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Antibiotics Part 1. Dr P Gayo Munthali Consultant Microbiologist UHCW Honorary Associate Clinical Professor University of Warwick. Objectives. By the end of this lecture you should be able to:

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Antibiotics part 1

Antibiotics Part 1

Dr P Gayo Munthali

Consultant Microbiologist UHCW

Honorary Associate Clinical Professor

University of Warwick


Objectives
Objectives

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

    • Explain the mode of action of beta lactams, aminoglycosides, fluoroquinolones, macrolides, tetracyclines and glycopeptides

    • Mention the major side effects of the antibiotic groups in (1)

    • Appreciate different types of resistance and in simple terms, explain the mechanisms of resistance to beta lactams

    • Explain some limitations in the use of antibiotics in (1)

    • Understand the general spectrum of activity of antibiotics in (1)


Antibiotics point of action
Antibiotics, Point of Action

Folic acid Metabolism

Trimethoprim, Sulphonamides

Cell membrane

Polymixin, bacitracin,colistin

Cell wall Synthesis

Beta-lactams,

Glycopeptides

Daptomycin

Fosfomycin

50S

30S

DNA Replication

Quinolones

DNA Dependent RNA Pol. Rifampicin

Protein Synthesis

30S Tetracyclines,Aminoglycosides

50SChloramphenicol, Clindamycin,

Erythromycin, Linezolid,Streptogramin



Lactams
ß-Lactams

Β-Lactam Ring

Thiazolidine Ring


Penicillins and cephalosporins
Penicillins and Cephalosporins

s

R-CONH

Penicillins 1940-

N

o

COOH

R-CONH

s

R

N

Cephalosporins 1948-

o

COOH


Carbapenems and others
Carbapenems and Others

CHз

Carbapenems 1976-

R

HO

S

HO

N

o

o

COOH

N

o

COOH

Clavulanic acid 1976


Mobactams
Mobactams

R

Monobactam 1981-

R-CONH

N

o

R


Mechanisms of action
Mechanisms of Action

  • Inhibit bacterial enzymes involved in cell wall synthesis

    • Penicillin binding proteins (PBPs) essential for peptidoglycan synthesis

  • Trigger membrane associated autolytic enzymes that destroy cell wall

  • Inhibit bacterial endopeptidase and glycosidase enzymes which are involved in cell wall growth

  • Time dependent activity


Beta Lactams Against Bacterial Cell Wall

Cell wall

Osmotic Pressure

Cell Membrane

Antibiotic against cell wall

Osmotic Pressure

Cell membrane

Rapture


Spectrum of activity
Spectrum of Activity

  • Very wide

  • Gram positive and negative bacteria

  • Anaerobes

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

  • Aztreonam only active against gram negatives


Pharmacokinetics
Pharmacokinetics

  • 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

      IV 3rd & 4th generation cephalosporins, meropenem, &

      Aztreonam – penetrate well

  • Metabolism & Excretion

    • Primarily renal elimination

    • Some have a proportion of drug eliminated via the liver

    • ALL -lactams have short elimination half-lives


Adverse effects
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%

  • Penicillins and carbapenems~1% (may be higher)

    • Desensitization is possible for mild hypersensitivity

  • Aztreonam does not display cross-reactivity with Penicillins and can be used in penicillin-allergic patients


  • Resistance to lactams
    Resistance to ß-Lactams

    • Penicillin-Binding Protein (PBP) mediated Resistance

    • ß-Lactamase

    • Efflux pumps/loss of porins


    Penicillin-Binding Protein (PBP) mediated Resistance

    • PBP over expression

    • Acquisition of Foreign PBPs genes

    • Mutation by recombination with foreign DNA

    • Point mutation


    Pbp over expression
    PBP over expression

    • Rare

      • The more PBPs are expressed, the more an organism becomes resistant

        • S.aureus increased resistance to methicillin by over expression of PBP4

        • E.faecium strains thatover express PBP5 have increased resistance to penicillin.

    AAC 39:2415-2422, AAC 38:1980-1983, AAC 45: 1480-1486


    Acquisition of foreign pbps
    Acquisition of Foreign PBPs

    • Represented best by Methicillin Resistant S.aureus (MRSA)

    • S.aureus acquires foreign PBP2a encoded by mecA gene

    • PBP2a has low affinity for all ß-lactams

    • PBP2a can perform all the combined functions of all the S. aureus PBPs

    • Almost all MRSAs express ß-Lactamase

    Clin. Microbiol. Rev.10:781-791, J.Infect.Dis.162:705-710


    Result
    Result

    • All PBPs in S.aureus become redundant

      • MRSA is resistant to all ß-lactams


    Mutation by recombination with foreign dna
    Mutation by Recombination with Foreign DNA

    • Streptococcus pneumoniae and Neisseria are capable of picking up foreign DNA and integrating it with their own DNA

      • Form mosaic gene

    • Pneumococcus picks up resistant genes from alpha haemolytic streps

      • Reduced affinity to beta lactams

        • Seen as penicillin resistant Pneumococci


    MICs

    Isolate

    MIC for meningitis

    BSAC

    JAC 1992,30(3);279-288


    Efflux pumps loss of porins
    Efflux pumps/Loss of Porins

    • Important type of resistance in Pseudomonas

      • A combination of ß-Lactamase production and porin loss can lead to complex resistance pattern

        • Can lead to carbapenem resistance without carbapenemase production


    Porins and Pumps

    Porins

    Overexpressed Efflux pumps

    Adapted from Journal of Bacteriology, April 2006, p. 2297-2299, Vol. 188, No. 7


    Resistance due to lactamases
    Resistance due to ß-Lactamases

    • Mode of action

      • Classification


    Lactamase
    ß-Lactamase

    ß -pleated sheet-5

    ά-helices

    AAC 39:2593-2601



    Lactamases action
    ß-Lactamases-action

    R-CONH

    s

    CH3

    C

    N

    CH3

    o

    COOH

    Enzyme-Ser-OH

    s

    R-CONH

    CH3

    o

    N

    C

    CH3

    HOH

    O

    H

    COOH

    Enzyme

    Ser

    Annu.Rev.Microbiol.45:37-67


    Beta lactam classification
    Beta Lactam Classification

    • You do not need to know the classification or detailed information on ß-Lactamases

    • However you need to appreciate the following concepts;

      • Simple betalactamases

      • Extended spectrum betalactamases (ESBL)

      • Betalactamases against the Carbapenems


    Simple lactamases
    Simpleß-Lactamases

    • Many Based on genes called TEM-1 and SHV-1 found on mobile DNA elements

      • TEM-1 and SHV-1 are simple penicillinases in Enterobacteriaceae

      • Inactive against cephalosporins

      • Confer resistance to Penicillins such as Benzylpenicillin and amoxicillin

      • On mobile elements and therefore transmissible

    • Staphylococci also produce simple beta lactamases not based on TEM-1 and SHV-1

      • Flucloxacillin designed to resist betalactamases in Staphylococcus aureus

    AAC 33:1131-1136


    Extended spectrum lactamases
    Extended Spectrum ß-lactamases

    • Based on TEM-1 and SHV-1

    • Amino acid mutations in active site progressively increase their activity against cephalosporins

      • When they hydrolyze extended-spectrum cephalosporins

        • They are then called ESBLs

      • Also attack a monobactam Aztreonam

        -On mobile elements thus transmissible

      • Carry other resistance genes, Gentamicin, Ciprofloxacin


    Esbls
    ESBLs

    • Hydrolyze extended-spectrum cephalosporins with an oxyimino side chain

    • These include;

      • Cefotaxime

      • Ceftazidime

      • Ceftriaxone

    • Loose term

    • Among the beta-lactam, only the Carbapenems are stable against ESBLs

      • Imipenem, Meropenem, Ertapenem and Doripenem are in clinical use


    Characteristics of esbls
    Characteristics of ESBLs

    • May appear sensitive to some cephalosporins and combinations of piperacillin and tazobactam as well as amoxicillin and clavulanic acid

      • However, use of these ß-lactam agents will lead to microbiological and clinical failure

      • Only carbapenems among the ß-lactams can be used successfully


    Ampc lactamases
    AmpC ß-Lactamases

    • Produced by almost all gram-negative bacteria

    • Chrosomally encoded versions important inCitrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Pseudomonas aeruginosa and Serratia marcescens (notfound in Salmonella and Klebsiella)

    • AmpCß-Lactamase genes have been found on transferable plasmids


    Class c lactamases
    Class C ß-Lactamases

    • All ß- lactams induce AmpC ß-lactamase production

      • Only carbapenems are resistant to AmpC ß-lactamases

        • If there is loss of porins as well, this will lead to carbapenem resistance

      • Other ß- lactams will be hydrolysed


    Metallo lactamases
    Metallo-ß-Lactamases

    • Require Zinc or other heavy metal for activity

    • Hydrolyse all ß-Lactams including carbapenems

    • Most will be associated with resistance to many antibiotic classes

    • Currently New Delhi Metallo-ß-Lactamase (NDM-1) is a new flavour in the UK

      • Associated with India

      • Resistant to almost all antibiotics in use in the UK


    Aminoglycosides
    Aminoglycosides

    • Highly positively charged compounds, concentration dependent activity

    • 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

    • Block mRNA and transfer RNA translocation

    • Inhibit ribosome recycling

      • Ribosome recycling follows the termination of protein synthesis


    Spectrum of activity1
    Spectrum of Activity

    • Gram-Negative Aerobes

      • Enterobacteriaceae;

        E. coli, K. pneumoniae, Proteussp.

        Citrobacter, Enterobactersp.

        Morganella, Providencia, Serratia

      • Pseudomonas aeruginosa

      • Acinetobacter

    • Gram-Positive Aerobes(Usually in combination with ß-lactams)

      S. aureus and coagulase-negative staphylococci

      Viridans streptococci

      Enterococcussp. (gentamicin)


    Mechanisms of resistance
    Mechanisms of Resistance

    • Ribosome changes

      • Prevents binding

    • Loss of cell permeability

    • Expulsion by efflux pumps

    • Enzyme inactivation by Aminoglycoside modifying enzymes

      • This is the most important mechanism


    Pharmacokinetics1
    Pharmacokinetics

    • 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


    Adverse effects1
    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


    Macrolides
    Macrolides

    • Erythromycin is the prototype antibiotic for this group

    • 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


    Macrolides1
    Macrolides

    Lactone Ring

    14

    14

    Erythromycin

    Telithromycin

    14

    15

    Clarithromycin

    Azithromycin


    Mechanisms of resistance1
    Mechanisms of Resistance

    • Altered target sites

      • Methylation of ribosomes preventing antibiotic binding

        • Resistance to macrolides , lincosamides (Clindamycin) and streptogramin B

        • Can be induced by macrolides

    • Efflux pumps

      • Resistance to macrolides only

    • Cross-resistance occurs between all macrolides


    Spectrum of activity2
    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 any Enterobacteriaceae

    • Anaerobes: upper airway anaerobes

    • Atypical Bacteria

    • Other Bacteria: Mycobacterium avium complex


    Pharmacokinetics 1
    Pharmacokinetics 1

    • 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
    Pharmacokinetics 2

    • Metabolism & Elimination

      • Clarithromycin partially eliminated by the kidney

      • ALL hepatic elimination


    Adverse effects2
    Adverse Effects

    • 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


    Fluoroquinolones

    Quinolone pharmacore


    Fluoroquinolones
    Fluoroquinolones

    • Synthetic antibiotics

      • Concentration-dependent bactericidal activity

      • Broad spectrum of activity

      • Excellent pharmacokinetics

        • bioavailability, tissue penetration, prolonged half-lives

      • In common use

        • Ciprofloxacin

        • Levofloxacin

        • Moxifloxacin


    Mechanism of action
    Mechanism of Action

    • Inhibit bacterial topoisomerases which is used by bacteria to;

      • Relax supercoiled DNA before replication

      • DNA recombination

      • DNA repair

    • DNA gyrase – Primary target for gram-negatives

    • Topoisomerase IV – Primary target for gram-positives


    Resistance
    Resistance

    • 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


    Spectrum of activity3
    Spectrum of Activity

    • Gram-positive (MSSA Streptococcus pneumoniae )

      • Moxifloxacin is most active

    • Gram-Negative (EnterobacteriaceaeH. influenzae, M. catarrhalis, Neisseria sp. Pseudomonas aeruginosa)

      • Ciprofloxacin is most active

    • Atypical bacteria: all have excellent activity


    Pharmacokinetics2
    Pharmacokinetics

    • 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 effects3
    Adverse Effects

    • Cardiac

      • Prolongation QTc interval

      • Assumed to be class effect

    • Articular Damage

      • Cartilage damage

      • Induced in animals with large doses


    Tetracyclines
    Tetracyclines

    • Hydronaphthacene nucleus containing four fused rings

    • Tetracycline

      • Short acting

    • Doxycycline

      • Long acting


    Mechanism of action1
    Mechanism of Action

    • Inhibit protein synthesis

      • Bind reversibly to bacterial 30S ribosomal subunits

        • Prevents polypeptide synthesis

    • Bacteriostatic


    Resistance1
    Resistance

    • Efflux

    • Alteration of ribosomal target site

    • Production of drug modifying enzymes


    Spectrum of activity4
    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


    Pharmacokinetics3
    Pharmacokinetics

    • 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

    Avoid in pregnancy and children


    Adverse effects4
    Adverse Effects

    • Oesophageal ulceration

    • Photosensitivity reaction


    Glycopeptides
    Glycopeptides

    Vancomycin

    Teicoplanin

    Vancomycin


    Mechanism of action2
    Mechanism of Action

    • Inhibit peptidoglycan synthesis in the bacterial cell wall

      • Complex with D-alanyl-D-alanine portion of the cell wall precursor


    Resistance2
    Resistance

    • Modification of D-alanyl-D-alanine binding site of peptidoglycan

      • D-alanyl-D-alanine terminal then ends in D-alanyl-D-lactate

        • Leads to lower glycopeptide affinity

    • Complex reactions to achieve this


    Spectrum of activity5
    Spectrum of Activity

    • Gram positive bacteria only including MRSA


    Pharmacokinetics4
    Pharmacokinetics

    • Absorption

      • oral is negligible

      • IV required therapy for systemic infections

    • Distribution

      • Distributes widely into body tissues and fluids, including adipose tissue

      • Variable penetration into CSF, even with inflamed meninges

    • Elimination

      • Primarily eliminated unchanged by the kidney


    Adverse effects5
    Adverse Effects

    • Red-Man Syndrome

      • Erythema multiforme-like reaction with intense pruritus, tachycardia, hypotension, rash involving face, neck, upper trunk, back and upper arms

        • Related to infusion rate

        • Resolves spontaneously after discontinuation

        • Lengthen infusion (over 2 - 3 hr)

    • Hematological

      • Neutropaenia

      • Eosinophilia


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