Chapter 38 Antibiotics Part 1 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Antibiotics Part 1
-
Upload
bernadine-wolf -
Category
Documents
-
view
38 -
download
0
description
Transcript of Antibiotics Part 1
![Page 1: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/1.jpg)
Antibiotics Part 1
Dr P Gayo MunthaliConsultant Microbiologist UHCW
Honorary Associate Clinical ProfessorUniversity of Warwick
![Page 2: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/2.jpg)
Objectives• By the end of this lecture you should be able
to:1) Explain the mode of action of beta lactams,
aminoglycosides, fluoroquinolones, macrolides, tetracyclines and glycopeptides
2) Mention the major side effects of the antibiotic groups in (1)
3) Appreciate different types of resistance and in simple terms, explain the mechanisms of resistance to beta lactams
4) Explain some limitations in the use of antibiotics in (1)
5) Understand the general spectrum of activity of antibiotics in (1)
![Page 3: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/3.jpg)
Antibiotics, Point of Action
Cell membranePolymixin, bacitracin,colistin
Folic acid MetabolismTrimethoprim, Sulphonamides
Cell wall SynthesisBeta-lactams,GlycopeptidesDaptomycinFosfomycin
DNA ReplicationQuinolones
DNA Dependent RNA Pol. Rifampicin
Protein Synthesis 30S Tetracyclines,Aminoglycosides50S Chloramphenicol, Clindamycin,Erythromycin, Linezolid,Streptogramin
50S
30S
![Page 4: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/4.jpg)
Important mechanisms of resistance to antibiotics
Mechanism Typical example Antibiotics affectedInactivation ß-Lactamases ß-Lactams
Aminoglycoside modifying enzymes
Aminoglycosides
Changes in target binding
Changes in PBPs/Peptide Terminal
ß-Lactams/
GlycopeptidesRibosomal methylation Macrolides
DNA gyrase mutation Fluoroquinolones
Efflux and permeability changes
Efflux pumps Pump specific
Porin protein loss Most except polymyxins and aminoglycoside
![Page 5: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/5.jpg)
ß-Lactams
Β-Lactam Ring
Thiazolidine Ring
![Page 6: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/6.jpg)
Penicillins and Cephalosporins
s
o
R-CONH
N
COOHs
No
R-CONH
COOH
R
Penicillins 1940-
Cephalosporins 1948-
![Page 7: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/7.jpg)
Carbapenems and Others
S R
COOH
No
CHз
HO
oN
o
HO
COOH
Carbapenems 1976-
Clavulanic acid 1976
![Page 8: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/8.jpg)
Mobactams
No
R
R
R-CONHMonobactam 1981-
![Page 9: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/9.jpg)
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
![Page 10: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/10.jpg)
Beta Lactams Against Bacterial Cell Wall
Cell wall
Osmotic Pressure
Antibiotic against cell wall
Osmotic Pressure
Cell membrane
Rapture
Cell Membrane
![Page 11: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/11.jpg)
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
![Page 12: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/12.jpg)
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
![Page 13: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/13.jpg)
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
![Page 14: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/14.jpg)
Resistance to ß-Lactams
•Penicillin-Binding Protein (PBP) mediated Resistance
•ß-Lactamase
•Efflux pumps/loss of porins
![Page 15: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/15.jpg)
• PBP over expression
• Acquisition of Foreign PBPs genes
• Mutation by recombination with foreign DNA
• Point mutation
Penicillin-Binding Protein (PBP) mediated Resistance
![Page 16: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/16.jpg)
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 that over express PBP5 have
increased resistance to penicillin.
AAC 39:2415-2422, AAC 38:1980-1983, AAC 45: 1480-1486
![Page 17: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/17.jpg)
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
![Page 18: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/18.jpg)
Result
• All PBPs in S.aureus become redundant
–MRSA is resistant to all ß-lactams
![Page 19: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/19.jpg)
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
![Page 20: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/20.jpg)
Beta Lactam Activity Against 100 Penicillin Resistant Pneumococci from Spain
0
1
2
3
4
5
6
7
8
9
MIC
90
Ag
ain
st
10
0 Is
ola
tes
/BS
AC
MIC
90
R
es
ista
nc
e B
rea
kp
oin
ts
Series1Series2Series3
JAC 1992,30(3);279-288
MIC for meningitis
Isolate
BSAC
MICs
![Page 21: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/21.jpg)
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
![Page 22: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/22.jpg)
Overexpressed Efflux pumps
Porins
Porins and Pumps
Adapted from Journal of Bacteriology, April 2006, p. 2297-2299, Vol. 188, No. 7
![Page 23: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/23.jpg)
Resistance due to ß-Lactamases
• Mode of action– Classification
![Page 24: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/24.jpg)
ß-Lactamase
ß -pleated sheet-5
ά-helices
AAC 39:2593-2601
![Page 25: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/25.jpg)
Bound ß-lactam by ß-Lactamase
![Page 26: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/26.jpg)
ß-Lactamases-action
s
o
R-CONH
N
COOH
No
R-CONH
COOH
CH3
CH3
Enzyme-Ser-OH
C
C
O
Ser
sCH3
CH3
HEnzyme
HOH
Annu.Rev.Microbiol.45:37-67
![Page 27: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/27.jpg)
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
![Page 28: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/28.jpg)
Simple ß-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
![Page 29: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/29.jpg)
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
![Page 30: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/30.jpg)
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
![Page 31: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/31.jpg)
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
![Page 32: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/32.jpg)
AmpC ß-Lactamases
• Produced by almost all gram-negative bacteria
• Chrosomally encoded versions important in Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Pseudomonas aeruginosa and Serratia marcescens (not found in Salmonella and Klebsiella)
• AmpC ß-Lactamase genes have been found on transferable plasmids
![Page 33: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/33.jpg)
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
![Page 34: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/34.jpg)
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
![Page 35: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/35.jpg)
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)
![Page 36: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/36.jpg)
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
![Page 37: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/37.jpg)
Spectrum of Activity• Gram-Negative Aerobes
– Enterobacteriaceae;E. coli, K. pneumoniae, Proteus sp.Citrobacter, Enterobacter sp.Morganella, Providencia, Serratia
– Pseudomonas aeruginosa– Acinetobacter
• Gram-Positive Aerobes (Usually in combination with ß-lactams)S. aureus and coagulase-negative staphylococciViridans streptococciEnterococcus sp. (gentamicin)
![Page 38: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/38.jpg)
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
![Page 39: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/39.jpg)
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
![Page 40: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/40.jpg)
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
![Page 41: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/41.jpg)
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
![Page 42: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/42.jpg)
Macrolides
Erythromycin Telithromycin
Clarithromycin
Lactone Ring
Azithromycin
15
14
14
14
![Page 43: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/43.jpg)
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
![Page 44: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/44.jpg)
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
![Page 45: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/45.jpg)
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
![Page 46: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/46.jpg)
Pharmacokinetics 2
• Metabolism & Elimination– Clarithromycin partially eliminated by the
kidney– ALL hepatic elimination
![Page 47: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/47.jpg)
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
![Page 48: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/48.jpg)
Fluoroquinolones
Quinolone pharmacore
![Page 49: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/49.jpg)
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
![Page 50: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/50.jpg)
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
![Page 51: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/51.jpg)
![Page 52: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/52.jpg)
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
![Page 53: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/53.jpg)
Spectrum of Activity
• Gram-positive (MSSA Streptococcus pneumoniae )– Moxifloxacin is most active
• Gram-Negative (Enterobacteriaceae H. influenzae, M. catarrhalis, Neisseria sp. Pseudomonas aeruginosa)– Ciprofloxacin is most active
• Atypical bacteria: all have excellent activity
![Page 54: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/54.jpg)
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
![Page 55: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/55.jpg)
Adverse Effects
• Cardiac• Prolongation QTc interval• Assumed to be class effect
• Articular Damage• Cartilage damage
• Induced in animals with large doses
![Page 56: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/56.jpg)
Tetracyclines
•Hydronaphthacene nucleus containing four fused rings
•Tetracycline
•Short acting
•Doxycycline
•Long acting
![Page 57: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/57.jpg)
Mechanism of Action
• Inhibit protein synthesis• Bind reversibly to bacterial 30S ribosomal subunits
• Prevents polypeptide synthesis
• Bacteriostatic
![Page 58: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/58.jpg)
Resistance
• Efflux
• Alteration of ribosomal target site
• Production of drug modifying enzymes
![Page 59: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/59.jpg)
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
![Page 60: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/60.jpg)
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
![Page 61: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/61.jpg)
Adverse Effects
• Oesophageal ulceration
• Photosensitivity reaction
![Page 62: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/62.jpg)
Glycopeptides
• Vancomycin
• Teicoplanin
Vancomycin
![Page 63: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/63.jpg)
Mechanism of Action
• Inhibit peptidoglycan synthesis in the bacterial cell wall• Complex with D-alanyl-D-alanine portion of the cell
wall precursor
![Page 64: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/64.jpg)
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
![Page 65: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/65.jpg)
Spectrum of Activity
• Gram positive bacteria only including MRSA
![Page 66: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/66.jpg)
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
![Page 67: Antibiotics Part 1](https://reader036.fdocuments.net/reader036/viewer/2022062517/568135e4550346895d9d589f/html5/thumbnails/67.jpg)
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