Beta lactams 4/5

• the four-membered beta-lactam ring is fused to a six-membered dihydrothiazine ring,

• two side chains

• low antimicrobial activity

• chemical modification by attaching various two side chains has enabled the synthesis of hundreds of potent semi-synthetic derivatives

• rare as 1st choice antibiotic

Cephalosporins

• C7 side chains vary

• antibacterial activity

• Modifications at position 3 on the dihydrothiazine ring alter the metabolism and pharmacokinetic properties of the drug

modification of cephalosporins

• bactericidal

• Interfere with bacterial cell wall peptidoglycan synthesis by binding to penicillin-binding proteins (PBPs) and activating autolysins.

• combined effects damage the cell wall, causing bacterial death by lysis.

• Most effective against cells undergoing active growth and division.

• Demonstrates bactericidal activity - they are not as effective against slow-growing bacteria).

cephalosporins mechanism of action

• Cefalexin - oral

• cefazolin

• good activity against gram neg

• 1st gen cephalosporins

moderate specturm

• Cefaclor - oral

• cefuroxime - oral

Moderate Spectrum with Antihaemophilus Activity

• Cefoxitin

Moderate spectrum with antianaerobic activity

• Ceftazidime

• cefepime,

• ceftolozane with tazobactam

Broad Spectrum with Antipseudomonal Activity

• Ceftaroline

Broad Spectrum with Activity Against MRSA

• Poor absorption from the gastrointestinal tract (GIT) generally.

• Most cephalosporins - administered parenterally via intramuscular (IM) or intravenous (IV) routes.

• Rapid IV administration of large doses can lead to seizures.

absorption of cephalosorphins

• Distribute well to most body fluids and tissues, though concentrations in ocular fluids are generally low.

  • 1st and 2nd generation agents show unreliable CSF penetration and should not be used for treating bacterial meningitis.

  • 3rd and 4th generation agents achieve sufficient CSF penetration to exert a bactericidal effect.

Distribution of cephalosporins

• Most agents are eliminated by the kidneys via glomerular filtration and tubular secretion.

• Dose reductions are required in renal insufficiency.

• Exception: Ceftriaxone is eliminated mainly by the liver (biliary pathway)

Elimination of cephalosporins

• Penetrates well into most body tissues.

• Does not penetrate the central nervous system (CNS) and cannot be used to treat meningitis.

• Drug of choice for surgical prophylaxis and streptococcal and staphylococcal infections requiring intravenous (IV) therapy.

• Can be used in patients with a mild penicillin allergy, provided it is not an immediate hypersensitivity reaction.

• Can be administered intramuscularly (IM), though this route is painful.

• excreted via kidneys - dose adjustment needed

• sodium levels - heart failure -inhibit y-carboxylation of glutamate - impacting vitamin K recycling

Cefazolin - pharmacokinetics

• stable to gastric acid.

• Plasma half-life (1/2) is 0.5–1 hour, which increases with decreased renal function.

• Urine concentration is usually very high.

• Levels in most tissues are variable and generally lower than in serum.

• The drug is not metabolized.

• Excreted via glomerular filtration and tubular secretion into the urine, with almost all of the dose recoverable unchanged in urine.

• Dose reduction is required in severe renal impairment.

• Probenecid blocks tubular secretion and can substantially increase serum levels of cefalexin.

• used for Epididymo-orchitis

Cefalexin - pharmcokinetics

• Staphylococcal & streptococcal infections in people with mild-to-moderate penicillin allergy

• UTI

indications for cefalexin and cefazolin

• Cefaclor, cefoxitin, and cefuroxime.

• addition of extended Gram-negative coverage than 1st gen

• Cefaclor & Cefuroxime - Exhibit greater stability than standard moderate-spectrum cephalosporins to certain Gram-negative beta lactamases, demonstrating increased activity against Haemophilus influenzae.

• Cefaclor - Structurally closely related to cefalexin, shares similar antimicrobial activity to cefalexin, but offers greater activity against many Gram-negative bacteria.

• Cefoxitin - Demonstrates activity against anaerobes, specifically Bacteroides fragilis. Resists a wider range of beta-lactamases compared to other moderate-spectrum cephalosporins.

2nd generation cephalosporins

• well absorbed from the gastrointestinal tract.

• Half-life 1/2 is 0.5–1 hour

• Rapidly excreted by the kidneys.

• taken with food

• serum sickness-like syndrome - common in children, symptoms for 6-12 days - avoid drug if causes this

• taken with presence of food enhances absorption and swallowed whole

• Half-life is prolonged in renal impairment, necessitating a dose reduction.

Cefaclor - pharmcokinetics

• surgical prophylaxis for some GI procedures:

• antibacterial combinations for mixed anaerobic infections (e.g., peritonitis

Indications for Cefoxitin

• Gonococcal infections (alternative to amoxicillin)

• Surgical prophylaxis (selected indications

Cefuroxime indications

• Acute otitis media

• Respiratory tract infections caused by H. influenzae

• Acute sinusitis

Cefaclor and Cefuroxime indications

• Cefotaxime, ceftazidime, and ceftriaxone.

• Expanded Gram-negative coverage compared to earlier generations.

• capable of crossing the blood-brain barrier (BBB).

• Spectrum includes Serratia marcescens, Providencia species, and $\beta$-lactamase-producing strains of Haemophilus and Neisseria

• Ceftazidime - useful activity against Pseudomonas aeruginosa.

• Space/ESCAPPM organisms such as Enterobacter, Serratia, Citrobacter, Providencia, Acinetobacter, Proteus, and Morganella) AmpC enzyme breaks down (hydrolyzes) the antibiotic, neutralizing it so it can no longer kill the bacteria, can cause resistance

third generation cephalosporins

• Penetrate body fluids and tissues well.

• When administered IV, achieve levels in the cerebrospinal fluid (CSF) sufficient to inhibit most susceptible pathogens.

• Ceftriaxone - longest half life

• Ceftriaxone: Excretion through biliary tract, but dose reduction may still be required in renal impairment.

• other third-generation cephalosporins are excreted by the kidney

  and therefore require dosage adjustment in renal insufficiency.

third generation cephalosporins - pharmacokinetics

• exhibit less Gram-positive activity compared to earlier generations, but are more stable against Gram-negative beta-lactamases than moderate-spectrum cephalosporins.

• demonstrate activity against many Gram-negative organisms that are resistant to other $\beta$-lactam drugs.

• equivalent efficacy & safety in most indications

• Ceftriaxone Benefits: Requires less frequent dosing making it more convenient and cost-effective.

• Cefotaxime is preferred in neonates.

• Ceftriaxone Risk: Ceftriaxone displaces bilirubin from plasma albumin, increasing the risk of hyperbilirubinemia and bilirubin encephalopathy in neonates.

• Cefotaxime - Rapid IV administration of cefotaxime can precipitate life-threatening arrhythmias.

Cefotaxime & ceftriaxone

• Displays excellent anti-pseudomonal activity.

• Effective against many aminoglycoside-resistant bacterial strains.

• Similar to cefotaxime and ceftriaxone in overall properties, but demonstrates weaker staphylococcal activity than first-generation (moderate-spectrum) cephalosporins and should not be used for staphylococcal infections.

Ceftazidime

• Addition to Ceftazidime restores activity against ceftazidime-resistant and many carbapenem-resistant Pseudomonas aeruginosa.

• Restores activity against Enterobacteriaceae expressing Klebsiella pneumoniae carbapenemases (KPCs) and AmpC beta-lactamases.

• Precaution required in patients with an aztreonam allergy due to identical/shared side-chain structures leading to potential cross-reactivity with ceftazidime.

Avibactam

• Ceftriaxone is eliminated by both renal (33–67%) and biliary pathways.

• Can bind calcium to form insoluble precipitates, leading to biliary pseudolithiasis and nephrolithiasis.

Nephrolithiasis:

• Formation of calcium-ceftriaxone renal stones.

• Usually reversible, though active treatment may occasionally be required.

• caution in patients on sodium restriction or with heart failure (HF).

• Increased risk of bleeding associated with impaired vitamin K synthesis.

Ceftriaxone

• Asymptomatic biliary sludge formation caused by calcium-ceftriaxone complexes.

• Dose-dependent occurrence that can be mistaken for true gallstones on ultrasound imaging.

• Typically resolves spontaneously after treatment cessation

• Pseudolithiasis:

• Formation of calcium-ceftriaxone renal stones.

• Usually reversible, though active treatment may occasionally be required.

Nephrolithiasis:

• Empirical treatment of severe community-acquired pneumonia (with azithromycin)

• Empirical treatment of orbital cellulitis

• Bacterial meningitis (usually with other agents)

• Gonococcal infection

• PID (Pelvic Inflammatory Disease)

• Epiglottitis

Cefotaxime and Ceftriaxone indications

• Prevention of meningococcal disease

• Prevention of H. influenzae type b disease (if rifampicin unsuitable)

• Severe Salmonella enteritis (if other antibacterials unsuitable)

• Typhoid, paratyphoid (enteric fever)

Ceftriaxone-Only Indications

• Reserved for the treatment of P. aeruginosa infections:

• Melioidosis:

• Empirical treatment of sepsis in neutropenic or otherwise immunocompromised people:

Cefotaxime indications

• Complicated intra-abdominal infections (with metronidazole):

• Complicated UTIs including pyelonephritis

• Hospital-acquired pneumonia

• Ceftazidime/tazobactam, Ceftazidime/avibactam indications

• Has similar Gram-positive activity to cefazolin AND is active against many Gram-negative microorganisms.

• Good activity against Pseudomonas aeruginosa, Enterobacterales, methicillin-susceptible Staphylococcus aureus (MSSA), and Streptococcus pneumoniae.

• Highly active against Haemophilus and Neisseria species.

• Very broad spectrum overall.

• Penetrates well into the cerebrospinal fluid (CSF).

• Cleared by the kidneys, requiring dose adjustment in renal impairment.

• used empirically in patients with febrile neutropenia.

Cefepime - 4th generation

• Spectrum of Activity:

  • Active against many Gram-positive and Gram-negative bacteria, including strains resistant to other antibacterials.

    • Pseudomonas aeruginosa, Enterobacteriaceae (except those producing AmpC $\beta$-lactamases), Streptococcus pneumoniae, Bacteroides fragilis

• Inactive against KPC-producing Klebsiella pneumoniae.

• Inactive against bacteria that produce metallo-$\beta$-lactamases or OXA-carbapenemases.

Ceftolozane with tazobactam specturm of activity

• Has increased binding affinity for penicillin-binding protein 2a (PBP2a), the modified peptidoglycan transpeptidase responsible for $\beta$-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA).

  • Active against Staphylococcus aureus, including MRSA.

  • Active against Streptococcus pyogenes and Streptococcus pneumoniae.

  • Uniquely, it is the only cephalosporin with activity against MRSA, vancomycin-intermediate S. aureus (VISA), and heterogeneous vancomycin-intermediate S. aureus (hVISA).

• Demonstrates broad-spectrum activity against many Gram-negative bacteria by binding to their PBPs.

• Escherichia coli, Haemophilus influenzae, and Klebsiella pneumoniae.

• Not active against Pseudomonas species.

Ceftaroline

• Complicated intra-abdominal infections (with metronidazole)

• Complicated UTIs, including pyelonephritis

• Hospital-acquired pneumonia, including ventilator-associated pneumonia

Ceftolozane / tazobactam Indications

• Complicated skin and soft tissue infections

• Community-acquired pneumonia

Ceftaroline Indications

• Diarrhoea, nausea, vomiting (D, N, V)

• Allergy

• Rash

• Dizziness

• Headache

• Inflammation and pain at injection site

• Clostridium difficile-associated diarrhoea (CDAD)

• Bleeding

• Blood dyscrasias: Neutropenia, thrombocytopenia

• Immunological reactions

adverse effects for cephalosporins

• Penicillins (Pc) and cephalosporins can cause similar allergic reactions.

• common misconception that cephalosporin allergy occurs in approximately 10% of patients who are allergic to penicillin.

• Recent reviews demonstrate that overall, only 1% to 2% of patients with a confirmed penicillin allergy actually have a cephalosporin allergy.

• rare, and patients should not automatically be labeled as cephalosporin-allergic.

• Cross-reactivity is more likely in patients with an amoxicillin or ampicillin allergy who receive cefalexin or cefaclor, due to their similar R1 side-chains.

cross reactivity for cephalsporins

• a history of penicillin (Pc) allergy should not rule out the use of cephalosporins.

• R1 side chain is thought to be responsible for immunological reactions.

• Amoxicillin and ampicillin share similar R1 side chains with cefalexin and cefaclor - cross-reactivity may occur between these specific agents, but not with other cephalosporins that possess distinct R1 side chains.

• If a beta-lactam is the preferred drug, antimicrobials with identical or similar R1 side-chains should be avoided based on potential cross-reactivity.

why cross-reactivity is believed

• Amoxicillin or Ampicillin Allergy: Avoid cefalexin and cefaclor.

• Ceftriaxone Allergy: Avoid cefotaxime, cefepime, and cefuroxime.

• Ceftazidime Allergy: Avoid aztreonam.

• Cefazolin - no similarities - best

drugs to be avoided for cross reactivity

• IV

• Inhibits bacterial cell wall synthesis by specifically binding to penicillin-binding protein 3 (PBP 3) of Gram-negative bacteria.

• Active against Gram-negative aerobic microorganisms, including Pseudomonas species.

• Gram-positive bacteria and anaerobic microorganisms are resistant.

• Rash, nausea (N), diarrhoea (D), vomiting (V), taste disturbance,

Monobactams

• More stable than cephalosporins against inducible AmpC beta-lactamases produced by certain enteric Gram-negative microorganisms

• Susceptible to hydrolysis by extended-spectrum beta-lactamases (ESBLs).

• Enterobacteriaceae producing NDM-1 and KPCs are often capable of hydrolysing aztreonam.

• Septicaemia.

• Lower respiratory tract infections due to Pseudomonas aeruginosa in cystic fibrosis.

• Cases involving severe penicillin allergy or where other agents are ineffective.

• precaution in patients with penicillin (Pc) or cephalosporin hypersensitivity.

Aztreonam

• Carbapenems are structurally related to $\beta$-lactam antibiotics.

• Class members include:

  • Ertapenem

  • Imipenem

  • Meropenem

• Structural Differences from Penicillins (Pc):

  • Substitution of a carbon atom (C) for the sulfur atom (S) in the ring structure.

  • Addition of a double bond to the five-membered ring of the penicillin nucleus.

  • IV

Carbapenams

• possess the broadest spectrum of activity of all antibacterial classes.

• Good activity against Gram-negative, Gram-positive, and anaerobic bacteria (excluding MRSA).

• Resistant to hydrolysis by most $\beta$-lactamases, including extended-spectrum $\beta$-lactamases (ESBL).

• acquired ability to produce metallo-beta- lactamases (carbapenemases; Group B) often inactivate all beta-lactams except aztreonam.

• inactive against MRSA and Enterococcus faecium.

Carbapenams specturm of activity

• Wide activity against enteric Gram-negative rods and Pseudomonas species.

• Excellent activity against anaerobes, including Bacteroides fragilis.

• Active against many Gram-positive microorganisms.

Imipenem and Meropenem Spectrum:

• Displays similar activity overall, BUT is inactive against Pseudomonas aeruginosa and Acinetobacter species.

• Ertapenem Spectrum & Exception:

• inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), with affinities that differ between individual carbapenems.

• bactericidal.

mechanism of action Carbapenems

• Not absorbed orally.

• Excreted primarily in the urine via glomerular filtration and tubular secretion.

• Rapidly inactivated by a dipeptidase located in the brush border of proximal renal tubules, converts imipenem into inactive, nephrotoxic metabolites, some amount of drug is excreted as unchanged drug

• administered in combination with cilastatin - dehydropeptidase inhibitor.

• Meropenem and ertapenem are more resistant to renal dipeptidases and are given alone.

• contraindicated (CI) in meningitis.

• Nausea (N), vomiting (V), diarrhoea (D), headache, and injection site reactions (e.g., phlebitis).

Imipenem - pharmcokinetics

• Effective in intra-abdominal, pelvic, and skin and soft tissue infections.

• Moderate-to-severe infections, including diabetic foot infections, caused by susceptible organisms where other antibacterials are unsuitable (inactive against P. aeruginosa and Acinetobacter).

• Empiric treatment of complicated intra-abdominal and acute pelvic infections, and other severe mixed aerobic and anaerobic infections when P. aeruginosa infection is unlikely.

• Not indicated for empirical treatment of nosocomial infections if Pseudomonas spp. infection is possible.

• IV or IM

Ertapenem: indications

• tx of intra-abdominal infection, UTIs & Lower respiratory tract infections

• empirical tx of nosocomial infections if Pseudomonas spp infection

Imipenem & Meropenem indications

• Attains better levels in CSF & has lower incidence of seizures than imipenem

• Effective in treating meningitis

 Meropenem

• Nosocomial infections and life-threatening infections (when other antibacterials are inappropriate or contraindicated), or when multi-resistant G-ve infections are

  suspected or proven

   Febrile neutropenia

   Severe mixed aerobic and anaerobic infections, particularly when combinations with an

  aminoglycoside are contraindicated

Imipenem with cilastatin/ Meropenem

• Exacerbations of lower respiratory tract infections in cystic fibrosis

   Meningitis

   Melioidosis

Meropenem

• Modification of target penicillin-binding proteins (PBPs)

• Impaired penetration of drug to target PBPs

• Efflux

• Destruction of the antibiotic (AB) by $\beta$-lactamase enzymes - most common

mechanisms of resistance to B lactams

• Some beta-lactamases have narrow substrate specificity, preferring penicillins to cephalosporins - such as staph aureus, Haemophilus influenzae, Escherichia coli

• Other beta-lactamases hydrolyze both cephalosporins and penicillins.

• Carbapenems are highly resistant to hydrolysis by penicillinases and cephalosporinases.

• they are hydrolyzed by metallo-beta-lactamases and other carbapenemases.

beta lactamases

• specific type of β-lactamase that is specific for penicillins

• Was renamed beta-lactamase when the structure of the beta-

lactam ring was determined

• All beta-lactamases catalyse the same basic reaction (hydrolysing the $\beta$-lactam ring).

• A number of different types of $\beta$-lactamases have been isolated and characterised.

• can hydrolyse a wider variety of $\beta$-lactam antibiotics are called extended-spectrum beta-lactamases (ESBL).

• can beta-lactamases with relatively narrow substrate specificity are called penicillinases or cephalosporinases.

Penicillinase

• Amino acid sequence

• Biochemical characteristics

• Classes A, C & D act by a serine-based mechanism

• Class B (metallo-β-lactamases) need zinc for their action

beta lactam classification

• TEM-1, TEM-2, SHV-1, ESBLs (Extended-Spectrum $\beta$-Lactamases), and KPC (Klebsiella pneumoniae carbapenemase).

• Penicillins, cephalosporins, and aztreonam.

• Inhibited by clavulanic acid.

• Narrow spectrum: TEM-1, SHV-1

• Extended spectrum: Mutated versions of parent TEM-1/SHV-1, imported classes (e.g., CTX-M)

• Carbapenemases: KPC

class A

• Enzymes: IMP, VIM, SPM, AIM, NDM, etc.

• substrates Penicillins, cephalosporins, carbapenems (not aztreonam).

• Inhibitors: Not inhibited by clavulanic acid.

• Use zinc ions to break down almost all $\beta$-lactam antibiotics, including carbapenems.

• Metallo-beta-lactamases / MBLs

class B

• AmpC (chromosomal or plasmid-mediated such as CMY).

• Penicillins, cephalosporins, and aztreonam.

• Inhibitors: Not inhibited by clavulanic acid.

• Organisms with Chromosomal AmpC: Enterobacter, Serratia, Citrobacter freundii, Hafnia alvei, Acinetobacter baumannii, Providencia, Pseudomonas aeruginosa, Morganella morganii.

class C

• Enzymes: OXA-1, OXA-23, OXA-48, OXA-181, etc.

• Substrates: Penicillins, cephalosporins, and sometimes carbapenems.

• Inhibitors: Usually not inhibited by clavulanic acid.

class D

• suicide inhibitors that inactivate $\beta$-lactamase enzymes, preventing the destruction of co-administered $\beta$-lactam antibiotics.

• Clavulanic acid

• Avibactam

• Tazobactam

• Resemble $\beta$-lactam molecules structurally.

• Possess very weak intrinsic antibacterial action on their own.

• Most active against Ambler class A beta-lactamases (particularly plasmid-encoded transposable element TEM beta-lactamases) - staphyloccoci, H influenza

• not good inhibitors of class C β-lactamases - chromosomally encoded and inducible, produced by: Enterobacter, Citrobacter, Serratia

• they do inhibit chromosomal β-lactamases of Bacteroides

beta lactamase inhibitors

• little inherent antibacterial activity on their own.

• Significantly extend the spectra of activity of penicillins (Pc's) when combined with them

• Combination therapy should be reserved.

• inhibitor extends the spectrum of a penicillin provided that:

  • The inactivity of the penicillin is due to destruction by a beta-lactamase.

  • The inhibitor is active against the specific beta-lactamase produced.

  • Piperacillin + tazobactam.

beta lactamase inhibitors specturm of activity

• adding clavulanic acid or tazobactam to amoxicillin or piperacillin extends their spectrum of activity to cover many $\beta$-lactamase-producing Gram-positive and Gram-negative microorganisms.

• only avaliable as fixed combinations

• Combinations can cause certain side effects more frequently than amoxicillin alone, including:

  • Diarrhoea

  • Cholestatic hepatitis

beta-lactamse inhibitors adverse effects