Dr. Kingshuk LahonProfessor of Pharmacology

MGMCRI

CEPHALOSPORINS, CARBAPENEMS & MONOBACTAMS

LEARNING OBJECTIVES What are cephalosporins?

How do they act and against which organisms?

What are the methods by which bacteria became resistant to cephalosporins?

What are the different classes of cephalosporins?

LEARNING OBJECTIVES How are they used and what are the

safety precautions during their use?

What are carbapenems and monobactams?

What is their antimicrobial spectrum and what infections are they used for?

What are their advantages and disadvantages?

Introduction

Among the most frequently prescribed class.

Beta-lactam ring structure that interferes with the synthesis of bacterial cell wall

7-aminocephalosporanic acid

HISTORY Semi-synthetic group of antibiotics. First isolated from cultures of Cephalosporium

acremonium from a sewer in 1948 by Italian scientist, Giuseppe Brotzu.

Derived from cephalosporin C, an acid-stable molecule with antibacterial activity, produced from Cephalosporium acremonium.

The first agent Cephalothin was launched by Eli Lilly in 1964.

Cephalosporium

acremonium

MOA

The site of action of beta-lactam antibiotics is the penicillin binding protein (PBP) on the inner surface of the bacterial cell membrane that are involved in the synthesis of the cell wall.

Penicillin Binding Proteins

MOA Bactericidal All bacterial cells have a protective cell wall Cephalosporins disrupt the synthesis of the

peptidoglycan layer of bacterial cell walls Causes the walls to break down and

eventually the bacteria die.

MOA

• Each organism has several PBPs and PBPs obtained from different species differ in their affinity towards different β-lactam antibiotics.

• Hence, differing sensitivity to the various β-lactam antibiotics.

MOA

ResistanceAcquired resistance due to: Alteration in target proteins (PBPs)

reducing affinity for the antibiotic. Impermeability to the antibiotic Efflux mechanisms β-lactamases which destroy specific

cephalosporins (cephalosporinases).

Classification

“Generations" based on their spectrum of antimicrobial activity as well as potency.

Also based on chronological sequence of development.

The first cephalosporins were designated first generation

Upto 5th generation till date

Each newer generation of cephalosporins has significantly greater gram-negative antimicrobial properties.

Fourth generation cephalosporins have true broad spectrum activity.

Classification

The 1st generation cephalosporins are:

Cefazolin (prototype) - least toxic Cefadroxil Cephalexin Cephaloridine Cephalothin Cephapirin Cephradine

1st generation cephalosporins

Moderate spectrum agents. Effective against gram +ve aerobes. For treating staphylococcal and streptococcal infections Alternatives for skin and soft-tissue infections, as well as

for streptococcal pharyngitis. Cephazolin is an alternative to anti-staphylococcal

penicillin for patients who are allergic to penicillin. It is also preferred in surgical prophylaxis.

2nd generation cephalosporins

CefaclorCefoxitinCefprozilCefamandoleCefonicidCefprozilLoracarbefCeforanideCefuroxime.

2nd generation cephalosporins

Antibacterial spectrum > 1st generation cephalosporins with extended gram -ve coverage.

Active against β-lactamase-producing H. influenzae or Moraxella catarrhalis, e.g, Cefuroxime against ampicillin-resistant H. Influenzae.

Useful for treating upper and lower respiratory tract infections and sinusitis.

Also active against E. coli, Klebsiella and Proteus, hence useful in UTI

NO ACTION against Pseudomonas

3rd generation cephalosporins

Cefotaxime (prototype)CefdinirCefiximeCefpodoximeCeftibutenCeftriaxoneCeftizoximeCeftazidime CefoperazoneMoxalactam

3rd generation cephalosporins

>> action against gram -ve organisms Some are able to cross BBB Resistant to beta-lactamases from gram –ve bacteria Parenteral 3rd generation cephalosporins (ceftriaxone,

cefotaxime) have excellent activity against most strains of penicillin resistant Streptococcus pneumoniae

Less active against gram +ve cocci and anerobes Useful in mixed aerobic-anaerobic infections in cancer

patients, those undergoing colorectal surgery, obstetric complications

Cefepime Cefluprenam Cefozopran Cefpirome

Cefquinome

4th generation cephalosporins

Extended spectrum agents with similar activity against gram+ve organisms as 1st generation cephalosporins.

>> activity against Enterobacteriaceae Greater resistance to beta-lactamases than 3rd

cephalosporins. Many can cross blood brain barrier and are

effective in meningitis.

4th generation cephalosporins

4th generation cephalosporinsCefepime is effective in many serious infections like hospital-acquired pneumonia, febrile neutropenia, bacteraemia, septicaemia etc.

Cefpirome has zwitter ion character which permits better penetration through porin channels of gram-negative bacteria.

5th generation cephalosporins Ceftaroline Ceftabiprole Increased binding to PBP 2a, which

mediates methicillin-resistance in Staphylococci, resulting in bactericidal activity against these strains.

Some activity against enterococci and gram – ve organisms

Not active against extended-spectrum β-lactamase (ESBL)producing strains.

Individual cephalosporins differ in their: Antibacterial spectrum & relative potency against specific organisms. Susceptibility to β-lactamases elaborated by different organisms. PK: A – many injected, some oral; M & E - majority not metabolized excreted rapidly by kidney; have short t1/2 probenecid inhibits their tubular secretion. Local irritancy on IM injection; few cannot be injected IM.

CEPHALOSPORINS: GENERATION GAP

Dosage1st GENERATION CEPHALOSPORINS:CEFADROXIL (PO) - 0.5-1 g qd-bidCEPHALEXIN (PO) - 0.25-0.5 g qidCEFAZOLIN (IV) - 0.5-2 g q8h

2nd GENERATION CEPHALOSPORINS:CEFOXITIN (IV) - 1-2 g q6-8hCEFOTETAN (IV) - 1-2 g q12hCEFUROXIME (IV) - 0.75-1.5 g q8h

3rd AND 4th GENERATION CEPHALOSPORINS:CEFOTAXIME (IV) - 1-2 g q6-12hCEFTAZIDIME (IV) - 1-2 g q8-12hCEFTRIAXONE (IV) - 1-4 g q24hCEFEPIME (IV) - 0.5-2 g q12h

Pharmacokinetics Organic acids, hydrophilic Poor oral bioavailability, unstable in acidic environment

Readily excreted by kidneys, via tubular secretion in the proximal convoluted tubule. This results in high concentrations of the drug in urine

Exceptions are Cefalexin which is stable in acid and henceforth suitable for oral administration and Ceforperazone which is excreted in bile rather than in urine.

Adverse Effects & Contraindications

Cephalosporins are considered to be among the safest antimicrobials in use

Prolonged treatment/high doses may produce hemopoetic effects with anaemia and bone marrow depression.

Hypersensitivity and allergic reactions may occur including anaphylaxis, fever, skin rashes and granulocytopenia.

Drugs with the methylthiotetrazole ring can also cause severe disulfuram-like reactions; consequently, alcohol and alcohol-containing medications must be avoided.

Often painful when given IM Thrombophlebitis, especially severe with

cephalothin. >> doses cause nephrotoxicity, maximum with

cephaloridine. Bleeding tendency because of interference with

the formation of vitamin K in the gut. Cross allergy with penicillins. Neutropenia and thrombocytopenia rarely

(Ceftazidime). Nausea, vomiting and diarrhoea

Adverse Effects & Contraindications

Q. Disulfiram like reaction is seen with which cephalosporin?

Indications Treatment of bacterial infections caused

by susceptible organisms.

Less or not active against enterococci and Listeria monocytogenes.

Respiratory tract infections (pneumonia,

tonsillitis, bronchitis) with cefuroxime, cefotaxime, ceftriaxone

Septicaemias caused by gram -ve organisms in combination with an aminoglycoside

Skin infections

Urinary tract infections

Indications

• Enteric fever (Ceftriaxone, reserve drug)

• Bacterial meningitis

• Gonorrhoea

• For surgical prophylaxis before, during, and after surgery

• Sometimes with other antibiotics to increase the spectrum of activity.

Indications

New class of beta lactams Imipenem, Meropenem, Faropenem,

Doripenem

Developed to deal with beta‑lactamase producing Gram-ve organisms

Derived from Streptomyces species e.g, semisynthetic imipenem which acts in the same way as the other beta-lactams.

Carbapenems

Antimicrobial spectrum: Broad-spectrum antibiotic with excellent activity against a variety of gram +ve and gram -ve organism (both aerobic and anaerobic)

Resistant to most forms of beta-lactamase,

including that produced by Staphylococcus Susceptible organisms - Streptococci,

Enterococci, Staphylococci, Listeria, Enterobacteriaceae, Pseudomonas, Bacteroides, and Clostridium

However, methicillin-resistant staphylococcus usually resistant

Imipenem

PKRapidly hydrolyzed by the enzyme,

dihydropeptidase, which is found in the brush border of the proximal renal tubule.

It is always administered with cilastatin, an inhibitor of dipeptidase.

Imipenem

ADR Individuals who are allergic to the

penicillins may demonstrate cross-reactivity with imipenem

Nausea and vomitingSeizures have been reported with high

doses, particularly in patients with renal failure.

Meropenem

Similar to imipenem.

It is not degraded by dehydropeptidase, thus no cilastatin is needed.

Excessive levels in kidney failure can cause seizures with imipenem but not with meropenem.

Monobactam

Aztreonam: Monocyclic beta-lactam (a

monobactam).Mechanism of action:

Aztreonam interacts with penicillin binding proteins and induces the formation of long filamentous bacteria.

Antimicrobial spectrum

Unusual spectrum with activity only against Gram-ve aerobic rods. More closely resembles the spectrum of the aminoglycosides.

Gram +ve and anaerobic bacteria are resistant Susceptible organisms include

Enterobacteriaceae, Pseudomonas, Hemophillus and Neisseria

Resistant to the beta-lactamase produced by gram negative organisms.

ADR

Generally, the drug is well tolerated No cross reactivity with penicillins

SUMMARY

Antibiotic stewardship and beta lactams

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