10. β-Lactams/Cell Wall Synthesis Inhibitors

Describe β-lactam antibiotics.

• Widely prescribed

• All share common structure and mechanism of action (inhibition of bacterial cell wall synthesis)

• Bactericidal

List β-lactam drugs.

1. Penicillins

2. Cephalosporins

3. Monobactams

4. Carbapenems

Describe the mechanism of action of β-lactams.

• Bacteria do not have mechanism to regulate osmolarity; surrounded by thick cell wall that provides stability and rigidity to cell structure

• Inhibit cell wall synthesis by inhibiting transpeptidases so that cross linking does not take place

• Also activate autolysing enzymes (autolysins) that cause cell death

Penicillins

Where are pencillins obtained from?

• Penicillium notatum

• Penicillium chryosogenum

Penicillins

What is the role of the side chain on penicillins?

Provides antibacterial activity and stability

Penicillins

List the classifications of penicillins.

1. Natural

2. Semi-synthetic

3. Beta-lactamase inhibitors

Penicillins

List natural penicillins.

Penicillin-G

Penicillins

List semisynthetic penicillins.

1. Acid resistant (alternative to Penicillin-G): Penicillin-V

2. Penicillinase resistant: Methicillin, Cloxacillin

3. Extended spectrum: Ampicillin, Amoxicillin, Piperacillin

Penicillins

List beta-lactamase inhibitors.

1. Clavulanic acid

2. Sulbactam

3. Tazobactam

Penicillins

The renal tubular secretion of penicillins by __________ (anti-gout drug), a drug that competes with penicillins for the organic acid ___________ located in the ________ tubule. __________ has been used to slow down the _________ and prolong the ____-____ of penicillin G.

probenecid

transporter

proximal

excretion

half-life

Penicillins - Natural

Penicilin-G (PnG) are ______ spectrum penicillins and are β-lactamase _________.

narrow

sensitive

Penicillins - Natural

Describe the uses of penicillin-G.

• Drug of choice for infections caused by organisms susceptible to it, unless patient is allergic

• Use declined very much - fear of causing anaphylaxis

Penicillins - Natural

Which bacterial infection is penicillin-G the drug of choice for and why?

Treponema pallidum (causes syphilis); has not shown any resistance

Penicillin-G (Natural)

List the adverse effects of penicillin-G.

1. Pain at IM site

2. Hypersensitivity reactions (major problem with penicillins, 1-10% incidence)

Semisynthetic Penicillins

Why were semisynthetic penicillins synthesized?

To overcome shortcomings of PnG

What are penicillinase enzymes/β-lactamase enzymes?

Enzymes produced by some bacteria to provide resistance to antibiotics (open the ring)

Penicillin-V

Describe Penicillin-V.

• Narrow-spectrum

• β-lactamase sensitive

• Antibacterial spectrum is similar to PnG

Penicillin-V

List the uses of Penicillin-V.

• Streptococcal pharyngitis

• Sinusitis

• Otitis media

• Prophylaxis of rheumatic fever

• Less serious pneumococcal infections

List some bacteria that produce β-lactamase, which inactivate the β-lactam ring and hydrolyze penicillins.

1. S. aureus

2. H. influenzae

3. E. coli

Which bacteria can hydrolyze penicillins and cephalosporins?

1. Pseudomonas

2. Neisseria gonorrhoeae

Name 2 penicillinase/β-lactamase resistant penicillins.

1. Cloxacillin

2. Methicillin

β-lactamase-resistance penicillins protect the β-lactam ring from attack by _______________ _____________.

staphylococcal penicillinase

Describe methicillin.

• Not used; nephrotoxic (causes interstitial nephritis)

• Only used in lab tests to identify resistant strains of S. aureus (Methicillin Resistant S. aureus, MRSA)

Which penicillins are S. aureus resistant to?

Methicillin, Cloxacillin, Nafcillin

Describe MRSA.

• Currently source of serious community and nosocomial infections

• Is resistant to most commercially available β-lactam antibiotics

Penicillinase-resistant penicillins have minimal to no activity against

gram-negative infections

List extended spectrum penicillins.

• Ampicillin

• Amoxicillin

• Piperacillin (Antipseudomonal)

• Ticarcillin (Antipseudomonal)

Extended Spectrum Penicillins

Describe ampicillin and amoxicillin.

• Acid stable

• Given orally

• Penicillinase/β-lactamase sensitive; hence used w/β-lactamase inhibitors

Extended Spectrum Penicillins

List the uses of ampicillin and amoxicillin.

1. Respiratory tract infections

2. Meningitis

3. Gonorrhea

4. Cholecystitis

Extended Spectrum Penicillins

Amoxicillin is used in multidrug regimens for eradication of

H. pylori in ulcers

Extended Spectrum Penicillins

List the adverse effects of ampicillin and amoxicillin.

• Diarrhea

• GI irritation

• Rashes (up to 10%)

• Hypersensitivity

Extended Spectrum Penicillins

Which is preferred between amoxicillin and ampicillin and why?

Amoxicillin

• Better oral absorption

• Food does not interfere with absorption

• Less diarrhea

Extended Spectrum Penicillins - Antipseudomonal

List the uses of piperacillin and ticarcillin.

• Active against gram-positive and gram-negative bacteria

• Used for serious infections due to Pseudomonas, Proteus in burns

• Septicemia

• UTI

• Neutropic/immuno-compromised patients with serious gram-negative infections

Usually combination of piperacillin with gentamycin/tobramycin is preferred

Define and describe β-lactamase.

• Family of enzymes produced by Gram-positive and Gram-negative bacteria that inactivate β-lactam antibiotics

• Different β-lactamases differ in their substrate affinities

List β-lactamase inhibitors.

1. Clavulinic acid

2. Sulbactam

3. Tazobactam

They do not possess any antibacterial action

Describe the mechanism of β-lactamase inhibitors.

Bind irreversibly to catalytic site of susceptible β-lactamase (produced by bacteria) to prevent hydrolysis of penicillins

Based on their pharmacokinetic features, which β-lactamase inhibitors are combined with each other and why?

1. Clavulanic acid is combined with amoxycillin (Augmentin)

   • Addition of clavulinic acid with amoxycillin extends the antimicrobial spectrum of amoxycillin against β-lactamase producing enzyme

2. Sulbactam with ampicillin

3. Tazobactam with pipercillin

List the uses of β-lactamase inhibitors.

1. Skin and soft tissue infections

2. Intra-abdominal and gynecological sepsis

3. Urinary, biliary and respiratory tract infections

4. Gonorrhea

5. Used when empiric antibiotic therapy is to be given for hospital acquired infections

List the adverse effects of β-lactamase inhibitors (clavulanic acid).

• Rare except GI intolerance esp. in children

• Stomatitis

• Rashes

• Same for amoxycillin alone

Describe cephalosporins.

• Semi-synthetic antibiotics derived from “Cephalosporin-C” obtained from fungus Cephalosporium

• All are bactericidal

• Similar to penicillins in mechanism of action and adverse effects

Describe the mechanism of action of cephalosporins.

• Inhibition of transpeptidation process, leading to formation of imperfect cell wall

• Bind to different proteins than those which bind penicillins; may explain differences in spectrum, potency, and lack of cross-resistance

Describe and list the classifications of cephalosporins.

Classified into generations based on antibacterial spectrum, stability to β-lactamase, and year of introduction

1. First generation

2. Second generation

3. Third generation

4. Fourth generation

5. Fifth generation

List first generation cephalosporins.

Cephalexin and Cefadroxil

List second generation cephalosporins.

Cefaclor and Cefuroxime

List third generation cephalosporins.

Ceftriaxone and Cefpodoxime

List fourth generation cephalosporins.

Cefepime and Cefpirome

List fifth generation cephalosporins.

Ceftaroline and Ceftobiprole

First Generation Cephalosporins

Describe first generation cephalosporins and list their uses.

• Developed in 1960s

• High activity against Gram-positive but weaker against Gram-negative bacteria

1. UTI

2. Minor Staphylococcal infections

3. Soft tissue abscesses

First Generation Cephalosporins

Which is the most commonly used first gen drug and which one is preferred for surgical prophylaxis/prophylaxis against infection?

• Most commonly used: cephalexin

• Surgical prophylaxis: cefazolin

Second Generation Cephalosporins

Describe second gen cephalosporins.

More effective against Gram-negative bacteria, with some members active against anaerobes as well

Second Generation Cephalosporins

Describe cefuroxime.

• Resistant to Gram-negative β-lactamase

• Has high activity against organisms producing these enzymes, including penicillin-producing Neisseria gonorrhea (PPNG) and ampicillin-resistant H. influenza and Klebsiella pneumonia

Second Generation Cephalosporins

List the uses of second gen cephalosporins.

1. Gonorrhea due to PPNG

2. URTI

3. Community acquired pneumonia

4. Meningitis (3rd gen preferred)

5. Anaerobic infections e.g. lower abdominal and gynecological infections

Third Generation Cephalosporins

Describe third gen cephalosporins.

• Introduced in 1980s

• Have highly augmented activity against Gram-negative cocci, bacilli, and anaerobes

• All highly resistant to β-lactamases from Gram-negative bacteria; less active on Gram-positive cocci and anaerobes

• Cross BBB, so provides adequate therapeutic levels in CSF

Third Generation Cephalosporins

How is ceftriaxone excreted? What is the significance of this?

• In bile

• No dose adjustment required for renal insufficiency

Third Generation Cephalosporins
List the uses of third gen cephalosporins.

• Meningitis

• Life-threatening/hospital-acquired infections

• Gonorrhea

• Septiciemias

• Infections in immuno-compromised patients

Fourth Generation Cephalosporins

Describe fourth generation cephalosporins.

• Developed in 1990s

• Antibacterial spectrum is similar to third generation

• Widest antibacterial spectrum - Gram-positive activity of first gen. and Gram-negative activity of third gen.

• Highly resistant to beta-lactamase, thus active against many bacteria resistant to earlier drugs

• P. aeruginosa and S. aureus are also inhibited, but not MRSA

Fourth Generation Cephalosporins

Which infections are fourth gen cephalosporins effective in and why?

Due to its high potency and extended spectrum, it is effective in many serious infections:

• hospital-acquired pneumonia

• febrile neutropenia

• bacterima

• septicemia

Fifth Generation Cephalosporins

List the parenteral fifth generation cephalosporins that are currently undergoing clinical trials.

Ceftaroline and Ceftobiprole (cleared Phase III clinical trials)

Fifth Generation Cephalosporins

Describe ceftaroline.

• Is the only commercially available β-lactam with activity against MRSA

• Is indicated for treatment of complicated skin and skin structure infections and community-acquired pneumonia

List the adverse effects of cephalosporins.

1. Pain after IM injection

2. Diarrhea

3. Hypersensitivity reactions (lower than penicillins): skin rash, fever, eosinophilia

4. Nephrotoxicity: used in combination with aminoglycosides

5. Bleeding/coagulation abnormalities: reduces synthesis of Vitamin K-dependent clotting factors (treatment for this is Vitamin K)

6. Superinfections, pseudomembranous colitis (PMC), and diarrhea can result from use of 3rd, 4th, and 5th gens

List another inhibitor of cell wall synthesis.

Vancomycin

Describe vancomycin.

• Damages cell membrane and alters cytoplasmic membrane permeability (bactericidal)

• Exclusively acts against aerobic and anaerobic Gram-positive species, including drug-resistant Gram-negative bacteria, MRSA, penicillin-resistant S. pneumoniae, S. enterocolitis, and S. endocarditis

List the adverse effects of vancomycin.

• Red-neck syndrome (histamine release, given as slow IV)

• Minor incidences of ototoxicity

• Nephrotoxicity

• Skin rash

• Fever

• Chills