DR. MABANAG - CEPHALOSPORINS, CARBAPENEMS, MONOBACTAMS & BETA LACTAMASE INHIBITORS Flashcards by Shiela Micah Gascon

All cephalosporins have the same basic structure containing the _____________________which is a Dihydrothiazine ring attached to a β-lactam ring.

7-AMINOCEPHALOSPORANIC ACID NUCLEUS

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● Very active vs. G(+) cocci: streptococci and staphylococci
● Limited activity vs G(-) such as Proteus mirabilis, E. coli, Klebsiella pneumoniae (Mnemonic: PEcKs first)

First Generation Cephalosporins

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First Generation Cephalosporins

● Examples (Mnemonic: FADer, help me FAZ my PHarmacology exam)
○ CeFADroxil
○ CeFAZolin
○ CePHalothin
○ CePHapirin
○ CePHradine
○ CePHalexin

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*WITH ADDITIONAL G- COVERAGE
○ H. influenza
○ Enterobacter
○ Neisseria
○ Proteus mirabilis
○ Escherichia coli
○ Klebsiella pneumoniae
○ Serratia marcescens
● Mnemonic: HEN PEcKs

Second Generation Cephalosporins

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Second Generation Cephalosporins

FAMily FOX FURing TEa
○ CeFAMandole
○ CeFOXitin
○ CeFURoxime
○ CefoTEtan

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Second Generation Cephalosporins

● Mnemonic: “FAC! LORA the PROfessional AZOLE is still on the FONe!”
○ CeFAClor
○ LORAcarbef
○ CefPROzil
○ CefmetAZOLE
○ CeFONicid

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● Expanded G(-) coverage, some are able to cross BBB
● All penetrate well into the CSF, so for CNS infections these are usually used

ThirdGenerationCephalosporins

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ThirdGenerationCephalosporins

● Mnemonic: “FEnge PO ng PERA to FIX my 3
(TRI) TTTTv”
○ CeFEtamet
○ CefPOdoxime
○ CefoPERAzone
○ CeFIXime*
○ CefTRIaxone
○ CefTazidime—most widely used in the
Philippines
○ CefoTaxime
○ CefTizoxime
○ CefTibuten

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●P. aeruginosa
Enterobacteriaceae
methicillin-susceptible S. aureus
S. pneumoniae
● Penetrates well into the CSF

FourthGenerationCephalosporins

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CEFEPIME

FourthGenerationCephalosporins

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● added activity against MRSA
● Unlike 4th gen cephalosporin—no activity against P. aeruginosa

FifthGenerationCephalosporins

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CEFTAROLINE

FifthGenerationCephalosporins

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○ Both FDA-approved for treatment of complicated intra-abdominal infections & UTIs
○ Relatively new antibiotics

● Ceftolozane + Tazobactam
● Ceftazidime + Avibactam

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These are the newer β-lactam inhibitors

● Tazobactam & Avibactam

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used for brain infections because they penetrate well into the CSF

Cefuroxime, 3rd and 4th generation
cephalosporins

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Used for treatment of UTI, staphylococcal and streptococcal infections including cellulitis and soft tissue abscess, surgical prophylaxis

FIRST GEN

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Used primarily for sinusitis, otitis, LRTIs & community-acquired pneumonia

SECOND GEN

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Used for serious infection requiring IV therapy (e.g. meningitis, neutropenic fever)

3RD GEN

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Used for infections caused by Pseudomonas aeruginosa and Enterobacter

4TH GEN

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Used for MRSA infection

5TH GEN - CEFTAROLINE

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Used for treatment of complicated intra-abdominal infections and urinary tract infections

Cephalosporins + Beta-Lactamase Inhibitor

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Adverse Reactions of Cephalosporins

ALLERGY
GI DISTURBANCES
HYPOPROTHROMBINEMIA & BLEEDING DISORDER
DISULFIRAM LIKE INFECTIONS (flushing, tachycardia, hypotension, nausea, dizziness) - Due to inhibition of the
enzyme acetaldehyde dehydrogenase

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DRUGS THAT CAUSE THE DISULFIRAM-LIKE REACTIONS:

● Metronidazole
● Cefotetan
● Cefamandole
○ Cefotetan and Cefamandole are 2nd gen cephalosporins
● Cefoperazone (3rd gen cephalosporin)
● Disulfiram

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● broadest-spectrum of all beta-lactam abx
○ Excellent activity against both Gram(+) and (-), aerobic and anaerobic bacteria
○ Good activity against Pseudomonas aeruginosa & Bacteroides fragilis (except Ertapenem)
‐ Does not have activity against MRSA

CARBAPENEMS

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FIRST CARBAPENEM inactivated dehydropeptidase in renal tubules, resulting in low urinary concentrations ○ Always administered together with an inhibitor of dehydropeptidase, Cilastatin, to prolong its half-life

IMIPENEM

competitive inhibitor of renal tubular dehydropeptidase, resulting in the inhibition of cleavage of Imipenem

CILASTATIN

ADVERSE EFFECT OF CARBAPENEMS

-SEIZURE -ALLERGY -GI DISTRESS

● Include Aztreonam ● Drugs with Monocyclic β-lactam ring ● Spectrum: only active for G(-) aerobic rods (Pseudomonas aeruginosa) ● Extremely resistance to β-lactamases

MONOBACTAMS

● These are added to β-lactam antimicrobials to counter the killing enzyme of bacteria.

Beta-Lactamase Inhibitors

Beta-Lactamase Inhibitors INCLUDE THE FOLLOWING

* CLAVULANIC ACID * SULBACTAM * TAZOBACTAM

No antimicrobial activity Most are against plasmid encoded β-lactamases and inactive against chromosomal β-lactamases Available only in flex combinations with a β-lactam antibiotic (specific Penicillins and Cephalosporins) ○ Piperacillin + Tazobactam (PipTazo) ○ Ampicillin + Sulbactam (AmpiSul) ○ Amoxicillin + Clavulanic acid (Co-Amoxiclav)

Beta-Lactamase Inhibitors

type of drugs used to treat bacterial infections, especially those caused by G(+) organisms and enterococcal infections which are resistant to other antibiotics

GLYCOPEPTIDES

Mechanism of Action: Inhibitors of Cell Wall Synthesis ○ Work by inhibiting the cell wall synthesis of the bacteria

GLYCOPEPTIDES

1st Gen Glycopeptides

VANCOMYCIN TEICOPLANIN RAMOPLANIN

Has an important role because of its effectiveness vs multiple drug-resistant organisms -MRSA -ENTEROCOCCI

VANCOMYCIN

2nd Generation Glycopeptides:

(-VANCIN) ORITAVANCIN DALBAVANCIN TELAVANCIN

○ Inhibits transglycosylation and transpeptidation steps of cell wall biosynthesis

2nd Generation Glycopeptides: ORITAVANCIN DALBAVANCIN TELAVANCIN

disrupts bacterial membrane integrity, while Dalbavancin does not.

ORITAVANCIN

GLYCOPEPTIDES: ADVANTAGES

-GIVEN SINGLE DOSE (2 DOSE-DALBAVANCIN) -TARGET ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTION -NO DRUG MONITORING -CONVENIENT

GLYCOPEPTIDES: DISADVANTAGES

-VERY EXPENSIVE -DELAYED HYPERSENSITIVITY -TREATMENT FAILURE -ADMIN.IV

Inhibits cell wall synthesis by interfering w/ 2nd stage of peptidoglycan synthesis–peptidoglycan polymerization

Vancomycin&1stGenGlycopeptides

like Vancomycin, mediates its antibacterial activity by binding to the D-alanyl-D-alain moiety and sequesters the lipid 2 substrate ○ Results in inhibition of bacterial peptidoglycan synthesis

TEICOPLANIN

blocks bacterial cell wall biosynthesis by interfering with peptidoglycan production

RAMOPLANIN

Mechanism of action distinct from glycopeptides: ‐ Does not complex with the D-alanyl-D-alanine sequence of cell wall precursor

RAMOPLANIN

IN ____ BACTERIA, Vancomycin binds to the transglycosylase enzymes = preventing the linkage of D-alanyl and D-alanine terminus of the cell wall precursor units = failure of the cross linkages between the two glycopeptide polymers

G+ BACTERIA

Has effectively been used against G(+) organisms Used in patients with ○ MRSA ○ MRSE (Methicillin-Resistant Staphylococcus epidermidis) ○ Enterococci infections

Vancomycin:ClinicalUses

BACTERICIDAL ○ Infections by G(+) bacteria resistant to β-lactams ○ People with G(+) infections but allergic to β-lactams

VANCOMYCIN

Alternative drug in: ○ Staphylococcal Endocarditis ○ Methicillin-resistant infections ○ Enterococcal infections ○ Diphtheroid infections ○ Clostridium difficile colitis

VANCOMYCIN

Prophylaxis and treatment: For patients with prosthetic heart valves or patients to be implanted with prosthetic devices

VANCOMYCIN

Alternatives for Vancomycin resistance: 1. CYCLIC LIPOPROTEIN

DAPTOMYCIN

Alternatives for Vancomycin resistance:

Quinupristin-dalfopristin + Linezolid

● Plasmid-mediated changes in the permeability of the bacterial membrane to the drug ● Decreased binding to Vancomycin receptors ○ Due to the replacement D-alanyl-D-alanine lactate in molecules of resistant organisms.

VANCOMYCIN RESISTANCE

VANCOMYCIN ADVERSE EFFECTS -IDEALLY IV SHOULD BE GIVEN VERY SLOWLY ● Effect manifesting as flushing and shock due to histamine release. ● Associated w/ rapid drug infusion.

RED-MAN SYNDROME

VANCOMYCIN ADVERSE EFFECTS ● Most essential and irreversible. ● Occurs in patients with renal impairment ● Hearing loss is permanent ● More common if administered concomitantly with aminoglycosides

OTOTOXICITY

VANCOMYCIN ADVERSE EFFECTS ● Impure preparations. ● Occurs in patients with renal impairment ● More common if administered concomitantly with aminoglycosides.

NEPHROTOXICITY

- NEWER DRUG -AS EFFECTIVE AS VANCOMYCIN IN TREATINGS. AUREUS *** LESS ADVERSE EFFECTS LIKE 1. SKIN RASHES 2. RED MAN SYNDROME 3. LESS DAMAGE TO THE KIDNEYS

TEICOPLANIN

● Cyclic lipopeptide antibiotic ● Alternative to vancomycin, linezolid, and quinupristin/dalfopristin for tx of G(+) infections ○ Ex. MRSA or MRSE infections **BACTERICIDAL **SYNTHESIS = CELLMEMBRANE DEPOLARIZATION **MOA = INHIBITOR OF CELLWALL

DAPTOMYCIN

Binds to the cytoplasmic membrane of bacteria → results to rapid depolarization of the membrane → disrupting its functions and inhibiting DNA, RNA & protein synthesis

DAPTOMYCIN

DAPTOMYCIN ADVERSE EFFECTS

● Constipation, nausea, vomiting, headache, and insomnia ● LFTs [liver function tests] [and CPK [creatine phosphokinase] may ↑ ● Discontinue concurrent statins

1. Trimethoprim is a drug that targets which one of the 4 major categories of bacterial targets? a. Cell Wall b. Nucleic acid c. Outer Cell Membrane d. Ribosomes

B.NUCLEIC ACID

2. All beta-lactams inhibit synthesis of the peptidoglycan layer by binding to and inhibiting the action of ___________ involved in the cross-linking of peptidoglycan chains. a. Transketolase b. Penicillinase c. Transpeptidase d. Beta-Lactamase

c. Transpeptidase

3. T/F. Natural or Penicillinase-sensitive penicillins are active against both Gram(+) and Gram(-) rods, and anaerobes.

FALSE

4. T/F. Antistaphylococcal Penicillins are active against Gram(-) bacteria and other classes of β-lactamase producing bacteria.

FALSE

5. T/F. Aminopenicillins and antipseudomonal penicillins have greater activity against Gram(-) bacteria due to their enhanced ability to penetrate outer membranes.

TRUE

6. All of the following are adverse effects of antistaphylococcal penicillins except: a. Hepatitis b. Interstitial nephritis c. Myoclonic seizures d. Neutropenia

c. Myoclonic seizures

7. Which cephalosporin? among the drugs is a fourth-generation a. Cefaclor b. Cefamandole c. Cefixime d. Cefepime

D. CEFEPIME

8. Which of the following is an adverse effect of Daptomycin a. Constipation, nausea, vomiting, headache, and insomnia b. LFTs and CPK may increase c. Discontinue concurrent statins d. AOTA

D. AOTA

9. Which of the following is true regarding Daptomycin a. Increase dose in bacteremia b. Decrease dose in bacteremia c. Increase dose in endocarditis d. Decrease dose in endocarditis e. AandC f. BandD g. AandD h. BandC

a. Increase dose in bacteremia c. Increase dose in endocarditis

10. In general, IV vancomycin should be given very slowly. If the infusion is fast, there is a risk of precipitating: a. Purple-glove syndrome b. Red-man syndrome c. Blue-man syndrome d. Red-glove syndrome

b. Red-man syndrome

DR. MABANAG - CEPHALOSPORINS, CARBAPENEMS, MONOBACTAMS & BETA LACTAMASE INHIBITORS Flashcards

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