ANTI BIOTICS &

LACTAM
ANTIBIOTICS

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 Antibiotic/Antimicrobial
 Antibiotic: Chemical produced by a
microorganism that kills or inhibits the
growth of another microorganism.

 Antimicrobial agent: Chemical that kills

or inhibits the growth of microorganisms

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Microbial
Sources of
Antibiotics

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Antibiotic Spectrum of Activity

 No antibiotic is effective against all

microbes
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 Mechanisms of
Antimicrobial Action
 Bacteria have their own enzymes for
 Cell wall formation
 Protein synthesis
 DNA replication
 RNA synthesis
 Synthesis of essential metabolites

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 Mechanisms of
Antimicrobial Action
 Viruses use host enzymes inside
host cells.
 Fungi and protozoa have own
eukaryotic enzymes.
 The more similar the pathogen and
host enzymes, the more side
effects the antimicrobials will
have.
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 Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
 Penicillin (over 50 compounds)

 Share 4-sided ring ( lactam ring)

 Natural penicillins

Narrow range of action

Susceptible to penicillinase (
lactamase) www.bpharmstuf.com
Modes of Antimicrobial Action

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Prokaryotic Cell Walls

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Penicillins
Fig 20.6

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Penicillinase ( Lactamase)

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Semisynthetic Penicillins

 Penicilinase-resistant penicillins
Carbapenems: very broad spectrum

Monobactam: Gram negative

 Extended-spectrum penicillins

 Penicillins + -lactamase inhibitors

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 Other Inhibitors of Cell Wall
Synthesis
 Polypeptide antibiotics
 Bacitracin

Topical application

Against gram-positives

 Vancomycin

Glycopeptide

Important "last line" against antibiotic

resistant S. aureus
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 Inhibitors of Protein Synthesis
 Broad spectrum, toxicity problems
 Examples

 Chloramphenicol (bone marrow)

 Aminoglycosides: Streptomycin,
neomycin, gentamycin (hearing, kidneys)
 Tetracyclines (Rickettsias & Chlamydia;
GI tract)
 Macrolides: Erythromycin (gram +, used
in children) www.bpharmstuf.com
 Injury to the Plasma Membrane

 Polymyxin B (Gram negatives)

 Topical

 Combined with bacitracin and neomycin

(broad spectrum) in over-the-counter
preparation

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Inhibitors of Nucleic Acid Synthesis
 Rifamycin
 Inhibits RNA synthesis

 Antituberculosis

 Quinolones and fluoroquinolones

 Ciprofloxacin

 Inhibits DNA gyrase

 Urinary tract infections

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 Competitive Inhibitors
 Sulfonamides (Sulfa drugs)

 Inhibit folic acid synthesis

 Broad spectrum

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Antibiotic Resistance

www.bpharmstuf.com Figure 20.20

 Antimicrobial Resistance
 Relative or complete lack of effect of
antimicrobial against a previously
susceptible microbe
 Increase in MIC

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 Mechanisms of Antibiotic
Resistance

• Enzymatic destruction of drug

• Prevention of penetration of drug
• Alteration of drug's target site
• Rapid ejection of the drug

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 The Future of
Chemotherapeutic Agents

 Antimicrobial peptides
 Broad spectrum antibiotics from
plants and animals
Squalamine (sharks)

Protegrin (pigs)

Magainin (frogs)

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 The Future of
Chemotherapeutic Agents

 Antisense agents
 Complementary DNA or peptide nucleic
acids that binds to a pathogen's virulence
gene(s) and prevents transcription

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 The Beta-Lactam Antibiotics

 Cell wall active agents

 Prevent the final step in the synthesis of
the bacterial cell wall
 Range from very narrow spectrum to very
broad spectrum

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 How do they work?
1. The β-lactam binds to Penicillin
Binding Protein (PBP)
2. PBP is unable to crosslink
peptidoglycan chains
3. The bacteria is unable to synthesize a
stable cell wall
4. The bacteria is lysed
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 Peptidoglycan Synthesis

“Penicillin binding
protein”

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 PK/PD
 The β-lactams are “time-dependent” killers
 The effect is directly proportional to the
amount of TIME the concentration of
the antibiotic at the site of infection is
ABOVE the MIC of the organism.
 The β-lactams are BACTERIOCIDAL…
(at therapeutically attainable levels)

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“Time Dependant”

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H Derendorf
 Classification
 Penicillins
 Natural penicillins
 PenG, PenVK, Benzathine Pen, Procaine Pen
 Aminopenicillins
 Ampicillin, Amoxicillin
 Anti-Staph penicillins
 Oxacillin, Dicloxacillin
 Anti-Pseudomonal
 [Carboxy] Ticarcillin
 [Ureido] Piperacillin

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 Classification
 Cephalosporins
 1st Generation

 Cephalexin, Cefazolin

 2nd Generation

 Cefoxitin, Cefuroxime, Cefotetan

 3rd Generation

 Cefotaxime, Ceftriaxone, Ceftazidime

 4th Generation

 Cefepime

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The Cephalosporins (generalized)

1st Generation Gram (+)

Decreasing Gram (+)

2 Generation
nd
and Increasing Gram (-)
Gram (-), but also some
3 Generation
rd
GPC

4th Generation Gram (+) and Gram (-)

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 Penicillin G
 Available PO, IM, IV (dosed in units)
 Drug of Choice (DoC) [2-4 MU IV q4h]
 T. pallidum, N. meningitidis, Group A Strep, and
Actinomycosis
 Long-acting forms
 Procaine PenG (12 hrs)
 Benzathine Pen (5 days) [2.4 MU IM for syphilis]
 Adverse Reactions – other than skin rash
 Penicillin “serum sickness”/drug fever
 Jarisch-Herxheimer reaction (1° and 2° syphilis)
 Hemolytic anemia, pancytopenia, neutropenia

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 Ampicillin/Amoxicillin
 Amp (IV, PO) Amox (PO)
 Spectrum: PenG + H. flu and some E. coli
 DoC: Listeria monocytogenes and
Enterococcus [Amp 2g IV q4h]
 Dental Prophylaxis
 Amox 1 gram PO x 1 prior to appt.
 Integral in H. pylori regimens
 ADRs
 Non-allergic rashes (9%) – esp. when associated with a viral
illness (mononucleosis - EBV)
 Amox better tolerated PO and better absorbed (Amp must be
taken on empty stomach)

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 Oxacillin
 IV
 DoC – MSSA, MSSE [2g IV q4h]
 Actually less active against Pen susceptible isolates than Pen
 More active than Vanc vs. MSSA
 Significant hepatic metabolism
 No need to dose adjust for renal impairment
 ADRs
 Hepatotoxicity (cholestatic hepatitis)
 Neutropenia
 Kernicterus in neonates

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 Dicloxicillin
 Oral
 NOT equivalent to IV Ox
(therapeutically)
 Poor oral absorption

 ~50% (better on empty stomach)

 Dose: 250-500mg po QID

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 Piperacillin
 IV
 DoC: Pseudomonas
 Spectrum: most Enterobacteriaceae (E. coli, Proteus,
Klebsiella, Enterbacter, Serratia, Citrobacter,
Salmonella and Shigella)
 Most active penicillin vs. Pseudomonas
 Often used in combination with Aminoglycoside or
Cipro/Levofloxacin
 ADRs
 Bleeding (platelet dysfunction)
 Neutropenia/Thrombocytopenia

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 Sulbactam
 Unasyn (Amp/Sulbactam)
 Spectrum: Amp + most anaerobes + many
enteric Gm (-) rods, OSSA
 DoC: for GNR mixed infection – E.coli, Proteus,
anaerobes when Pseudomonas is not implicated
 Diabetic foot (once Pseudomonas ruled out)
 Wound infections
 Sulbactam alone is very active against Acinetobacter
spp.

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 Tazobactam
 Zosyn (Pip/Tazo)
 THE most broad-spectrum penicillin
 Tazobactam may improve the activity of
piperacillin vs. gram-negative rods, including
anaerobes
 4.5g IV q8h = 3.375g IV q6h
 4.5g IV q6h for Pseudomonas

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 Cephalexin/Cefazolin
 PO/IV
 Stable vs Staph penicillinase
 Spectrum: MSSA, PSSP, most E. coli, and some Klebs
 Can be dose thrice weekly in HD pts
 [1.5 grams IV TIW]
 DoC: surgical prophylaxis, bacterial peritonitis in
CAPD pts [1 gm in the dwell bag]
 ADRs
 Positive Coombs’ test (though, hemolytic anemia is
rare)

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 Carbapenems
 Resistance:
 Gram negative: usually combination of mechanisms
(Carbapenemase production + decreased entry)
 Imipenem
 Decreased production of OprD (outer membrane protein for
carbapenems)
 Imipenem utilizes OprD > meropenem, ertapenem
 Pseudomonas, Enterobacter
 Susceptible to efflux system in Enterobacter
 Meropenem: substrate for multi-drug efflux systems
 May have increased MIC for meropenem but not imipenem
 All: low affinity PBPs

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 Monobactams
 Monobactams: Aztreonam
 Spectrum: ONLY  Gram negative aerobic bacteria
 Lack of Coverage:
 Some resistant P. aeruginosa, E. cloacae, and C. freundii
 Acinetobacter sp., Stenotrophomonas sp.
 Pharmacokinetics:
 Well distributed into tissues, esp. inflamed tissues
 Excretion: renal clearance
 Adverse reactions:
 Skin rash
 No cross-reactivity with Beta-Lactam class

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 References
 Holten KB, Onusko EM (August 2000).
"Appropriate prescribing of oral beta-lactam antibiotics" . American family
physician 62 (3): 611–20. PMID 10950216.
http://www.aafp.org/afp/20000801/611.html .
 Britta Kasten und Ralf Reski (1997): β-lactam antibiotics inhibit chloroplast
division in a moss (Physcomitrella patens) but not in tomato (Lycopersicon
esculentum). Journal of Plant Physiology 150, 137-140 [1]
 "Mayo Clinic Proceedings".
http://www.mayoclinicproceedings.com/inside.asp?AID=2547 . Retrieved
2008-12-26.[dead link]
 a b c Rossi S (Ed.) (2004). Australian Medicines Handbook 2004 . Adelaide:
Australian Medicines Handbook. ISBN 0-9578521-4-2.
 Pichichero ME (April 2005). "A review of evidence supporting the American
Academy of Pediatrics recommendation for prescribing cephalosporin
antibiotics for penicillin-allergic patients". Pediatrics 115 (4): 1048–57.
doi:10.1542/peds.2004-1276. PMID 15805383. PMID 15805383

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CONCLUSION

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 THANK YOU ….

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