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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
Thank you