
Systemic inflammatory response syndrome
2 or more of the following criteria:
Temperature < 36 0C or > 38 0C HR > 90 PaCO2< 32mmHg RR > 20 WBC > 12.0 < 4.0, or > 10% immature (band) forms

(? Include change in mental state / hyperglycaemia in absence of diabetes)

Associated definitions
Sepsis
Documented infection together with 2 or more SIRS criteria

Severe sepsis
Sepsis associated with organ dysfunction

Septic shock
Sepsis with refractory hypotension or hypoperfusion abnormalities in spite of adequate fluid resuscitation

Rationale
Ideally narrow spectrum Consider likely organisms Start broad spectrum then narrow with culture results

Other considerations
Route Length of course Appropriate dose
Renal failure

Information / guidelines
BNF Local guidelines Microbiologist

Summary
Classification of bacteria
Gram Negative Vs. Gram Positive

Discussed the broad mechanisms of action of antibiotics Consider important features of some of the main classes of antibiotic Discussed penicillin allergy Defined SIRS, sepsis & septic shock Discussed prescribing strategies & where to access help / information
All Figures were produced using Servier Medical Art - www.servier.com