Antimicrobial Drugs - II: Beta-Lactams

Beta-lactams

Beta-lactam antibiotics are bactericidal agents. They work by:

Interrupting bacterial cell-wall formation.
Covalently binding to essential penicillin-binding proteins (PBPs).
PBPs are enzymes involved in the terminal steps of peptidoglycan cross-linking in both Gram-negative and Gram-positive bacteria.
Every bacterial species has its own set of PBPs, ranging from three to eight enzymes per species

Penicillins

Natural Penicillins

Benzyl penicillin (Penicillin G or PnG):
- Narrow spectrum antibiotic.
- Activity limited primarily to Gram-positive bacteria and a few others.
  - Streptococci, Pneumococci, Staph. aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Bacilla anthracis, Corynebacterium diphtheriae, Clostridia, Listeria, and spirochetes (Treponema pallidum).
  - Anaerobes involved in orodental infections: fusobacteria, peptostreptococci, Eubacterium, Campylobacter, Prevotella and Porphyromonas.
  - Actinomyces israelii is only moderately sensitive.
- Majority of aerobic Gram-negative bacilli, Mycobacterium tuberculosis, rickettsiae, chlamydiae, protozoa, fungi, and viruses are totally insensitive to PnG.
- Resistance is progressive, primarily through the production of penicillinase.
- Destroyed by gastric acid; less than 1/3rd of an oral dose is absorbed in the active form.
- Pharmacokinetics of PnG is dominated by rapid renal excretion (10% glomerular filtration, the rest by tubular secretion).
- Plasma t_{1/2} of PnG in healthy adults is 30 minutes.

Mechanism of Action

Bacteria synthesize UDP-N-acetyl muramic acid pentapeptide ('Park nucleotide') and UDP-N-acetyl glucosamine.
Peptidoglycan residues are linked, forming long strands, and UDP is split off.
Transpeptidases cleave the terminal D-alanine of the peptide chains.
Cross-linking provides stability and rigidity to the cell wall.
β-lactam antibiotics inhibit transpeptidases, preventing cross-linking and weakening the cell wall leading to bactericidal action.

Doses (1 MU = 0.6 g)

Sodium penicillin G (crystalline penicillin) injection: 0.5–5 MU i.m./i.v. every 6–12 hours.
- Available as dry powder in vials, dissolved in sterile water at the time of injection.
Repository penicillin G injections: Insoluble salts of PnG given by deep i.m. (never i.v.).
- Release PnG slowly at the injection site.
Procaine penicillin G inj.: 0.5–1 MU i.m. every 12–24 hours as aqueous suspension.
- Lower plasma concentrations, sustained for 1–2 days.
Benzathine penicillin G: 0.6–2.4 MU i.m. every 2–4 weeks as aqueous suspension.
- Releases penicillin extremely slowly; very low plasma concentrations, effective for up to 4 weeks.

Clinical Uses of PnG

Streptococcal infections: pharyngitis, tonsillitis, otitis media, scarlet fever, rheumatic fever, bacterial endocarditis
Pneumococcal infections (pneumonia, meningitis): only if the infecting strain is sensitive to PnG.
Meningococcal meningitis and other meningococcal infections.
Gonorrhoea caused by nonpenicillinase producing N. gonorrhoeae
Syphilis: benzathine penicillin is the drug of choice for all stages of syphilis
Diphtheria, tetanus, and other rare infections like gas gangrene, anthrax, actinomycosis.
Prophylaxis to prevent recurrence of rheumatic fever: benzathine penicillin is the preparation of choice.

Penicillin Allergy

Individuals with an allergic diathesis are more prone to develop penicillin reactions.
PnG is the most common drug implicated in drug allergy.
Manifestations: rash, itching, urticaria, and fever.
Less common: wheezing, angioneurotic edema, serum sickness, and exfoliative dermatitis.
Anaphylaxis is rare
In dental practice, the use of PnG is rare

Semisynthetic Penicillins

Phenoxymethyl penicillin (PnV):
- Acid stable; better oral absorption.
- Peak blood level reached in 1 hour; plasma t_{1/2} is 30–60 min.
- Antibacterial spectrum identical to PnG but less active against Neisseria.
- Dose: 250–500 mg, children 125–250 mg every 6 hours.
- Mostly used in ENT and respiratory infections.
Methicillin:
- Penicillinase-resistant but not acid resistant.
- No longer clinically used because it caused haematuria, interstitial nephritis, and albuminuria.
- Methicillin-resistant Staph. aureus is widespread and treated mostly by vancomycin/linezolid.
Extended Spectrum Penicillins:
- Ampicillin:
  - Active against all organisms sensitive to PnG plus several Gram-negative bacilli (H. influenzae, E. coli, Proteus, Salmonella, Shigella, and Helicobacter pylori).
  - Due to widespread use, many bacteria have developed resistance.
  - Not degraded by gastric acid; oral absorption is adequate, but food interferes with absorption.
  - Penicillinase-producing Staph. are not affected, nor are other Gram-negative bacilli (Pseudomonas, Klebsiella, indole-positive Proteus and anaerobes like Bacteroides fragilis).
  - Dose: 0.5–2 g oral/i.m./i.v. every 6 hours; children 25–50mg/kg/day.
- Amoxicillin:
  - Close congener of ampicillin; similar in all respects with better oral absorption.
  - Food does not interfere with absorption.
  - Less active against Shigella and H. influenzae.
  - More active against relatively penicillin-resistant Strep. pneumoniae.
  - One of the most frequently used antibiotics for treatment of dental infections (250–500 mg 3 times per day for 5 days).
  - First choice drug for prophylaxis of postextraction local wound infection and distant infection (endocarditis) following dental surgery in susceptible patients.
  - Dose: 0.25–1 g 3 times per day oral/i.m. or slow i.v. injection; children 25–50 mg/kg/day.
- Aminopenicillins:
  - Used in urinary tract infections, respiratory tract infections, gonorrhoea caused by nonpenicillinase-producing N. gonorrhoeae, bacillary dysentery due to Shigella, typhoid fever, cholecystitis, subacute bacterial endocarditis, septicaemias, and as a component of H. pylori eradication triple drug regimen.
- Ticarcillin:
  - Inactive orally; administered i.m. or i.v.; t_{1/2} is 1 hour.
  - High doses can cause bleeding by interfering with platelet function.
  - Replaced carbenicillin for treating Pseudomonas and Proteus infections insensitive to PnG or aminopenicillins.
  - Indications: serious infections caused by Pseudomonas (combined with Gentamicin) or Proteus (burns, urinary tract infection, septicaemia).
  - Combination with clavulanic acid extends efficacy to cover β-lactamase producing strains.
  - Dose: 3 g i.m./i.v. every 6 hours.
- Piperacillin:
  - About 8 times more active than carbenicillin.
  - Good activity against Klebsiella and some Bacteroides.
  - Mostly used for serious Gram-negative infections in neutropenic/immunocompromised patients and in burn cases.
  - Combined with tazobactam to cover β-lactamase producing strains.
  - Dose: 100–150 mg/kg/day in 3 divided doses.

Clavulanic Acid

β-Lactamase Inhibitor
- Has a β-lactam ring but no antibacterial activity itself.
- Inhibits a wide variety of β-lactamases produced by both Gram-positive and Gram-negative bacteria.
- Permeates the outer layers of the cell wall of Gram-negative bacteria and inhibits the periplasmically located β-lactamase.
- Elimination t_{1/2} of 1 hour and tissue distribution matches amoxicillin.
- Reestablishes activity of amoxicillin against β-lactamase-producing resistant Staph. aureus (but not MRSA), Peptococcus, H. influenzae, N. gonorrhoeae, E. coli, Proteus, Klebsiella, Salmonella, Shigella and Bact. fragilis.
- Does not potentiate the action of amoxicillin against strains already sensitive to it.
- Indications: skin and soft tissue infections, intraabdominal and gynaecological sepsis, urinary, biliary and respiratory tract infections, dental infections caused by β-lactamase producing bacteria and gonorrhoea.
- Available as Amoxicillin 250 mg + clavulanic acid 125 mg tab; 500 mg + 125 mg tab.
- Side effects are the same as for amoxicillin alone, but gastrointestinal tolerance is poorer—especially in children.
- Other adverse effects are Candida stomatitis/vaginitis and rashes

Cephalosporins

Semisynthetic antibiotics derived from ‘cephalosporin-C’ obtained from a fungus Cephalosporium.
Chemically related to penicillins
All cephalosporins are bactericidal and have the same mechanism of action as penicillin (inhibition of bacterial cell wall synthesis).
Bind to different proteins than those which bind penicillins, explaining differences in spectrum, potency and lack of cross resistance.
Resistance has developed by some organisms, even against the third-generation compounds.

First Generation

Cefazolin:
- Active against most PnG-sensitive organisms (streptococci, gonococci, meningococci, C. diphtheriae, H. influenzae, clostridia, and Actinomyces).
- Klebsiella and E. coli are sensitive, but cefazolin is susceptible to staphylococcal β-lactamase.
- Given i.m. or i.v.; longer t_{1/2} (2 hours) due to slower tubular secretion; attains higher concentration in plasma and bile.
- Preferred cephalosporin for surgical prophylaxis.
- Dose: 0.5 g every 8 hours (mild cases), 1 g every 6 hours (severe cases) i.m. or i.v.; surgical prophylaxis 1.0 g ½ hour before surgery.
Cephalexin:
- Orally effective, similar in spectrum to cefazolin, but less active against H. influenzae.
- Little bound to plasma proteins, attains high concentration in bile, and is excreted unchanged in urine; t_{1/2} ~60 min.
- Used in dentistry as an alternative to amoxicillin.
- Dose: 0.25–1 g every 6–8 hours (children 25–100 mg/kg/day).

Second Generation

More active against Gram-negative organisms, with wider coverage, including some strains resistant to first-generation compounds.
Few members are active against anaerobes as well.
Cefuroxime:
- Resistant to Gram-negative β-lactamases and has high activity against PPNG and ampicillin-resistant H. influenzae.
- Significant activity on Gram-positive cocci and certain anaerobes.
- Well-tolerated by the i.m. route and used in some mixed infections.
- Cefuroxime axetil is effective orally, though absorption is incomplete.
- Frequently chosen for dental infections because of activity on anaerobes.
- Dose: 250–500 mg BD, children half-dose.
Cefaclor:
- Given orally and is more active than the first-generation compounds against H. influenzae, E. coli, Pr. mirabilis and anaerobes found in the oral cavity.
- Susceptibility to β-lactamases limits its utility.

Third Generation

Highly augmented activity against Gram-negative Enterobacteriaceae and few members inhibit Pseudomonas as well.
Highly resistant to β-lactamases from Gram-negative bacteria.
Less active on Gram-positive cocci and anaerobes; less suitable for dental infections.
Cefotaxime:
- Potent action on aerobic Gram-negative and some Gram-positive bacteria, but not very active on anaerobes, Staph. aureus and Ps. aeruginosa.
- Indications: meningitis caused by Gram-negative bacilli, life-threatening resistant/hospital-acquired infections, septicaemias and infections in immunocompromised patients.
- Plasma t_{1/2} of cefotaxime is 1 hour.
- Dose: 1–2 g i.m. or i.v. every 6–12 hours.
Ceftriaxone:
- Longer duration of action (t_{1/2} 8 hr), permitting once or twice daily dosing.
- High efficacy in serious infections including bacterial meningitis, multiresistant typhoid fever, abdominal sepsis and septicaemias; also useful in gonorrhoea and syphilis.
- Specific adverse effects: hypoprothrombinaemia and bleeding. Haemolysis is reported.
Cefoperazone:
- Stronger activity on Pseudomonas and weaker activity on other organisms.
- Good for S. typhi and B. fragilis also, but more susceptible to β-lactamases.
- Indications: severe urinary, biliary, respiratory, skin-soft tissue infections, and septicaemias.
- Primarily excreted in bile; t_{1/2} is 2 hours.
- Has hypoprothrombinaemic action but does not affect platelet function.
- Dose: 1-2 g i.m./i.v. every 12 hours.
Cefixime:
- Orally active, highly active against Enterobacteriaceae, H. influenzae, Strep. pyogenes, Strep. Pneumoniae and is resistant to many β-lactamases.
- Not active on Staph. aureus and Pseudomonas.
- Longer acting (t_{1/2} 3 hr) and has been used in a dose of 200–400 mg BD for respiratory, urinary and biliary infections.
- Stool changes and diarrhoea are the most prominent side effects.

Fourth Generation

Non-susceptibility to β-lactamases produced by certain resistant bacteria, while retaining high activity against Enterobacteriaceae.
Cefepime:
- Antibacterial spectrum similar to that of third-generation compounds, but highly resistant to β-lactamases; active against many bacteria resistant to the earlier drugs.
- Ps. aeruginosa, Strep. pneumoniae, H. influenzae and Staph. aureus are also inhibited but not MRSA.
- Effective in serious infections like hospital-acquired pneumonia, febrile neutropenia, bacteraemia, septicaemia, etc.
- Dose: 1–2 g i.v. every 8–12 hours.
Cefpirome:
- Used for the treatment of serious and resistant hospital-acquired infections including septicaemias, lower respiratory tract infections, etc.
- Resistant to many β-lactamases and is more potent than the third generation compounds.
- Dose: 1–2 g i.m./i.v. every 12 hours.

Fifth Generation

Ability to kill MRSA and some other bacteria which have developed β-lactam resistance by producing altered PBPs.
Effective in many resistant and hospital-acquired infections.
Ceftaroline fosamil:
- Prodrug; after i.v. infusion, rapidly converted by phosphatases to active ceftaroline.
- Exerts bactericidal action on MRSA, penicillin-resistant Strep. pneumoniae, Enterococcus faecalis and some other Gram-positive and negative bacteria.
- Approved for use in skin/soft tissue infections and for community-acquired pneumonia (CAP) caused by MRSA and resistant Strep. pneumoniae respectively.
- Mainly excreted by the kidney with a t_{1/2} of 2.6 hours.
- Adverse effects: headache, itching, rashes, diarrhoea and irritation of the injected vein.
Ceftobiprole medocaril:
- Active against MRSA, and several other Gram-positive and negative bacteria associated with CAP as well as hospital-acquired pneumonia (HAP).
- Prodrug that is rapidly hydrolysed by type A esterases in the human body to active ceftobiprole.
- Mostly excreted by the kidney with a t_{1/2} of 3 hours.
- Approved for treatment of HAP, severe cases of CAP and for resistant skin/soft tissue infections.

Adverse Effects of Cephalosporins

Pain after i.m. injection occurs with some cephalosporins. Thrombophlebitis can occur on i.v. injection.
Diarrhoea due to alteration of gut ecology or irritative effect (more common with oral cephalexin, cefixime and parenteral cefoperazone which is largely excreted in bile).
Hypersensitivity reactions: similar to those with penicillin, but incidence is lower. Rashes are the most frequent reactions, while anaphylaxis, angioedema, asthma and urticaria are occasional.
Bleeding: due to hypoprothrombinaemia caused by the same mechanism as warfarin (occurs with cefoperazone, ceftriaxone).

Monobactams

Aztreonam:
- Atypical β-lactam antibiotic with a missing other ring (monobactam).
- Acts by binding to specific PBPs; the spectrum of action is narrow.
- Inhibits Gram-negative enteric bacilli and H. influenzae at very low concentrations and Pseudomonas at moderate concentrations, but does not affect Gram-positive cocci or faecal anaerobes.
- Resistant to Gram-negative β-lactamases.
- Main indications: hospital-acquired infections originating from urinary, biliary, gastrointestinal and female genital tracts.
- Eliminated in urine with a t_{1/2} of 1.8 hours.
- Lack of cross sensitivity with other β-lactam antibiotics allows its use in patients allergic to penicillins or cephalosporins.
- No specific indication of aztreonam in dentistry.
- Dose: 0.5–2 g i.m. or i.v. every 6–12 hours.

Carbapenems

Imipenem:
- Potent and broad-spectrum β-lactam antibiotic.
- Range of activity includes Gram-positive cocci, Enterobacteriaceae, Ps. aeruginosa, Listeria, as well as anaerobes like Bact. fragilis and Cl. difficile.
- Resistant to most β-lactamases and inhibits penicillinase-producing staphylococci, but is not reliable for MRSA.
- Effective in serious hospital-acquired infections, including those in neutropenic, cancer and AIDS patients.
- Limited by rapid hydrolysis by the enzyme dehydropeptidase I of renal tubular cells.
- Therefore, mostly used with cilastatin, a reversible inhibitor of dehydropeptidase I, which has matched pharmacokinetics with imipenem (t_{1/2} of both is 1 hr) and protects it.
- Dose: Imipenem-cilastatin 0.5 g i.v. every 6 hours (max 4 g/day).
- Has propensity to induce seizures at higher doses and in predisposed patients. Diarrhoea, vomiting and rashes are the other side effects.
Meropenem:
- Not hydrolysed by renal peptidase, and thus does not need to be protected by cilastatin.
- Active against both Gram-positive and Gram-negative bacteria, aerobes as well as anaerobes and is not destroyed by many β-lactamases.
- Reserve drug for the treatment of serious nosocomial infections like septicaemia, febrile neutropenia, intraabdominal and pelvic infections, etc. caused by cephalosporin-resistant bacteria.
- Can also be employed for serious/difficult to treat orodental infections.
- Adverse effects of meropenem are similar to imipenem, but it is less likely to cause seizures.
- Dose: 0.5-2.0 g (10-40 mg/kg) by slow i.v. injection every 8 hours.