Carbapenems - Pharmacology

1. Carbapenems
Areej Abu Hanieh
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2. Carbapenems
 MOA :Inhibits bacterial cell wall synthesis , bind to penicillin binding protein and inhibit
transpeptidation of peptidoglycan .
 Imipenem, Meropenem, Ertapenem and Doripenem
 Converge :
 Aerobic gram negatives (including ESBLs), aerobic gram positives (MSSA, Streptococcus),
anaerobes except MRSA, VRE and Atypical
 Ertapenem do Not cover: Enterococcus, Acinetobacter, Pseudomonas, and MRSA
 It is a bactericidal , time dependent
 Mechanism of resistance: poor binding affinity for PBP 2a (found on MRSA) and PBP 5
(found on E. faecium).
 Alteration of targets, decreased accumulation due to decreased permeability, and
enzymatic inactivation.
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3.  Contraindications: Hypersensitivity ,ertapenem(Infants less than
3 months),
 Side effects: Nausea , vomiting, diarrhea ,seizures(imipenem)
 Pregnancy category : B
 Dosage Form : IV , IM
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4.  Meropenem :
 CrCl >50 mL/minute: No dosage adjustment necessary.
 CrCl 26 to 50 mL/minute: Administer recommended dose based on
indication every 12 hours
 CrCl 10 to 25 mL/minute: Administer one-half recommended dose
based on indication every 12 hours
 CrCl <10 mL/minute: Administer one-half recommended dose based
on indication every 24 hours
 No hepatic dose adjustment
 Dose : every 8 hours
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5. Imipenem
 Renal dose adjustment :
 CrCl >50 mL/minute: No dosage adjustment necessary.
 CrCl 26 to 50 mL/minute: Administer recommended dose based on
indication every 12 hours
 CrCl 10 to 25 mL/minute: Administer one-half recommended dose
based on indication every 12 hours
 CrCl <10 mL/minute: Administer one-half recommended dose based
on indication every 24 hours
 Hepatic : no dose adjustment provided
 Max dose : 4000 mg/day , every 6 hours.
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6. Ertapenem
 Renal dose adjustment :
 CrCl >30 mL/minute/1.73 m2: No dosage adjustment necessary.
 CrCl ≤30 mL/minute/1.73 m2 and ESRD: 500 mg/day
 Hemodialysis: When the daily dose is given within 6 hours prior to
hemodialysis, a supplementary dose of 150 mg is required following
hemodialysis. If ertapenem is given at least 6 hours prior to
hemodialysis, no supplementary dose is needed
 Hepatic : no adjustment provided from manufacture .
 Dose : every day
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7. Doripenem
 Renal adjustment :
 CrCl >50 mL/minute: No dosage adjustment necessary.
 CrCl 30 to 50 mL/minute: 250 mg every 8 hours
 CrCl 11 to 29 mL/minute: 250 mg every 12 hours
 End-stage renal disease (ESRD) on intermittent hemodialysis (IHD):
Dialyzable (~52% of dose removed during 4-hour session in ESRD
patients): 250 mg every 24 hours; if treating infections caused by
Pseudomonas aeruginosa, administer 500 mg every 12 hours on day 1,
followed by 500 mg every 24 hours.
 Hepatic : no dose adjustment provided
 Frequency : every 8 hours
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8. Carbapenems
ErtapenemDoripenemMeropenemImipenem
IV/IMIVIVIVDosage form
Not Cross BBBCross BBBCross BBBCross BBB
Weak
BBB penetration
lesslessLessMostcause seizure
CrCl<30ml/minCrCl<50ml/minCrCl<50ml/minCrCl<90ml/minrenal adjustment
BBBCpregnancy
category
1g/day1.5g/day6g/day4g/daymax doses
NoYesYesYescover
pseudomonas
Once dailyEvery 8 hoursEvery 8 hoursEvery 6-8 hoursfrequency of the
dosing
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9. Imipenem/cilastatin
 Role of cilastatin in imipenem/cilastatin combonation:
 Imipenem undergoes cleavage by a dehydropeptidase found in the brush border
of the proximal renal tubules. This enzyme forms an inactivate metabolite that is
potentially nephrotoxic.
 Cilastatin prevents renal metabolism of imipenem by competitive inhibition of
dehydropeptidase along the brush border of the renal tubules.
 Compounding the imipenem with cilastatin protects the parent drug and thus
prevent the formation of the toxic metabolite.
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10. Teicoplanin
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11. Teicoplanin
 MOA :
 Inhibit bacterial cell wall synthesis.
 Peptidoglycan synthesis is blocked by specific binding to D-alanyl-D-alanine residues. –
inhibit transpeptidation and transglycosylation .
 Converge :Gram-positive aerobic and anaerobic bacteria.
 Mechanism of resistance:
 Exchange of the terminal D-alanine-D-alanine function of the amino-acid chain in a
murein precursor with D-Ala-D-lactate, thus reducing the affinity .
 The reduced sensitivity or resistance of staphylococci to teicoplanin is based on the
overproduction of murein precursors to which teicoplanin is bound.
 Cross-resistance between teicoplanin and the glycoprotein vancomycin may occur.
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12. Teicoplanin
 Bacteristatic, Time-dependent Killing
 Hepatic adjustment : do not need
 Renal adjustment:
 Clcr 40-60 ml/min) the daily dose of teicoplanine should be halved or administered on
alternate days.
 Clcr is less than 40 ml/min and hemodialysis patients, the daily dose of teicoplanine
should be reduced to a third or administered every 3 days.
 Contraindications: Hypersensitivity
 Side effects: Gastrointestinal : nausea, vomiting, diarrhea, Local reactions:
erythema, localized pain, thrombophlebitis ,and Dermatological: rash, pruritus,
thrombocytopenia, hypersensitivity.
 Dosage forms:(IV or IM) or oral solution
 Pregnancy category :C
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13. TeicoplaninVancomycin
LD:400mg
MD:200- 800 mg
LD:25-30mg/kg(1g)
MD:15-20mg/kg , Q 12
hours
loading dose and
maintenance
Time dependent
(pubmed)
Time dependenttime or concentration
dependence
Less nephrotoxic drugMore nephrotoxic drugnephrotoxic
Do Not cross BBBCross BBBcrosses blood brain barrier
thrombocytopenia,
hypersensitivity , diarrhea ,
red man syndrome
Renal failure,
thrombophlebitis, red man
syndrome , nephrotoxicity ,
ototoxicity
major side effects
IV,IM, IPIV, oral , intrathecaldosage form
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14. Fosfomycin
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15. Fosfomycin
 MOA :It blocks cell wall synthesis by inhibiting the enzyme UDP-N-
acetylglucosamine enolpyruvyl transferase,which catalyzes the first step in
peptidoglycan synthesis.
 Converge :E.coli (including ESBLs) , E. faecalis (For the treatment of cystitis only).
 It is a bactericidal , concentration-dependent
 Mechanism of resistance :
 Mutational Resistance(loss of transport systems required for uptake in E. coli )
 Fosfomycin-Modifying Enzymes: Several fosfomycin-modifying enzymes have been
found that inactivate the drug.
 Due to its unique structure and mechanism of action, cross resistance with other
antimicrobial agents is unlikely
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16. Fosfomycin
 Renal and hepatic adjustment: NO dosage adjustments provided
 Contraindications: Hypersensitivity
 Side effects: diarrhea, vaginitis , nausea, and headache.
 Dosage forms: Oral
 Pregnancy category : B
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17. Streptogramins17

18. Streptogramins
 Quinupristin-dalfopristin (30/70) is a combination of 2 agents of streptogramins in a ratio
of 30 to 70.
 MOA : Each component binds to a separate site of the 50S bacterial ribosome. Dalfoprisitn
disrupts elongation by interfering with the addition of new amino acida to the peptide
chain.Quinupristin prevents elongation and causes release of incomplete peptide chains.
 Coverage :Antibacterial activity includes penicillin-resistant pneumococci, methicillin-
resistant (MRSA) and vancomycin-resistant staphylococci (VRSA), and resistant E
faecium.
 It is a bactericidal , time dependent
 Mechanism of resistance :
 Enzymatic processes ribosomal enzyme that methylates the target bacterial 23S ribosomal
RNA site can interfere quinupristin binding
 Enzymatic modification: change the action from bactericidal to bacteriostatic
 Plasmid-associated acetyltransferase inactivate dalfopristin
 Efflux pump
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19. Streptogramins
 Renal and hepatic adjustment: No renal dose adjustment needed. No hepatic
adjustment provided but adjustment may be necessary.
 Contraindications: Hypersensitivity, Children less than 12 years
 Side effects: Venous irritation , hyperbilirubinemia, arthralgia and myalgia.
 Dosage forms: IV, Intrarhecal , Powder (for reconstitution) for injection.
 Pregnancy category: B
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20. Linezolid
 MOA :
Inhibits bacterial protein synthesis by binding to bacterial 23S ribosomal RNA of the 50S
subunit. This prevents the formation of a functional 70S initiation complex .
 Bacteriostatic against enterococci and staphylococci, bactericidal against most strains of
streptococci, Time dependent .
 Oxazolidinone grp : Linezolid, Tedizolid.
 Mechanism of Resistance : some organism by mutations in multiple copies of the 23S
rRNA genes that reduce drug binding to the ribosome, Other by efflux pump .
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21.  Spectrum & Coverage :
o Narrow - aerobic Gram positives
o Staphylococci (MSSA, MRSA, CNST)
o Streptococci (penicillin-resistant)
o Enterococci (E. faecalis, E. faecium, VRE)
 Useful for: resistant aerobic Gram positives
 Not useful for: any gram negative, any anaerobe.
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22.  Dosage form: Solution, IV ,tablet , Suspension
 Side effect: Gastrointestinal acidosis(Lactic acidosis),
Myelosuppression:Thrombocytopenia, Irreversible Peripheral and optic neuropathy (with
vision loss), Serotonin syndrome( agitation, confusion, tachycardia ,sweeting ),
Superinfection.
 Pregnancy category : C
 Renal adjustment: No need
 Hepatic adjustment: no need for adjustment in child pugh class A , B , and there is no
dose adjustment provided by the manufacterer In class C,D .
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23.  Contraindication:
o Hypersensitivity
o Concurrent use or within 2 weeks of MAO inhibitors ,
o Uncontrolled hypertension, pheochromocytoma, thyrotoxicosis.
o Sympathomimetic agents (eg, pseudoephedrine, phenylpropanolamine)
o Vasopressive agents (eg, epinephrine, norepinephrine), dopaminergic agents (eg, dopamine,
dobutamine).
o S/S of serotonin syndrome
o Patients with carcinoid syndrome
o Patients taking any of the following: SSRIs, TCAs, serotonin 5-HT1 receptor agonists (triptans),
meperidine or buspirone.
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