Beta lactams 1/2

• thiazolidine ring + b-lactam ring + side chain

• side chain - influences pharmacokinetics, antibacterial, affinity for PBP, enhance ability of drugs to pass outer membrane

• not active against plasmodia, rickettsiae, funghi, viruses

penicillin structure

• penicllin g

• unstable in acid - oral absorption varies

• benzathine penicllin - releases penicllin G slowly in injection

• enter CSF if meninges are inflammed

• wide distrubution - kidneys, liver lymph

• active transport out of csf is reduced with probenacid

• eliminated by kidneys

• IV

benzylpenicillin

• sodium levels must be tested

• bacterical endocarditis

• meningitis

• aspiration pneumonia

• syphilis - can cause Jarisch-Herxheimer reaction - Fever, chills, headache, hypotension and flare-up of lesions lasting for 12– 24 hours - due to pyrogenes after treating syphilis

benzylpenicillin indications

• more stable in acid - better absorption

• 2-5 higher plasm conc than Pcg

• food reduces absorption

• max plasma conc - 30-60 mins

• oral

phenoxymethylpenicillin

• s pygogenes tonsilitis pharyngitis, skin infections

• rhematic fever prevention

• moderate to severe gingivitis

phenoxymethylpenicillin indications

• same antimicrobial action as penicllin G

• deep IM

• absorbed in circulation and hydrolysed to benzylpenicillin up to 4 weeks - used when appropriate

benzathine benzylpenicillin

• treatment and prevention of rhemuatic fever

• for infections susceptible to prolonged conc of benzylpenicllin

benzathine benzylpenicillin indications

• highly resistant to cleavage by penicillinase

• prepared from 6-APA

• resistant to all beta lactam

methicillin

• side chain modified to become pencillinase and resistant acid

Isoxazolyl penicillins

• resistant to beta lactamase

• useful for s.pneumonia s.pyogenes with pencillin-resistant staphylocci

• inactive against E.faecalis

• better absorbed than cloxacillin

• decrease absorption due to food

• take 30 mins - 2 hrs before food

• oral or iv

• reduce dose - if renal impairment

Dicloxacillin/flucloxacillin

• Pneumonia

   Osteomyelitis, septic arthritis

   Septicaemia

   Empirical Tx for endocarditis

   Staphylococcal skin infections 

Narrow specturm Penicillins With

Antistaphylococcal Activity indications

• biochemical precursors are added to a culture to incorporate side chains

• very limited side chains used

• e.g. phenoxymethylpencillin - precursor - phenoxyacetic acid

natural penicllins

• 6-aminopencillanic acid - no limit of semi-synthetic penicllins

• semi-synthetic penicllin - produced by hydrolsying PcG using microbial amidase enzyme

penicillin nucleus

• similar structure

• bacterial transpeptidase gets confused and binds to penicillin

• once bound permenant chemical bond actylation - weakens bacterium cell wall

penicillin and d-alanyl d-alanine

• bactericidal

• inhibiting development of functional cell wall - affecting peptioglycan cell wall

• peptioglycan cell wall - has NAM and NAG

• inhibits transpeptidase - catalyse formation of cross-bridge between peptioglycan polymer strands affecting stength of cell wall

• disinhibition of autolysisn - cleav bonds in cell wall

mode of action of penicillin

• transpeptidases and autolysins

• enzymes anchored in the cytoplasmic membrane and periplasmic space

• responsible for assembly, maintence, regulation of peptidoglycan portion of bacterial cell wall

• some bacteria have transpeptidase( strength bacteria cell wall) others have transglycosylase (build or break sugar chains) and carboxypeptidase (enzyme breakdown of proteins and peptides)

• each bacteria have unique PBP

• each have different afffinity for b lactams

Penicillin binding proteins

• crosslinking amino acids and side chains

• glyostyltransferase links subunits of glycopeptide polymer - partially embedded in membrane

• linked

transpeptidase and glyostyltransferase

• similar for aerobic and anaerobic gram postivie

• strepcocci susceptible

• staphylocci and nesseria

• aureus, epidermidis, gnocci, bacterioids fragilis - resistant

• P. multiocida, L monocytogenes - inhibited by achieveable conc

specturm of activity for PcG and PcV

Benzylpenicillin (PcG)

 Benzathine penicillin

 Phenoxymethylpenicillin (PcV)

Narrow spectrum penicillins:

• Dicloxacillin & flucloxacillin

Narrow spectrum penicillins with antistaphylococcal activity

• Ampicillin

   Amoxicillin

• bactercidial - gram + and gram - Listeria, S,pyogenes, S. pneumonia

• resistant to pseudomonas, klebisella, serratia, acineobacter

• inactived by beta lactamase producing bacteria

• beta lactamase acts as virulence factor

• when administered iv - equivalent

• check for sodium levels

Moderate specturm

• Amoxicillin with clavulanic acid

   Piperacillin with tazobactam

• Combination therapy should only be used if the bacteria's resistance comes from an enzyme (beta-lactamase) that the inhibitor can actually block.

Broad specturm

• acid stable - well absorbed

• 20% protein bound

• excreted by urine

• probenecid - delays excretion

Ampicillin

• bactericidal

• superior oral absorption

• acid stable

• not interfered with food

• 20% protein bound

• peak plasma conc 2x - higher than ampicillin

Amoxicillin

• b - lactamase catalyses hydrolysis of b-lacatam ring

• split amide bond converts pencillin to pencilloic acid (not antibacterial)

• no cell wall synthesis inhibition

destruction of antibiotics via b-lactamases - resistance

• Acute otitis media

   Sinusitis

• Eradication of H. pylori

indications for amoxicillin

• Exacerbation of chronic bronchitis

   Community-acquired pneumonia

• Epididymo-orchitis

   Acute prostatitis

   Acute pyelonephritis

   Endocarditis prophylaxis in high-risk

indications for ampicillin

-extends its spectrum of activity to cover many

beta-lactamase producing G+ve & G-ve mo,

including G-ve anaerobes

addition of clavuanic acid

• Retains the baseline antibacterial activity of amoxicillin.

• Extends activity to beta-lactamase–producing organisms due to the addition of clavulanic acid

• Staphylococcus aureus (note: not MRSA).

• Gram-negative micro-organisms (G-ve mo): e.g., Haemophilus influenzae, Escherichia coli, Klebsiella spp., etc.

• Gram-negative anaerobes: e.g., Bacteroides fragilis.

amoxicillin + clavanic acid

• Hospital-acquired pneumonia

• Epididymo-orchitis (urinary tract source)

• Pelvic inflammatory disease (PID) (not sexually acquired)

• Urinary tract infections (UTI)

• Animal/human bites and clenched fist injuries

Indications of amoxicillin with clavulanic

acid

• Piperacillin

• Caused severe SE

   Interfered with platelet fn → bleeding.

   Contained a lot of Na+

   No longer available

Antipseudomonal Penicillins

• Restriction & Heart Failure (HF): Contains approximately 64 mg of sodium per gram of piperacillin, requiring caution in patients on sodium-restricted diets or with heart failure.

• Cystic Fibrosis: Associated with a higher incidence of rash and drug fever in this patient population.

• Coagulation Disorders: Increases the risk of bleeding abnormalities.

Precautions with piperacillin/ tazobactam

Piperacillin is sensitive to destruction by beta-lactamase

 Tazobactam inhibits beta-lactamase – extends spectrum of

activity to cover some beta-lactamase producing no

Piperacillin with tazobactam

• Mixed (aerobic & anaerobic) infections, esp if P. aeruginosa is

  involved

   Febrile neutropenia

   Often used with an aminoglycoside

• powder or iv

Indications of Piperacillin with tazobactam

• drug-induced hypersensitivity reactions.

• Reactions occur when penicillin degrades to penicilloic acid and other compounds.

• Can result in urticaria (hives) or anaphylactic shock.

  • Serum sickness

  • Interstitial nephritis

  • Hepatitis (more common with antistaphylococcal and extended-spectrum penicillins)

  • Various skin rashes

• Ampicillin - maculopapular skin rash in patients with certain viral infections, such as infectious mononucleosis.

• Apart from hypersensitivity reactions, penicillins are remarkably nontoxic.

• High concentrations (large doses) can irritate the central nervous system (CNS), leading to seizures.

• Neurotoxicity

• Black tongue

• bleeding

• Inflammation and pain at injection site

• Can disturb normal microflora.

adverse effects of penicillins