ANTI BIOTICS & ANTI BIOTICS & LACTAM LACTAM

ANTIBIOTICSANTIBIOTICS

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Antibiotic/Antibiotic/AntimicrobialAntimicrobial

AntibioticAntibiotic:: Chemical Chemical produced produced by a microorganismby a microorganism that kills or that kills or inhibits the growth of another inhibits the growth of another microorganism.microorganism.

Antimicrobial agentAntimicrobial agent:: Chemical Chemical that kills or inhibits the growth that kills or inhibits the growth of microorganismsof microorganisms

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MicrobiMicrobial al

Sources Sources of of

AntibiotAntibioticsics

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Antibiotic Antibiotic Spectrum of Spectrum of ActivityActivity

No antibiotic is effective against No antibiotic is effective against all microbesall microbes

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Mechanisms of Mechanisms of Antimicrobial Antimicrobial

ActionAction Bacteria have their own Bacteria have their own

enzymes forenzymes forCell wall formationCell wall formationProtein synthesisProtein synthesisDNA replicationDNA replicationRNA synthesisRNA synthesisSynthesis of essential Synthesis of essential

metabolitesmetaboliteswww.bpharmstuf.com

Mechanisms of Mechanisms of Antimicrobial ActionAntimicrobial Action

Viruses use host enzymes Viruses use host enzymes inside host cells.inside host cells.

Fungi and protozoa have Fungi and protozoa have own eukaryotic enzymes.own eukaryotic enzymes.

The more similar the The more similar the pathogen and host enzymes, pathogen and host enzymes, the more the more side effectsside effects the the antimicrobials will have.antimicrobials will have.

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Penicillin (over 50 compounds)Penicillin (over 50 compounds)Share 4-sided ring (Share 4-sided ring ( lactam lactam ring)ring)

Natural penicillinsNatural penicillinsNarrow range of actionNarrow range of actionSusceptible to Susceptible to penicillinase (penicillinase ( lactamase) lactamase)

Antibacterial AntibioticsAntibacterial Antibiotics Inhibitors of Cell Wall Inhibitors of Cell Wall

SynthesisSynthesis

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Modes of Antimicrobial Modes of Antimicrobial ActionAction

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Prokaryotic Cell WallsProkaryotic Cell Walls

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PenicilliPenicillinsns

Fig 20.6Fig 20.6

Figure 20.6www.bpharmstuf.com

Penicillinase (Penicillinase ( Lactamase)Lactamase)

Figure 20.8www.bpharmstuf.com

Penicilinase-resistant penicillinsPenicilinase-resistant penicillinsCarbapenems: very broad Carbapenems: very broad spectrumspectrum

Monobactam: Gram negativeMonobactam: Gram negative Extended-spectrum penicillinsExtended-spectrum penicillins Penicillins + Penicillins + -lactamase -lactamase

inhibitorsinhibitors

Semisynthetic Semisynthetic PenicillinsPenicillins

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Polypeptide antibioticsPolypeptide antibioticsBacitracinBacitracin

Topical applicationTopical applicationAgainst gram-positivesAgainst gram-positives

VancomycinVancomycinGlycopeptideGlycopeptideImportant "last line" against Important "last line" against antibiotic resistant antibiotic resistant S. aureusS. aureus

Other Inhibitors of Cell Other Inhibitors of Cell Wall SynthesisWall Synthesis

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Broad spectrum, toxicity Broad spectrum, toxicity problemsproblems

ExamplesExamplesChloramphenicol (bone marrow)Chloramphenicol (bone marrow)Aminoglycosides: Streptomycin, Aminoglycosides: Streptomycin,

neomycin, gentamycin (hearing, neomycin, gentamycin (hearing, kidneys)kidneys)

Tetracyclines (Rickettsias & Tetracyclines (Rickettsias & Chlamydia; GI tract)Chlamydia; GI tract)

Macrolides: Erythromycin (gram Macrolides: Erythromycin (gram +, used in children)+, used in children)

Inhibitors of Protein Inhibitors of Protein SynthesisSynthesis

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Polymyxin B (Gram negatives)Polymyxin B (Gram negatives)TopicalTopicalCombined with bacitracin and Combined with bacitracin and

neomycin (broad spectrum) in neomycin (broad spectrum) in over-the-counter preparationover-the-counter preparation

Injury to the Plasma Injury to the Plasma MembraneMembrane

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RifamycinRifamycin Inhibits RNA synthesisInhibits RNA synthesisAntituberculosisAntituberculosis

Quinolones and fluoroquinolonesQuinolones and fluoroquinolonesCiprofloxacinCiprofloxacin Inhibits DNA gyraseInhibits DNA gyraseUrinary tract infectionsUrinary tract infections

Inhibitors of Nucleic Acid Inhibitors of Nucleic Acid SynthesisSynthesis

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Sulfonamides (Sulfa drugs)Sulfonamides (Sulfa drugs)Inhibit folic acid synthesisInhibit folic acid synthesisBroad spectrumBroad spectrum

Competitive InhibitorsCompetitive Inhibitors

Figure 5.7www.bpharmstuf.com

Figure 20.20

Antibiotic ResistanceAntibiotic Resistance

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Antimicrobial Antimicrobial ResistanceResistance

Relative or complete lack of Relative or complete lack of effect of antimicrobial effect of antimicrobial against a against a previously previously susceptiblesusceptible microbe microbe

Increase in MICIncrease in MIC

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• Enzymatic destruction of drugEnzymatic destruction of drug• Prevention of penetration of Prevention of penetration of

drugdrug• Alteration of drug's target siteAlteration of drug's target site• Rapid ejection of the drugRapid ejection of the drug

Mechanisms of Mechanisms of Antibiotic ResistanceAntibiotic Resistance

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Antimicrobial peptidesAntimicrobial peptidesBroad spectrum antibiotics Broad spectrum antibiotics

from plants and animalsfrom plants and animalsSqualamine (sharks)Squalamine (sharks)Protegrin (pigs)Protegrin (pigs)Magainin (frogs)Magainin (frogs)

The Future of The Future of Chemotherapeutic Chemotherapeutic

AgentsAgents

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Antisense agentsAntisense agentsComplementary DNA or peptide Complementary DNA or peptide

nucleic acids that binds to a nucleic acids that binds to a pathogen's virulence gene(s) pathogen's virulence gene(s) and prevents transcriptionand prevents transcription

The Future of The Future of Chemotherapeutic Chemotherapeutic

AgentsAgents

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The Beta-Lactam The Beta-Lactam AntibioticsAntibiotics

Cell wall active agentsCell wall active agentsPrevent the final step in the Prevent the final step in the

synthesis of the bacterial cell synthesis of the bacterial cell wallwall

Range from very narrow Range from very narrow spectrum to very broad spectrumspectrum to very broad spectrum

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How do they work?How do they work?

1.1. The The ββ-lactam binds to Penicillin -lactam binds to Penicillin Binding Protein (PBP)Binding Protein (PBP)

2.2. PBP is unable to crosslink PBP is unable to crosslink peptidoglycan chainspeptidoglycan chains

3.3. The bacteria is unable to The bacteria is unable to synthesize a stable cell wallsynthesize a stable cell wall

4.4. The bacteria is lysedThe bacteria is lysed

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“Penicillin binding protein”

Peptidoglycan Synthesis

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PK/PDPK/PD

The The ββ-lactams are “time-dependent” -lactams are “time-dependent” killerskillersThe effect is directly proportional to The effect is directly proportional to

the amount of TIME the the amount of TIME the concentration of the antibiotic at the concentration of the antibiotic at the site of infection is ABOVE the MIC of site of infection is ABOVE the MIC of the organism.the organism.

The The ββ-lactams are -lactams are BACTERIOCIDALBACTERIOCIDAL… … (at therapeutically attainable levels) (at therapeutically attainable levels)

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““Time Dependant”Time Dependant”

H Derendorfwww.bpharmstuf.com

ClassificationClassification PenicillinsPenicillins

Natural penicillinsNatural penicillins PenG, PenVK, Benzathine Pen, Procaine PenG, PenVK, Benzathine Pen, Procaine

PenPen AminopenicillinsAminopenicillins

Ampicillin, AmoxicillinAmpicillin, Amoxicillin Anti-Staph penicillinsAnti-Staph penicillins

Oxacillin, DicloxacillinOxacillin, Dicloxacillin Anti-PseudomonalAnti-Pseudomonal

[Carboxy] Ticarcillin[Carboxy] Ticarcillin [Ureido] Piperacillin[Ureido] Piperacillin

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ClassificationClassification

CephalosporinsCephalosporins 11stst Generation Generation

Cephalexin, CefazolinCephalexin, Cefazolin 22ndnd Generation Generation

Cefoxitin, Cefuroxime, CefotetanCefoxitin, Cefuroxime, Cefotetan 33rdrd Generation Generation

Cefotaxime, Ceftriaxone, CeftazidimeCefotaxime, Ceftriaxone, Ceftazidime 44thth Generation Generation

CefepimeCefepimewww.bpharmstuf.com

The Cephalosporins The Cephalosporins (generalized)(generalized)

11stst Generation Generation Gram (+)Gram (+)

22ndnd Generation GenerationDecreasing Gram Decreasing Gram (+) and Increasing (+) and Increasing Gram (-)Gram (-)

33rdrd Generation Generation Gram (-), but also Gram (-), but also some GPCsome GPC

44thth Generation Generation Gram (+) and Gram (+) and Gram (-)Gram (-)

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Penicillin GPenicillin G Available PO, IM, IV Available PO, IM, IV (dosed in units)(dosed in units) Drug of Choice (DoC) Drug of Choice (DoC) [2-4 MU IV q4h][2-4 MU IV q4h]

T. pallidum, N. meningitidis, Group A Strep, and T. pallidum, N. meningitidis, Group A Strep, and ActinomycosisActinomycosis

Long-acting formsLong-acting forms Procaine PenG (12 hrs)Procaine PenG (12 hrs) Benzathine Pen (5 days) Benzathine Pen (5 days) [2.4 MU IM for [2.4 MU IM for

syphilis]syphilis] Adverse Reactions – other than skin rashAdverse Reactions – other than skin rash

Penicillin “serum sickness”/drug feverPenicillin “serum sickness”/drug fever Jarisch-Herxheimer reaction (1Jarisch-Herxheimer reaction (1° and 2° syphilis)° and 2° syphilis) Hemolytic anemia, pancytopenia, neutropeniaHemolytic anemia, pancytopenia, neutropenia

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Ampicillin/AmoxicillinAmpicillin/Amoxicillin Amp (IV, PO)Amp (IV, PO) Amox (PO)Amox (PO) Spectrum: PenG + H. flu and some E. coliSpectrum: PenG + H. flu and some E. coli DoC: Listeria monocytogenes and DoC: Listeria monocytogenes and Enterococcus Enterococcus [Amp 2g IV q4h][Amp 2g IV q4h] Dental ProphylaxisDental Prophylaxis

Amox 1 gram PO x 1 prior to appt.Amox 1 gram PO x 1 prior to appt. Integral in H. pylori regimensIntegral in H. pylori regimens ADRsADRs

Non-allergic rashes (9%) – esp. when associated Non-allergic rashes (9%) – esp. when associated with a viral illness (mononucleosis - EBV)with a viral illness (mononucleosis - EBV)

Amox better tolerated PO and better absorbed Amox better tolerated PO and better absorbed (Amp must be taken on empty stomach)(Amp must be taken on empty stomach)

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OxacillinOxacillin IVIV DoC – MSSA, MSSE DoC – MSSA, MSSE [2g IV q4h][2g IV q4h]

Actually less active against Pen susceptible Actually less active against Pen susceptible isolates than Penisolates than Pen

More active than Vanc vs. MSSAMore active than Vanc vs. MSSA Significant hepatic metabolismSignificant hepatic metabolism

No need to dose adjust for renal impairmentNo need to dose adjust for renal impairment ADRsADRs

Hepatotoxicity (cholestatic hepatitis)Hepatotoxicity (cholestatic hepatitis) NeutropeniaNeutropenia Kernicterus in neonatesKernicterus in neonates

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DicloxicillinDicloxicillin

OralOral NOT equivalent to IV Ox NOT equivalent to IV Ox

(therapeutically)(therapeutically)Poor oral absorptionPoor oral absorption~50% (better on empty ~50% (better on empty

stomach)stomach) Dose: 250-500mg po QIDDose: 250-500mg po QID

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PiperacillinPiperacillin IVIV DoC: PseudomonasDoC: Pseudomonas Spectrum: most Spectrum: most EnterobacteriaceaeEnterobacteriaceae (E. (E.

coli, Proteus, Klebsiella, Enterbacter, coli, Proteus, Klebsiella, Enterbacter, Serratia, Citrobacter, Salmonella and Serratia, Citrobacter, Salmonella and Shigella)Shigella)

Most active penicillin vs. PseudomonasMost active penicillin vs. Pseudomonas Often used in combination with Often used in combination with

Aminoglycoside or Cipro/LevofloxacinAminoglycoside or Cipro/Levofloxacin ADRsADRs

Bleeding (platelet dysfunction)Bleeding (platelet dysfunction) Neutropenia/ThrombocytopeniaNeutropenia/Thrombocytopenia

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SulbactamSulbactam UnasynUnasyn (Amp/Sulbactam) (Amp/Sulbactam) Spectrum: Amp + most anaerobes + Spectrum: Amp + most anaerobes +

many enteric Gm (-) rods, OSSAmany enteric Gm (-) rods, OSSA DoC: for GNR mixed infection – E.coli, DoC: for GNR mixed infection – E.coli,

Proteus, anaerobes when Pseudomonas is Proteus, anaerobes when Pseudomonas is not implicatednot implicated Diabetic foot (once Pseudomonas ruled Diabetic foot (once Pseudomonas ruled

out)out) Wound infectionsWound infections Sulbactam alone is very active against Sulbactam alone is very active against

Acinetobacter spp.Acinetobacter spp.www.bpharmstuf.com

TazobactamTazobactam

Zosyn (Pip/Tazo)Zosyn (Pip/Tazo) THE most broad-spectrum penicillinTHE most broad-spectrum penicillin Tazobactam may improve the Tazobactam may improve the

activity of piperacillin vs. gram-activity of piperacillin vs. gram-negative rods, including anaerobesnegative rods, including anaerobes

4.5g IV q8h = 3.375g IV q6h4.5g IV q8h = 3.375g IV q6h 4.5g IV q6h for Pseudomonas4.5g IV q6h for Pseudomonas

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Cephalexin/CefazolinCephalexin/Cefazolin PO/IVPO/IV Stable vs Staph penicillinaseStable vs Staph penicillinase Spectrum: MSSA, PSSP, most E. coli, and Spectrum: MSSA, PSSP, most E. coli, and

some Klebssome Klebs Can be dose thrice weekly in HD ptsCan be dose thrice weekly in HD pts

[1.5 grams IV TIW][1.5 grams IV TIW] DoC: surgical prophylaxis, bacterial peritonitis DoC: surgical prophylaxis, bacterial peritonitis

in CAPD pts in CAPD pts [1 gm in the dwell bag][1 gm in the dwell bag] ADRsADRs

Positive Coombs’ test (though, hemolytic Positive Coombs’ test (though, hemolytic anemia is rare)anemia is rare)

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CarbapenemsCarbapenems Resistance:Resistance:

Gram negative: usually combination of mechanisms Gram negative: usually combination of mechanisms (Carbapenemase production + decreased entry)(Carbapenemase production + decreased entry)

Imipenem Imipenem Decreased production of OprD (outer membrane Decreased production of OprD (outer membrane

protein for carbapenems)protein for carbapenems) Imipenem utilizes OprD > meropenem, ertapenemImipenem utilizes OprD > meropenem, ertapenem Pseudomonas, EnterobacterPseudomonas, Enterobacter Susceptible to efflux system in EnterobacterSusceptible to efflux system in Enterobacter

Meropenem: substrate for multi-drug efflux systemsMeropenem: substrate for multi-drug efflux systems May have increased MIC for meropenem but not May have increased MIC for meropenem but not

imipenemimipenem All: low affinity PBPsAll: low affinity PBPs

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MonobactamsMonobactams Monobactams: AztreonamMonobactams: Aztreonam Spectrum: ONLY Spectrum: ONLY Gram negative aerobic bacteria Gram negative aerobic bacteria Lack of Coverage: Lack of Coverage:

Some resistant P. aeruginosa, E. cloacae, and C. Some resistant P. aeruginosa, E. cloacae, and C. freundii freundii

Acinetobacter sp., Stenotrophomonas sp. Acinetobacter sp., Stenotrophomonas sp. Pharmacokinetics:Pharmacokinetics:

Well distributed into tissues, esp. inflamed tissuesWell distributed into tissues, esp. inflamed tissues Excretion: renal clearanceExcretion: renal clearance

Adverse reactions: Adverse reactions: Skin rash Skin rash No cross-reactivity with Beta-Lactam classNo cross-reactivity with Beta-Lactam class

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ReferencesReferences Holten KB, Onusko EM (August 2000). Holten KB, Onusko EM (August 2000).

"Appropriate prescribing of oral beta-lactam antibiotics". . American family American family physicianphysician 6262 (3): 611–20. (3): 611–20. PMID  10950216. . http://www.aafp.org/afp/20000801/611.html..

Britta Kasten und Britta Kasten und Ralf Reski (1997): β-lactam antibiotics inhibit chloroplast (1997): β-lactam antibiotics inhibit chloroplast division in a moss (division in a moss (Physcomitrella patens) but not in ) but not in tomato (Lycopersicon (Lycopersicon esculentum). esculentum). Journal of Journal of Plant Physiology 150, 137-140 150, 137-140 [1]

"Mayo Clinic Proceedings". . http://www.mayoclinicproceedings.com/inside.asp?AID=2547. Retrieved . Retrieved 2008-12-26.[2008-12-26.[dead link]]

aa bb cc Rossi S (Ed.) (2004). Rossi S (Ed.) (2004). Australian Medicines Handbook 2004Australian Medicines Handbook 2004. Adelaide: . Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.Australian Medicines Handbook. ISBN 0-9578521-4-2.

Pichichero ME (April 2005). "A review of evidence supporting the Pichichero ME (April 2005). "A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients". cephalosporin antibiotics for penicillin-allergic patients". PediatricsPediatrics 115115 (4): (4): 1048–57. doi:10.1542/peds.2004-1276. PMID 15805383. PMID 158053831048–57. doi:10.1542/peds.2004-1276. PMID 15805383. PMID 15805383

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CONCLUSIONCONCLUSION

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THANK YOU …. THANK YOU ….

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