(MIDTERM) Beta-Lactam Antibiotics: Cephalosporin Flashcards by Monica Anne Colina

Discovery in 1945 of a mold isolated from sewage outfall

Giuseppe Brotzu

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Formerly: Cephalosporium acremonium

Acremonium chrysogenum

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Isolated in 1953 from Cephalosporium culture

Cephalosporin C

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NATURAL phalosporin

Cephalosporin C

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Structure was elucidated in 1959, determined to also contain the B- LACTAM RING, similar to Penicillins

Cephalosporin C

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Used as a starting material for the synthesis and structure
modification of many different semi-synthetic cephalosporins

Cephalosporin C

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Cephalosporins
Activity:

Broad Spectrum Antibiotics

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Cephalosporins are active against Both Gram- Positive and Gram-Negative Organisms

Broad Spectrum Antibiotics

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Cephalosporins are active against ___________________ Organisms

Both Gram- Positive and Gram-Negative

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Cephalosporins
Mechanism of Action:

Cell Wall Synthesis Inhibitor
Bactericidal

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Cephalosporins
Generations:

FIVE GENERATIONS

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Successive modifications of the Cephem ring structure have resulted in “_____________” of cephalosporin antibiotics

generations

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There is no concrete and official scientific correlation that the higher the generation of cephalosporins confers a broader spectrum of activity

Classification of Cephalosporins

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_________________ of different
cephalosporins is useful in distinguishing them into
different generations

relative acivity

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Similar activity against certain groups or strains of bacteria

Relative Activity

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Classification of Antibiotics that Posses the B-lactam Ring:
- A four-membered cyclic amide

Members:
1.) Penciliins
2.) Cephalosphorins
3.) Carbapenems
4.) Monobactams

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Bicyclic Ring System:

CEPHEM RING

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Fused Beta-Lactam and Dihydrothiazine
Ring

Basic Cephalosporin Nucleus

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Contributes to Angle Strain, however, STRAIN IS LESSER AS COMPARED TO PENICILLINS

Lesser Strain = Less Instability and
Reactivity Towards Beta-Lactamases

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Provides ABILITY TO RESIST EFFECTS OF BETA- LACTAMASES

Due to less strain

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PENAM

Penicillins

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CEPHEM

Cephalosporins

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CARBAPENEM

Carbapenems

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Confers Electrophilic nature due to lack of resonance of electrons within the ring

Carbonyl Group

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Carbonyl Group; Makes the group Susceptible to ___________________

Nucleophilic Attack

Six-Membered Sulfur-Containing Ring

Dihydrothiazine Ring

Forms the Cephem Ring (Bicyclic Ring System)

Dihydrothiazine Ring

Confers lesser strain to the Beta-Lactam Ring as compared to the Thiazolidine Ring

Dihydrothiazine Ring

Lesser strain provides increased resistance against Beta-Lactamases

Dihydrothiazine Ring

6 Structure-Activity Relationship

1. Carbonyl Group 2. Dihydrothiazine Ring 3. Carboxyl Group 4. Sulfur 5. Beta-Carbon 6. Cis-Stereochemistry

Modified for Formulation Development

Carboxyl Group

* Carboxylate Ion is formulated into either a Sodium or Hydrochloride Salt - Increased solubility

Carboxyl Group

Formulation into Prodrugs

Carboxyl Group

Carboxylate Ion is formulated into either a ________________________

Sodium or Hydrochloride Salt

Formulation into Prodrugs Example:

Ceftaroline fosamil

- Increase in Bioavailability - Confers Potent Inhibition of Beta- Lactamases

Ceftaroline fosamil

May be substituted to produce analogs of Cephalosporins

Sulfur

May be substituted to produce analogs of Cephalosporins, which include:

* Oxygen * Carbon

Produces an OXACEPHAM RING

Oxygen

Enhanced Spectrum of Activity Than Sulfur

Oxygen

Produces an CARBACEPHAM RING

Carbon

Enhanced Resistance Against Beta-Lactamases

Carbon

No modification/substitution allowed

Beta-Carbon

Essential configuration for binding to Transpeptidases

Cis-Stereochemistry

Substitution will Improve PHARMACOKINETIC PROPERTIES

Position 3 Substituent

Substitution will Improve Resistance Against Beta-Lactamases

Position 3 Substituent

_____________ is prone to Hydrolysis at the Carbon Number 3 Position

Ring

Attachment of Electron- Withdrawing Groups = Resists Chemical or Metabolic Instability = ____________-Stable

ACID

Position 7 Substituent R-Group Substitution Influences;

* Spectrum of Antibacterial Activity * Affects Binding of Beta-Lactamases

Introduction of POLAR and/or IONIZABLE Groups

Spectrum of Antibacterial Activity

Attachment of Bulky Groups = Provides _______________ Hindrance

STEARIC

May Be Substituted to Produce Semi- Synthetic Derivatives

Position 7 Substituent R-Group

Introduction of _______________ and/or _______________ Groups

POLAR IONIZABLE

- Introduction of ___________ Groups - Provides steric hindrance

BULKY

- Introduction of BULKY Groups - Provides steric hindrance

Affects Binding of Beta-Lactamases

Structural breakdown = Inactivation of the Ring Structure RESULT=_________________

LOSS OF ANTIBACTERIAL ACTIVITY

Interventions: Introduction of Bulky Groups to Provides ______________

Steric Hindrance

* Structural breakdown = Inactivation of the Ring Structure - Result = LOSS OF ANTIBACTERIAL ACTIVITY * Interventions: Introduction of Bulky Groups to Provides Steric Hindrance - Higher generation cephalosporins incorporates this modification

Effects of Hydrolysis by Beta-Lactamases

Structural breakdown=

Inactivation of the Ring Structure

The only 1st gen administered as ____________ or _____________

IV IM

FIRST GENERATION: Ce____alexin Ce____alotin Ce____adrine Ce____apirin Cefu_____xil Cefa_____in

PH PH PH PH DRO ZOL

Active against Methicillin-Resistant Staphylococcus aureus (MRSA) and Group A Streptococcus

First Generation

First Generation All are generally active against ___________________

G - NEGATIVE

AKA Streptococcus PYOGENES

Methicillin-Resistant Staphylococcus aureus (MRSA)

Useful for skin infections

First Generation

SECOND GENERATION: Ce____clor Ce____mandole Ce____nicid Ce____xitin Ce____tetan Ce____roxime Cef_____zil Cef______zole ______carbef

FA FA FO FO FO FU PRO META LORA

Second Generation: All are generally active against ___________________ and ______________________

G (+) G (-)

THIRD GENERATION: Cef____axone Cef______xime Ceftazi______ Cefo______zone Cefo_____ime Cef______ren Ce____ime Ceftibu____ Cef______xime _______lactam

TRI PODO DIME PERA TAX DITO FIX TEN TIZO MOXA

use to tx MENINGITIS

CeftaziDIME

use to tx MENINGITIS & STREPTOCOCCUS INFECTIONS

CEFOPERAZONE

Resistant to B- Lactamases

Third Generation

Can cross BLOOD BRAIN BARRIER

Third Generation

Third Generation Can cross BLOOD BRAIN BARRIER - Some are able to treat susceptible ____________________________

BACTERIAL MENINGITIS

Cefe____me Cef____rome

PI PI

Use for NOSOCOMIAL and COMMUNITY-ACQUIRED infections

Fourth Generation

Broad-Spectrum of activity against PSEUDOMONAS AEROGINOSA

Fourth Generation

2 Mainly of Fourth Generation

* COMMUNITY-ACQUIRED Pneumonia * Chemotherapy-Induced Febrile NEUTROPENIA

Severe and life-threatening adverse drug reactions with chemotherapy used against cancer

Chemotherapy-Induced Febrile NEUTROPENIA

Patient experiences High _________________ (>38.5°C) at the same time experiencing a Low __________________ Count in the blood.

TEMPERATURE NEUTROPHIL

Patient experiences High TEMPERATURE (>38.5°C) at the same time experiencing a Low NEUTROPHIL Count in the blood.

Chemotherapy-Induced Febrile NEUTROPENIA

FIFTH GENERATION: Ce______roline Ce______biprole Ce______lozane

FTA FTO FTO

Prodrug: Ce____roline fosamil

CeFTAroline

Ce______biprole medocaril

CeFTObiprole

Not a Prodrug

CeFTOlozane

Fifth Generation: PRODRUGS (Except Ce______lozane)

CeFTOlozane

Combined with TAZOBACTAM(piperacillin)

CeFTOlozane

Used against ___________________Staphylococcus aureus

METHICILLIN-RESISTANT

Oxime group B-lactamase resistance

BULKY GROUP

Pharmacokinetics

MODIFIED BIOAVAILABILITY

Polar or Ionizable Group

SPECTRUM OF ACTIVITY

Risk Factor of SEIZURE

CHRONIC KIDNEY DISEASE

ADR:

* Seizure * GI upset

Occurs at ________ Doses

HIGH

AKA Renal Failure: Decreased renal clearance of drugs

CHRONIC KIDNEY DISEASE

Especially when there is no appropriate DOSE adjustment

CHRONIC KIDNEY DISEASE

GI upset

p.c. (after meals)

(MIDTERM) Beta-Lactam Antibiotics: Cephalosporin Flashcards

(96 cards)