Antibiotics

MR. H GEE MD, FRCOGHon. Assoc. Clinical Professor

University of Warwick

Objectives• By the end of this lecture you should be able to:

1) Classify commonly used antibiotics into six major antibiotic classes of;

a) Beta lactamsb) Aminoglycosidesc) Fluoroquinolonesd) Macrolidese) Tetracyclinesf) Glycopeptides g) Metronidazole

2) Understand the mechanism of action of each antibiotic class.

3) Understand clinical use of each class of antibiotic

4) Possible major side effects.

There are Three in this RelationshipThere are Three in this Relationship

Drug

Bacteria

Resistance

Pharmacodynam

ics

(PD)

Infection

Host defence

Toxici

ty

Pharm

acok

inet

ics

(PK)

Host

Improving the probability of Improving the probability of positive outcomespositive outcomes

• Window of opportunity– Early recognition and treatment of infection

– Selection of appropriate antibiotic(e.g. through in vitro susceptibility determination)

– Optimization of DOSE using Pharmacodynamic principles

– Use optimized dosing that would allow for the minimization of selecting further resistance

Early recognition of infection Early recognition of infection (Sepsis)(Sepsis)

• Systemic inflammatory response syndrome (SIRS) Systemic inflammatory response syndrome (SIRS) (Bone et al Crit Care med 1989.;17 :389) (Bone et al Crit Care med 1989.;17 :389)

Systemic activation of the immune responseSystemic activation of the immune response 2 of the following in response to an insult:2 of the following in response to an insult:

• T > 38 .C or < 36.CT > 38 .C or < 36.C• HR > 90 bpmHR > 90 bpm• RR > 20 bpm RR > 20 bpm • WBC > 12 000 cells/mm3 WBC > 12 000 cells/mm3

• SepsisSepsisSIRS + suspected or confirmed infectionSIRS + suspected or confirmed infection

Key Message 1Key Message 1

• Diagnose sepsis early and give antibiotics promptly to reduce mortality from sepsis

Antibiotics

ActionsBactericidal

Kills bacteria, reduces bacterial load

Bacteriostatic

Inhibit growth and reproduction of bacteria

All antibiotics require the immune system to work properly

Bactericidal appropriate in poor immunity

Bacteriostatic require intact immune system

ß-Lactams

Β-Lactam Ring

Thiazolidine Ring

ß-Lactams

ß-LactamsPenicillinNarrow Spectrum•Benzylpenicillin (Penicillin G)•Phenoxymethylpenicillin (Pen V)•Flucloxacillin Broad Spectrum•Amoxicillin/Co-amoxiclav•Ampicillin•Piperacillin with Tazobactam (Tazocin)

Cephalosporin•Cefalexin •Cefuroxime •Cefotaxime •Ceftriaxone

Carbapenem•Meropenem

•Imipenem

•Doripenem

•Ertapenem

Mechanisms of Action

• Anti Cell Wall Activity

• Bactericidal

Beta Lactams Against Bacterial Cell Wall

Cell wall

Osmotic Pressure

Antibiotic against cell wall

Osmotic Pressure

Cell membrane

Rupture

Cell Membrane

Spectrum of Activity

• Very wide

• Gram positive and negative bacteria

• Anaerobes

• Spectrum of activity depends on the agent and/or its group

Adverse Effects

Penicillin hypersensitivity – 0.4% to 10 %– Mild: rash – Severe: anaphylaxis & death

• There is cross-reactivity among all Penicillins

• Penicillins and cephalosporins ~5-15%

Resistance to ß-Lactams

•ß-Lactamase•Other mechanisms are of less importance

•Augmentin

Important PointsImportant Points

• Beta lactams need frequent dosing for successful therapeutic outcome– Missing doses will lead to treatment failure

• Beta lactams are the safest antibiotics in renal and hepatic failure– Adjustments to dose may still be required in

severe failure

Summary

• Cell wall antibiotics– Bactericidal

• Wide spectrum of use– Antibiotics of choice in many infections– Limitations

• Allergy• Resistance due to betalactamase

• Very safe in most cases– No monitoring required

Aminoglycosides Inhibit bacterial protein synthesis by irreversibly binding to 30S ribosomal unit

•Naturally occurring:

•Streptomycin

•Neomycin

•Kanamycin

•Tobramycin

•Gentamicin

•Semisynthetic derivatives:

•Amikacin (from Kanamycin)

•Netilmicin (from Sisomicin)

30S Ribosomal Unit Blockage by Aminoglycosides

•Causes mRNA decoding errors

Spectrum of Activity• Gram-Negative Aerobes

– Enterobacteriaceae;E. coli, Proteus sp., Enterobacter sp.

– Pseudomonas aeruginosa

• Gram-Positive Aerobes (Usually in combination with ß-lactams)S. aureus and coagulase-negative staphylococciViridans streptococciEnterococcus sp. (gentamicin)

Adverse Effects• Nephrotoxicity

– Direct proximal tubular damage - reversible if caught early– Risk factors: High troughs, prolonged duration of therapy,

underlying renal dysfunction, concomitant nephrotoxins

• Ototoxicity– 8th cranial nerve damage – irreversible vestibular and

auditory toxicity• Vestibular: dizziness, vertigo, ataxia• Auditory: tinnitus, decreased hearing

– Risk factors: as for nephrotoxicity

• Neuromuscular paralysis– Can occur after rapid IV infusion especially with;

• Myasthenia gravis• Concurrent use of succinylcholine during anaesthesia

Prevention of Toxicity

a) Levels need to be monitored to prevent toxicity due to high serum levels

b) To be avoided where risk factors for renal damage exist

1) Dehydration

2) Renal toxic drugs

Mechanisms of Resistance

• Inactivation by Aminoglycoside modifying enzymes– This is the most important mechanism

Important PointsImportant Points

• Aminoglycosides should be given as a large single dose for a successful therapeutic outcome– Multiple small doses will lead to treatment failure and likely

to lead to renal toxicity

• Aminoglycosides are toxic drugs and require monitoring– Avoid use in renal failure but safe in liver failure– Avoid concomitant use with other renal toxic drugs – Check renal clearance, frequency according to renal

function

Summary

• Restricted to aerobes• Toxic, needs level monitoring• Best used in Gram negative bloodstream

infections • Good for UTIs• Limited or no penetration

– Lungs– Joints and bone– CSF– Abscesses

Macrolides

Macrolides

Erythromycin Telithromycin

Clarithromycin

Lactone Ring

Azithromycin

15

14

14

14

Mechanism of Action

• Bacteriostatic- usually

• Inhibit bacterial RNA-dependent protein synthesis

– Bind reversibly to the 23S ribosomal RNA of the 50S ribosomal subunits• Block translocation reaction of the

polypeptide chain elongation

Spectrum of Activity

• Gram-Positive Aerobes: – Activity: Clarithromycin>Erythromycin>Azithromycin

• MSSA• S. pneumoniae• Beta haemolytic streptococci and viridans streptococci

• Gram-Negative Aerobes:– Activity: Azithromycin>Clarithromycin>Erythromycin• H. influenzae, M. catarrhalis, Neisseria sp.• NO activity against Enterobacteriaceae

• Anaerobes: upper airway anaerobes• Atypical Bacteria

Mechanisms of Resistance - Microlides

• Altered target sites– Methylation of ribosomes preventing antibiotic binding

• Cross-resistance occurs between all macrolides

Clinical Use

• Cellulitis/Skin and soft tissue– Beta haemolytic streptococci– Staphylococcus aureus

• Intra-cellular organisms– Chlamydia– Gonococcus

Summary• Bacteriostatic• ALL hepatic elimination• Gastrointestinal Sideeffects (up to 33 %)

(especially Erythromycin) • Nausea• Vomiting• Diarrhoea• Dyspepsia

• Best used in atypical pneumonia• Excellent tissue and cellular penetration

– Very useful in susceptible intracellular infections

Fluoroquinolones

Fluoroquinolones

Quinolone pharmacore

Mechanism of Action

• Prevent:• Relaxation of supercoiled DNA before

replication

• DNA recombination

• DNA repair

Spectrum of Activity

• Gram-positive

• Gram-Negative (Enterobacteriaceae H. influenzae, Neisseria sp. Pseudomonas aeruginosa)– Ciprofloxacin is most active

• Atypical bacteria: all have excellent activity

Summary

• Wide range of activity against Gram positive and negative bacteria.

• Sepsis from Intra-abdominal and Renal Sources– Coliforms (Gram negative bacilli)

• UTI– E. coli

• Very good tissue penetration• Excellent oral bioavailability• High risk for C.difficile

Tetracyclines

•Hydronaphthacene nucleus containing four fused rings

•Tetracycline

•Short acting

•Doxycycline

•Long acting

Mechanism of Action

• Inhibit protein synthesis• Bind reversibly to bacterial 30S ribosomal

subunits• Prevents polypeptide synthesis

• Bacteriostatic

Spectrum of Activity

• All have similar activities• Gram positives aerobic cocci and rods

– Staphylococci– Streptococci

• Gram negative aerobic bacteria

• Atypical organisms– Mycoplasmas– Chlamydiae– Rickettsiae– Protozoa

Adverse Effects

• Oesophageal ulceration

• Photosensitivity reaction

• Incorporate into foetal and children bone and teeth

Avoid in pregnancy and children

Summary

• Very good tissue penetration

• Use usually limited to;– Skin and soft tissue infections– Chlamydia

Glycopeptides

• Vancomycin

• Teicoplanin

Vancomycin

Mechanism of Action

• Inhibit peptidoglycan synthesis in the bacterial cell wall• Prevents cross linkage of peptidoglycan chains

Summary

• Large molecule

• Only active against Gram positive bacteria

• Second choice in all its uses except;– MRSA– C.difficile

Metronidazole

• Antibiotic

• Amoebicide

• Anti-protozoal– Trichomonas Vaginalis

Mechanisms of Action

• Molecular reduction– Nitroso intermediates– Sulfamides

• Melatbolised– Bacterial DNA de-stabilised

Spectrum of Activity & Uses

• Anaerobes – Bacterial Vaginosis– Pelvic Inflammatory Disease– C. Diff

Bio-Availability

• Oral

• Intra-venous– Expensive

• Rectal– Cheap

Summary

• Wide spectrum of activity

• Anaerobes

• In combination

Use of Pharmacokinetics in TreatmentBeta lactams

Good/variable (Dependant on individual antibiotic)

Soft tissue

Bone and joints

Lungs

CSF

Poor

Abscesses

Examples of good Tissue PenetratorsTetracyclinesMacrolidesQuinolonesClindamycin

AminoglycosidesGood

Circulating organisms

Poor

Soft tissue

Bone and joints

Abscesses

Lungs

CSF

Key Message 2Key Message 2

• When selecting an antibiotic consider the following;– Where is the infection?– Which antibiotics will reach the site of

infection

• Match the two and select your antibiotic

Key Message 3Key Message 3

• Always check the impact of an antibiotic on other drugs that a patient is on– Consult BNF or equivalent

PHEW!!!

Any Questions?

Chlamydia Trachomatis

• Obligate, intracellular bacterium• Rigid cell wall but NO peptidoglycan layer• Cervicitis• Slapingitis• Pelvic Inflammatory Disease• Neonate - mucopurulent conjunctivitis• Reiter's syndrome(urethritis, uveitis, arthritis)• Lymphogranuloma Venereum

Chlamydia Trachomatis

• Diagnosis– Giemsa stain

• Inclusion bodies in epithelial cells• Gram stain of no value

– ELISA - antigens in exudates or urine– Immunofouresence– PCR– Culture

Chlamydia Trachomatis• Life Cycle

Elementary BodyCell

ReticulateBody

Binary FissionDaughter

Elementary Bodies

Release from Cell

Chlamydia Trachomatis

• Treatment– Tetracyclines (Doxicycline)– Erythromycin– Azythromycin

PK/PD Principles in PK/PD Principles in Antibiotic Prescribing And Antibiotic Prescribing And

Prescribing in Organ FailurePrescribing in Organ FailureSAHD May 17, 2013SAHD May 17, 2013

Peter Gayo MunthaliPeter Gayo MunthaliConsultant MicrobiologistConsultant Microbiologist

UHCWUHCWHonorary Associate Clinical ProfessorHonorary Associate Clinical Professor

University of WarwickUniversity of Warwick

Pharmacokinetics - Beta-Lactams

• Absorption– PO forms have variable absorption– Food can delay rate and extent of absorption

• Distribution– Widely to tissues & fluids– CSF penetration:

IV – limited unless inflamed meninges

• Metabolism & Excretion– Primarily renal elimination– Some have a proportion of drug eliminated via the liver– ALL -lactams have short elimination half-lives

Clinical Use - Beta- Lactams

• Cellulitis/Skin and soft tissues• Commonest causes

– Beta haemolytic streptococci– Staphylococcus aureus

• Which Antibiotics?– Benzylpenicillin (Streptococci only)– Flucloxacillin (Staphylococcus aureus and streptococci)

• Other beta lactams can be used but spectrum too wide

Clinical Use - Beta- Lactams

• UTI– Commonest cause

• E. coli

– Which antibiotics• Cephalexin• Co-Amoxiclav

– Secondary choice, better non beta lactam alternatives exist» Nitrofurantoin» Trimethoprim

Clinical Use - Beta- Lactams

• Sepsis from Intra-abdominal and Renal Sources

• Commonest causes– Coliforms (Gram negative bacilli)

• Which antibiotics?– Co-Amoxiclav– Tazocin– Meropenem/imipenem/ertapenem (ESBL

suspected)

Pharmacokinetics - Aminoglycosides• All have similar pharmacologic properties• Gastrointestinal absorption: unpredictable but always

negligible• Distribution

– Hydrophilic: widely distributes into body fluids but very poorly into;• CSF• Vitreous fluid of the eye• Biliary tract• Prostate • Tracheobronchial secretions• Adipose tissue

• Elimination– 85-95% eliminated unchanged via kidney– t1/2 dependent on renal function– In normal renal function t1/2 is 2-3 hours

Clinical Use 1 - Aminoglycosides

• Sepsis from Intra-abdominal and Renal Sources

• Commonest causes– Coliforms (Gram negative bacilli)

• Which antibiotics?– Gentamicin/Amikacin (with beta lactam and or

metronidazole)

Clinical Use 2 - Aminoglycosides

• UTI• Very effective in UTI as 85-95% of the drug

is eliminated unchanged via kidney• Commonest cause

– E. coli– Which antibiotics

• Gentamicin– Secondary choice, better alternatives exist

» Nitrofurantoin» Trimethoprim» Beta lactams

Pharmacokinetics 1- Microlides• Erythromycin ( Oral: absorption 15% - 45%)• Short t1/2 (1.4 hr)

• Acid labile• Absorption (Oral)

– Erythromycin: variable absorption of 15% - 45%– Clarithromycin: 55%– Azithromycin: 38%

• Half Life (T1/2)– Erythromycin 1.4 Hours– Clarithromycin (250mg and 500mg 12hrly) 3-4 & 5-7 hours respectively– Azithromycin 68hours – Improved tolerability

• Excellent tissue and intracellular concentrations– Tissue levels can be 10-100 times higher than those in serum

• Poor penetration into brain and CSF• Cross the placenta and excreted in breast milk

Pharmacokinetics 2 - Microlides

• Metabolism & Elimination– ALL hepatic elimination

Adverse Effects - Microlides

• Gastrointestinal (up to 33 %) (especially Erythromycin) • Nausea• Vomiting• Diarrhoea• Dyspepsia

• Thrombophlebitis: IV Erythromycin & Azithromycin

• QTc prolongation, ventricular arrhythmias• Other: ototoxicity with high dose erythromycin in

renal impairment

Pharmacokinetics - Fuoroquinolones

• Absorption• Good bioavailability

• Oral bioavailability 60-95%

• Divalent and trivalent cations (Zinc, Iron, Calcium, Aluminum, Magnesium) and antacids reduce GI absorption

• Distribution• Extensive tissue distribution but poor CSF penetration

• Metabolism and Elimination• Combination of renal and hepatic routes

Adverse Effects - Fluoroquinolones

• Cardiac• Prolongation QTc interval• Assumed to be class effect

• Articular Damage• Cartilage damage

• Induced in animals with large doses

Resistance - Fluoroquinolones

• Altered target sites due to point mutations.• The more mutations, the higher the resistance

to Fluoroquinolones • Most important and most common

• Altered cell wall permeability • Efflux pumps • Cross-resistance occurs between

fluoroquinolones

Clinical Use 1- Fluoroquinolones

• Sepsis from Intra-abdominal and Renal Sources

• Commonest causes– Coliforms (Gram negative bacilli)

• Which antibiotics?– Ciprofloxacin

• High risk for C.difficile, safer alternatives should be used

Clinical Use 2 - Fluoroquinolones

• UTI– Commonest cause

• E. coli

– Which antibiotics• Ciprofloxacin

– High risk for C.difficile, safer alternatives should be used

Pharmacokinetics - Tetracyclines

• Incompletely absorbed from GI, improved by fasting

• Metabolised by the liver and concentrated in bile (3-5X higher than serum levels)

• Excretion primarily in the urine except doxycycline ( 60% biliary tract into faeces,40% in urine)

• Tissue penetration is excellent but poor CSF penetration– Incorporate into foetal and children bone and teeth

Resistance - Tetracyclines

• Efflux

• Alteration of ribosomal target site

• Production of drug modifying enzymes

Clinical Use - Tetracyclines

• Cellulitis/Skin and soft tissues/ Bone and Joint Infections

• Commonest causes– Beta haemolytic streptococci– Staphylococcus aureus

• Which Antibiotics?– Doxycycline

PharmacodynamicsPharmacodynamics

Drug Absorption CurveDrug Absorption Curve

Key Message 4&5Key Message 4&5• Aminoglycosides are toxic drugs and require monitoring

– Avoid use in renal failure but safe in liver failure– Avoid concomitant use with other renal toxic drugs – Check renal clearance, frequency according to renal function

• Beta lactams are the safest antibiotics in renal and hepatic failure– Adjustments to dose may still be required in severe failure