CELL WALL SYNTHESIS INHIBITORS

PENICILLIN

• Penicillinase-susceptible

• Penicillinase-resistant

CEPHALOSPHORIN

• 1st generation

• 2nd generation

• 3rd generation

• 4th generation

• 5th generation

PENEMS

• Carbapenem 

• Sulfapenem

MISCELLANEOUS

• Monobactam

• Cyclic lipopeptide

• Cyclic polypeptide

• Glycopeptide and intracellular agents

PENICILLIN

GENERAL INFORMATION

• 1929, Alexander Fleming  

• Penicillium notatum 

• 1941 – Benzylpenicillin

PENICILLIN

Basic structure 

• thiazolidine ring attached to a beta-lactam ring, and a side chain of 6-aminopenicillanic acid

NATURAL PENICILLIN

• Pen G- PO, IV or IM

• Pen V- PO

Pen G

- PO, IV or IM

Pen V-

PO

SYNTHETIC PENICILLIN

• penicillinase-resistant

• aminopenicillin

• carboxypenicillin

• ureidopenicillin 

PENICILLINASE- RESISTANT

• Methicillin

• Nafcillin

• Oxacillin

• Cloxacillin

• Dicloxacillin

AMINOPENICILLIN

• Ampicillin

• Amoxicillin

• Bacampicillin

CARBOXYPENICILLIN

• Carbenicillin

• Ticarcillin

UREIDOPENICILLIN

• Azlocillin

• Mezlocillin

• Piperacillin

PENICILLIN

have __ 

β-lactam ring that binds to proteins → inhibit penicillin-binding protein → autocatalysis of the cell wall

PENICILLIN

bactericidal/ bacteriostatic? 

• BACTERICIDAL

PENICILLINASE-RESISTANT PENICILLIN

spectrum

very narrow 

PENICILLINASE-RESISTANT PENICILLIN

methicillin-sensitive

staphylococci, streptococci

PENICILLINASE-RESISTANT PENICILLIN

• Methicillin

• is linked to interstitial nephritis 

PENICILLINASE-RESISTANT PENICILLIN

• Nafcillin

• associated with neutropenia

AMINOPENICILLIN

Greater penetration of outer membrane of gram-negative rods and higher affinity for Penicillin-binding proteins (PBPs)

AMINOPENICILLIN

spectrum 

Wide, still susceptible to β-lactamase

AMINOPENICILLIN

it cover __ 

• most enterococci, Listeria, Proteus mirabilis

• 60% Streptococcus pneumoniae, Haemophilus influenzae, E. coli, Salmonella and Shigella 

AMINOPENICILLIN

enhanced when used with 

clavulanate 

AMINOPENICILLIN

• Enterococci infections

used with aminoglycoside

CARBOXYPENICILLIN

spectrum

• same as ampicillin, but with less gram positive coverage 

CARBOXYPENICILLIN

has greater _

gram-negative spectrum

CARBENICILLIN

first antipseudomonal carboxypenicillin (no longer used in the US)

TICARCILLIN

less active than ampicillin against enterococci

UREIDOPENICILLIN

widely known drug 

piperacillin 

UREIDOPENICILLIN

• Also active against

• selected gram-negative bacilli (Klebsiella pneumoniae) 

UREIDOPENICILLIN

Possess in vitro activity against

Pseudomonas and other gram-negative organism

UREIDOPENICILLIN

resistant bacteria 

Β-lactamase producing staphylococci and H. influenzae

PENICILLIN

distribution 

• All are distributed in pleural cavity, pericardial fluid, peritoneal fluids, or ascites, synovial fluid, urine and bile

• Poor penetration across the BBB (except in meningitis)

PENICILLIN

half life 

Relatively short lived (Generally <1 hour)

PENICILLIN

metabolism 

• Most are not extensively metabolized

• Penicillinase-resistant undergo

• hepatic metabolism

PENICILLIN

excretion 

• Most are excreted primarily in the urine (unchanged)

• Penicillinase-resistant and mezlocillin

• - excreted through bile

PENICILLIN

adverse effects

• Generally well-tolerated

• Hypersensitivity

• In patients with renal failure, high doses could lead to seizures

• GI - NVD with PO use

PENICILLIN

adverse effects: oxacillin 

• hepatitis

PENICILLIN

adverse effects: ampicillin 

• Pseudomembranous colitis

PENICILLIN

adverse effects: Oxacillin, Nafcillin, and Carbenicillin

•  Increased transaminase

β-LACTAMASE INHIBITOR

drugs 

• Clavulanic acid

• Sulbactam

• Tazobactam

β-LACTAMASE INHIBITOR

active against

β-lactamase producing:

• S. aureus,

• H. influenzae,

• Moraxella catarrhalis,

• Bacteroides,

• E. coli, and

• other Enterobacteria

CEPHALOSPORIN

Similar to penicillin, more stable to

many bacterial β-lactamases

CEPHALOSPORIN

spectrum

Broader spectrum of activity

CEPHALOSPORIN

• Some strains of E. coli and Klebsiella

• expresses an extended spectrum β-lactamases than can hydrolyze most cephalosporin

CEPHALOSPORIN

not active against 

•  L. monocytogenes

CEPHALOSPORIN

INDICATION & MOA

• Bactericidal

• Inhibits the peptidoglycan synthesis in the bacterial cell wall -> formation of defective cell -> cell lysis and cell death

CEPHALOSPORIN

PHARMACOKINETICS

• Oral cephalosporin are rapidly absorbed

• Half-lives tends to be short; Mostly <1 hour, every 4 hours

CEPHALOSPORIN

PHARMACOKINETICS: cefazolin 

• longer half-life, every 8 hours

CEPHALOSPORIN

PHARMACOKINETICS: ceftriaxone 

longer half-life, every 24 hours

ALL cephalosporin achieve therapeutic levels in

• pleural fluid,

• pericardial fluid,

• peritoneal fluid,

• synovial fluid, and

• urine

CEPHALOSPORIN

• Penetration into the BB

• - 3rd and 4th generation

CEPHALOSPORIN

protein binding & excretion

• Protein binding varies between drugs

• Excretion is primarily renal.

REMEMBER: All cephalosporin except ceftriaxone

requires dose modification for patients with renal failure.

CEPHALOSPORIN

ADVERSE EFFECTS

• Hypersensitivity reactions

• Gi: Nausea and vomiting, diarrhea

• Seizure - potential risk with higher doses 

• Blood dyscrasia

CEPHALOSPORIN

ADVERSE EFFECTS: Cefoperazone, Cefmetazole, Cefotetan

bleeding disorders or hypothrombinemia due to the presence of N-methylthiotetrazole side chain

FIRST GENERATION OF CEPHALOSPORINS

drugs 

• Cefazolin

• Cefadroxil

• Cephalexin

• Cephalothin

• Cephradine

FIRST GENERATION OF CEPHALOSPORINS

GRAM-POSITIVE ACTIVITY AGAINST

• Staphylococcus aureus

• S. epidermidis

• Streptococcus pyogenes

• S. agalactiae 

• S. pneumoniae

FIRST GENERATION OF CEPHALOSPORINS

LIMITED GRAM-NEGATIVE ACTIVITY AGAINST

• E. coli

• Klebsiella pneumoniae

• Proteus mirabilis

• Shigella

FIRST GENERATION OF CEPHALOSPORINS

INDICATIONS

• Oral drugs may be used in the treatment of UTI

• Used in surgical infections (Drug of choice: Cefazolin)

SECOND GENERATION OF CEPHALOSPORIN

DRUGS

• Cefaclor

• Cefamandole

• Cefonicid

• Cefuroxime

• Cefprozil

• Laracarbef

• Ceforanide

SECOND GENERATION OF CEPHALOSPORIN

GRAM-POSITIVE ACTIVITY

Similar to the first generation but more extensive gram negative activity

SECOND GENERATION OF CEPHALOSPORIN

GRAM- NEGATIVE ACTIVITY AGAINST

• More extensive gram-negative activity than the first generation:

  • Acinetobacter

  • Citrobacter

  • Enterobacter

  • Neiserria

  • Proteus

  • Serratia

SECOND GENERATION OF CEPHALOSPORIN

• Active against

• Haemophilus influenzae

SECOND GENERATION OF CEPHALOSPORIN

Inactive against

Pseudomonas

THIRD GENERATION OF CEPHALOSPORINS

drugs 

• Cefoperazone

• Cefotaxime

• Ceftazidime

• Ceftriaxone

• Cefixime

• Cefpodoxime proxetil

• Cefdinir

• Cefditoren pivoxil

• Ceftibuten 

• Moxolactam

THIRD GENERATION OF CEPHALOSPORINS

EXPANDED GRAM-NEGATIVE COVERAGE

Some cross BBB (not all)

THIRD GENERATION OF CEPHALOSPORINS

ACTIVE AND EFFECTIVE AGAINST

• Citrobacter, 

• S. marcescens

• Providencia

Also effective against β-lactamase producing strains of Haemophilus and Neisseria

THIRD GENERATION OF CEPHALOSPORINS

indications 

• Often work against organisms that are resistant to penicillin

• Only used in serious infections

FOURTH GENERATION OF CEPHALOSPORIN

DRUGS 

• Cefepime

• Cefpirome

FOURTH  GENERATION OF CEPHALOSPORIN

RESISTANCE 

• More resistant to hydrolysis by chromosomal β-lactamase

• Hydrolyzed by the extended-spectrum β-lactamase

FOURTH  GENERATION OF CEPHALOSPORIN

GOOD ACTIVITY AGAINST 

• Entereobacter

• Haemophilus

• Neisseria

FOURTH GENERATION OF CEPHALOSPORIN

INDICATIONS 

Penetrates the CSF

FIFTH GENERATION OF CEPHALOSPORINS

drugs 

• Ceftaroline

• Ceftolozane

• Ceftobiprole

FIFTH  GENERATION OF CEPHALOSPORINS

ceftaroline 

MRSA coverage

FIFTH  GENERATION OF CEPHALOSPORINS

ceftolozane 

• Often combined with Tazobactam

• Complicated intraabdominal infections

• Complicated UTI

FIFTH  GENERATION OF CEPHALOSPORINS

ceftobiprole 

• Powerful antipseudomonal activity

• VRE coverage (Vancomycin-resistant enterococci)

PENEMS

drugs

• Doripenem

• Ertapenem

• Imipenem

• Meropenem

PENEMS

resistant to _ 

most beta-lactamase but not carabapenems or metallo-beta-lactamase

PENEMS

indications 

• Bactericidal

• Treatment for severe infection  caused by drug-resistant organisms

• For UTI, lower respiratory tract infection, intra-abdominal and gynecological infection; skin, soft tissue, bone and joint infection

IMIPENEM

• Has a wide spectrum and good activity against gram-negative rods including P. aeruginosa, gram positive organisms and anaerobes

• Administered with cilastatin

PENEMS

PENETRATION

Penetrates well into all bodily fluid and tissues

PENEMS

protein binding 

• <20% Metopenem, Imipenem, Doripenem

• > 85% Ertapenem

PENEMS

metabolism Imipenem

- metabolized in the PCT by renal dehydropeptidase

PENEMS

metabolism Others

- Stable against dehydropeptidase; hepatic hydrolysis of the beta-lactam ring

PENEMS

half life 

• Ertapenem - approximately 4 hours

• Others - 1-2 hours

PENEMS

excretion 

• Excreted unchanged in the urine

• Very small amount in the feces

PENEMS

adverse effects 

• Nausea and vomiting

• Diarrhea

• Pseudomembranous colitis

• Seizure

• Dizziness 

• Hypotension

• Cross-reactivity

SULFAPENEM

drugs 

Faropenem

SULFAPENEM

• Orally active

• unsaturated β-lactam antibiotic

SULFAPENEM

Resistant to

many different forms of extended spectrum of β-lactamase

SULFAPENEM

Improve

chemical stability

SULFAPENEM

indications 

Completed trials in tuberculosis, pulmonary TB, and CAP, but not yet used for treatment

MONOBACTAM

drugs

Aztreonam

MONOBACTAM

structure 

Monocyclic β-lactam ring

MONOBACTAM

spectrum 

• limited to aerobic gram-negative rods

MONOBACTAM

no activity against 

gram-positive bacteria or anaerobes