Beta Lactam Compounds

Moises Jaime A. Jamila Jr., RPh University of Immaculate Conception MS Pharmacy class 24 July 2010

Beta Lactam Compounds

Penicillins y Cephalosporins y Monobactam y Carbapenems y Beta-lactamase inhibitors
y

- so named because of their unique fourmembered lactam ring

PENICILLINS

Chemistry
A) B)

Thiazolidine ring Beta-lactam ring - carries secondary amino group

6-aminopenicillanic acid nucleus (A+B) - essential for the biologic activity of these compounds

beta-lactamase

Beta-lactam ring

penicilloic acid
(no antibacterial activity)

3 Basic Groups:
Penicillins y Antistaphylococcal Penicillins
y

Nafcillin
y

Extended-Spectrum Penicillins
Ampicillin

Compounds stable to gastric acid:

Penicillin V y Dicloxacillin y Amoxicillin
y

Penicillin (Pen G)
y

Greatest activity against:

Gram (+) organisms Gram (-) cocci Non beta-lactamase producing anaerobes

Lesser activity against:

Gram (-) rods

Antistaphylococcal Penicillins (Nafcillin) Nafcillin)

resistant to staphylococcal betalactamases y Active against:
-

Staphylococci Streptococci
y

Not active against:

Enterococci Anaerobic bacteria Gram (-) cocci and rods

ExtendedExtended-Spectrum Penicillins (Ampicillin and Antipseudomonal Penicillins) Penicillins)

y

Possess the antibacterial spectrum of penicillins + an improved activity against gram (-) organisms Hydrolyzed by beta-lactamases

Penicillin Units and Formulations

1 unit 1,600 units 1 M units = = = 0.6 mcg 1 mg 0.6 g

Penicillin Units and Formulations

MIC* salt : mcg/mL : Na+ or K+

Pen G K

: 1.7 mEq of K / M units (2.8 mEq/g) Nafcillin Na : 2.8 mEq/g Procaine and Benzathine salts
- Provide repository forms for IM injections
*minimum

inhibitory concentration

Stability
Dry crystalline form
stable for years at 4oC

Solution
stable for 24 hours at 20oC freshly prepared

Mechanism of Action
-

Interferes with the transpeptidation reaction of bacterial cell wall synthesis

Resistance
1. 2. 3. 4.

Inactivation of antibiotic by betalactamase Modification of transport PBPs* Impaired penetration of drug to target PBPs Efflux

*penicillin-binding protein(s)

1. Inactivation of antibiotic by betabetalactamases

y y

Penicillins
S. aureus, Haemophilus sp & E. coli

Penicillins and Cephalosporins

P. Aeruginosa & Enterobacter Sp (AmpC -lactamases) ESBLs*

Carbapenems
Metallo -lactamases & carbapenemases
*extended spectrum -lactamases

2. Modification of target PBPs

y y

Methicillin-resistance
Staphylococci

Penicillin resistance
Pneumococci & Enterococci
- Organisms produce PBPs that have low affinity for binding -lactam antibiotics, and consequently they are not inhibited except at high, often clinically unachievable drug concentrations.

3. Impaired penetration of drug to target PBPs

y

G(-) species
- Impermeable outer cell wall membrane w/c is absent in G(+) species - B-lactam antibiotics cross the outer membrane & enter G(-) organisms via outer membrane protein channels (porins) - B-lactamase: may hydrolyze drug faster than it enters the cell.

4. Efflux
y

G(-) organisms
- May produce an efflux pump (cytoplasmic and periplasmic protein components)

PHARMACOKINETICS

Absorption
y

Dicloxacillin, Ampicillin & Amoxicillin

- Acid-stable - 500mg oral dose: 4-8 mcg/mL serum conc - Taken 1-2 hours before or after a meal (except amoxicillin)

Administration
y

IV is preferred to the IM route because of irritation and local pain from IM inj of large doses.

Distribution
y

Polar

- intracellular conc are low than those found in extracellular fluids 1g Pen G IV: 20-50 mcg/mL serum conc Nafcillin : highly protein-bound Pen G & Ampicillin : less protein-bound

Distribution
Benzathine and Procaine
- Formulated to delay absorption

1.2 M u IM inj of Benzathine Penicillin : 0.02 mcg/mL serum conc 10 days : hemolytic streptococcal infection 600, 000 u IM inj of Procaine Penicillin : 1-2 mcg/mL serum conc for 12-24 hours

Distribution
Tissue Conc = Serum Conc Eye, Prostate & CNS: poor penetration Bacterial Meningitis
18-24 M u daily dose of Penicillin will yield 15 mcg/mL serum conc, sufficient to kill strains of pneumococci & meningococci

Half - Life
Penicillin - t : 30 minutes; 10 hours (renal failure) Ampicillin & Extended-Spectrum Penicillins - t : 1 hour

Excretion
Renal Excretion
10% glomerular filtration 90% tubular secretion

Creatinine Clearance (Clcr )

10 mL/min or less 1/4 to 1/3 of the normal dose

No dosage adjustment in renal failure: y Nafcillin

Biliary excretion
y

Oxacillin, Dicloxacillin & Cloxacillin

Both kidney & biliary excretion

Cockcroft and Gault equation

(1976)
Clcr (ml/min) = (140 - age ) x BW (kg) x *F ----------------------------------Serum creatinine (mg/dL) x 72

(140 - age ) x BW (kg) x *F ------------------------------------Serum creatinine (mmol/L) x 815 *F = (multiply by) 1 if male, and 0.85 if female

CLINICAL USE

Probenecid - Increases blood levels of Penicillin - Impairs renal tubular secretion of weak acids (B-lactam cmpds) - 0.5 g (10 mg/kg in children) q6o PO

Penicillin G
DOC
-

streptococci, meningococci, enterococci, penicillinsusceptible pneumococci, non-lactamase producing staphylococci,T. pallidum & other spirochetes, clostridium spp, actinomyces, & other G(+) rods & non B-lactamase producing G(-) anaerobic orgs.

Dose
-

4-24 M u/day IV in 4-6 divided doses

Penicillin V
Oral form of penicillin y Indicated for minor infections y Poor bioavailability y QID dosing y Narrow antibacterial spectrum
y

Benzathine Penicillin & Procaine Penicillin G

IM inj yield low but prolonged drug levels. y Benzathine Penicillin
-

1.2 M u IM q 3-4 wks B-hemolytic streptococcal pharyngitis 2.4 M u IM once a week for 1-3 wks (syphilis)

Methicillin, Methicillin, Nafcillin & Isoxazolyl Penicillins

-

Resistant to staphylococcal B-lactamase

Systemic Staphylococcal Infections Oxacillin or Nafcillin

x 8-12 g/day given by intermittent IV infusion of 1-2 g q4-6o (50100 mg/kg/day for chidren)

Oxacillin, Cloxacillin & Dicloxacillin (Isoxazolyl) 0.25-0.5 g orally q4-6o 15-25 mg/kg/day for children Acid-stable Given 1 hr before or after meals

Aminopenicillins, Aminopenicillins, Carboxypenicillins & Ureidopenicillins (ESPs)

Enhanced ability to penetrate G(-) outer membrane y Inactivated by B-lactamases
y

Aminopenicillins (Amoxicillin & Ampicillin) Ampicillin)

Both have identical spectrum of activity but amoxicillin is better absorbed orally. Amox 250-500mg TID = Ampi QID Tx: UTI, sinusitis, otitis, LRTI
-

Ampicillin
effective for shigellosis

B-lactamase Inhibitor Combination

Ampicillin, Amoxicillin, Ticarcillin (Carboxypenicillin) & Piperacillin (Ureidopenicillin) are available in combination with one of these B-lactamase inhibitors:
Clavulanic acid Sulbactam Tazobactam - The addition of B-lactamase inhibitors extends the activity of these penicillins

CEPHALOSPORINS & CEPHAMYCINS

Cephalosporins
y

More stable than penicillins to many Blactamases; broader spectrum

Attachment of Various R1 & R2 groups

Yielded drugs of good therapeutic activity and low toxicity. y Soluble in water y Relatively stable to pH y Relatively stable to temperature changes
y

4 Generations
y

First Generation have better activity against G(+) organisms and the later Generations exhibit improve activity against G(-) aerobic organisms.

OTHER BETA-LACTAM BETADRUGS

Monobactams
Monocyclic B-lactam ring y Relatively resistant to B-lactamase and active against G(-) rods (pseudomonas & serratia) Aztreonam
y Resembles aminoglycosides (spectrum of activity) - 1-2g IV q8o - t : 1-2 hrs; prolonged in renal failure - Penicillin allergic Px tolerate Aztreonam w/o reaction
-

BetaBeta-lactamase inhibitors:
Clavulanic Acid, Sulbactam & Tazobactam

Resembles B-lactam molecules; have weak antibacterial action. y Active against class A:
y
staphylococci, H. influenzae, N. gonorrheae, salmonella, shigella, E. coli, & K. Pneumoniae

Not active against class C:

enterobacter, citrobacter, serratia & pseudomonas (chromosomally encoded)

Inhibit Chromosomal B-lactamases:

legionella, bacteroides and brahmanella

BetaBeta-lactamase inhibitors
Available in fixed combination w/ specific penicillins. y An inhibition will extend the spectrum of a penicillin provided that the inactivity of the penicillin is due to the destruction by Blactamases and that the inhibition is active against the B-lactamase produced
y

Ampi+Sulbactam: active against S aureus & H influenzae but not against serratia
y

Emperical therapy: aerobic & anaerobic infections (intra-abdominal infections)

Carbapenems
(Imipenem, Meropenem & Ertapenem) Imipenem, Ertapenem) Imipenem
inactivated by dehydropeptase in renal tubules Administered w/ cilastatin (renal dehydrogenase inhibitor) Penetrate CSF

Carbapenems
y

The B-lactam antibiotic of choice for the treatment of enterobacter infections. Dose: Imipenem: 0.25-0.5g IV q6-8o (t: 1 hr) Meropenem: 1g IV q8o Ertapenem: 1g q24o IV or IM (t: 4 hrs) : 1% lidocaine for IM

Carbapenems
ADR: Imipenem
N/V, diarrhea, skin rashes Excessive levels of imipenem in Px w/ RF may lead to seizures

OTHER INHIBITORS OF CELL WALL SYNTHESIS

Vancomycin
y y y y

Produced by Streptococcus orientalis Active only against G(+) bacteria (staphylococcus) Poorly absorbed from the GIT Not removed by hemodialysis MOA:
inhibit cell wall synthesis

Indication:
Sepsis and endocarditis

Resistance:
Due to modification of the D-ala-D-ala binding site, terminal D-ala is replaced by D-lactate

Vancomycin + Gentamicin
y

Alternative regimen for Tx of enterococcal endocarditis (Px w/ serious penicillin allergy)

Vancomycin +
Cefotaxime / Ceftriaxone / Rifampicin

Treatment of meningitis suspected or caused by highly penicillin-resistant strain of pneumococcus. Dose: A: 30mg/kg/d 2-3 div doses; 1g q12o P: 40mg/kg/d 3-4 div doses Renal Px: 1g every week PO: 0.125 0.25g q6o : Tx antibiotic-associated enterocolitis : vanco-resistant enterococci: metronidazole initial therapy
y

Vancomycin
ADR: Phlebitis at the site of inj, chills, fever Red man or red neck syndrome:
infusion related flushing (caused by the release of H1 Prevented by prolonging infusion period to 1-2 hrs or by increasing the dosing interval.

Teicoplanin
IM or IV y t: 45-70 hours; OD dosing y Similar to Vancomycin MOA
y

Fosfomycin
MOA:
Inhibits cytoplasmic enzyme enolpyruvate transferase (early stage of bacterial cell wall synthesis)

Resistance:
Inadequate transport of drug into the cell.

Susceptibility test:
Growth medium w/ glucose 6-phosphate.

Indication:
Single 3g dose: Tx uncomplicated UTI in women. Safe in pregnancy. G(+) & G(-) t : 4 hours

Bacitracin
y y y y

Obtained from Bacillus subtilis Nephrotoxic, limited to topical use; poorly absorbed Combined with polymyxin & neomycin Soln of 100-200 u/mL in saline: irrigation ( joints, wounds or pleural cavity) Inhibit cell wall formation by interfering w/ dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan to the growing cell wall.

MOA:

Cycloserine
y y y

Produced by Streptomyces orchidaceus Water soluble and very unstable to acid pH Inhibits G(+) & G(-), used almost exclusively to treat TB Structural analog of D-alanine & inhibits the incorporation of D-alanine

MOA: Dose:
0.5-1g/d in 2-3 divided doses

ADR:
Headache, tremors, acute psychosis & convulsions (dose: < 0.75 g/d)

G(+)

G(-) cocci / x

G(-) rods L x G

Entero -cocci

Staph

Strep

Anaerobic

Beta
Lactamase resistant

Penicillin Nafcillin Ampillin Monobactam Imipenem Meropenem Ertapenem Vancomycin Fosfomycin Cycloserine

x x / / x / x x / / / / / (methicillin & nafcillin-resistant bacteria) /

/ x / L

/ (pseudo & serratia) / (pseudomonas) G L

/ / / /

/ (exclusive for M. tuberculosis)

thank you

-moe