BMS2037: Antimicrobial Chemotherapy

A Brief History of Antimicrobial Chemotherapy

• Early treatments against infectious diseases:
  • Oils and crude plant extracts as anti-helminths (e.g. Chenopodium ambrosioides for tapeworms and roundworms)
  • Quinine for malaria
  • Mercury for syphilis
  • Chaulmoogra oil for leprosy
• Lister used carbolic acid to treat wound infections, but it had low efficacy and was damaging to healthy tissue
• In the 1900s, arsenicals were used as antiprotozoal agents and for schistosomiasis and syphilis
• Sulfa drugs were introduced in the 1930s, but had a limited spectrum of activity

Biocides: Disinfectants and Antiseptics

• 70% IMS/isopropyl alcohol/rubbing alcohol: denatures proteins and has a broad spectrum of activity
• Bleach: difficult to purify and produce in clinically useful amounts

Mechanisms of Action and Resistance

• Nucleic acid synthesis inhibitors:
  • Quinolones bind to unpaired DNA bases and have a complex interaction with gyrase, DNA, and quinolone molecules
  • Inhibit topoisomerases, which untwist supercoiled DNA by 'nicking' one of the strands
• Cell wall/membrane inhibitors:
  • Beta-lactams (e.g. penicillin) bind to penicillin-binding proteins (PBPs) in the growing cell wall, inhibiting cross-links between peptidoglycan chains and leading to cell lysis
  • Vancomycin binds to the growing peptidoglycan chain and prevents transglycosylation
• Protein synthesis inhibitors:
  • Anti-metabolites (e.g. sulphonamides, trimethoprim) inhibit enzyme activity
  • Glycopeptides (e.g. vancomycin) bind to the growing peptidoglycan chain and prevent transglycosylation

Beta-Lactam Antibiotics

• Mechanism of action:
  • Bind to penicillin-binding proteins (PBPs) in the growing cell wall
  • Inhibit cross-links between peptidoglycan chains, leading to cell lysis
• Different classes of beta-lactams:
  • Penicillins (e.g. penicillin G, ampicillin)
  • Cephalosporins (e.g. cephalosporin C, cephalexin)
  • Extended-spectrum beta-lactams (ESBLs)
• Beta-lactamase inhibitors:
  • Clavulanate: binds to beta-lactamase and inhibits its activity
  • Tazobactam: binds to beta-lactamase and inhibits its activity

Inhibitors of Cell Membrane Function and Synthesis

• Polymyxins:
  • Disrupt inner and outer cell membranes, causing cell lysis
  • Act only on Gram-negative bacteria

Inhibitors of Nucleic Acid Synthesis

• Quinolones:
  • Bind to unpaired DNA bases and have a complex interaction with gyrase, DNA, and quinolone molecules
  • Inhibit topoisomerases, which untwist supercoiled DNA by 'nicking' one of the strands
  • Have a broad spectrum of activity, with 1st, 2nd, 3rd, and 4th generation quinolones having increasing potency

Antimicrobial Agents

• Triclosan dissolves lipids and is ineffective against spores and some viruses.
• Chlorine denatures proteins, affecting multiple targets in the membrane and cytoplasm.
• Bisphenol is found in dentifrices and incorporated into plastic and fabrics.

Principles of Selective Toxicity

• Antibiotics work by targeting bacterial cells, not mammalian eukaryotic cells.
• Antibiotics become concentrated in bacterial cells, not host cells.

Types of Antibiotics

• Bactericidal antibiotics kill bacteria, while bacteriostatic antibiotics inhibit bacterial growth.
• Antibiotics vary in their ability to fulfill the criteria of selective toxicity.

Discovery of Clinically Useful Antibiotics

• Paul Ehrlich developed arsphenamine (Neosalvarsan) in 1912, which has limited activity against spirochaetes.
• Penicillium chrysogenum is used for drug production, not Penicillium rubens, which was discovered by Flemming.
• Mary Hunt discovered antimicrobial components in the 1930s.
• Selman Waksman discovered streptomycin, the first drug to treat tuberculosis, in 1944.

Mechanisms of Action

• Nucleic acid inhibitors: quinolones, metronidazole
• Cell wall/membrane inhibitors: beta-lactams, vancomycin
• Protein synthesis inhibitors: sulphonamides, trimethoprim
• Anti-metabolites: isoniazid

Beta-Lactam Antibiotics

• Bind to penicillin-binding proteins (PBPs) in growing cell walls
• Inhibit cross-links between peptidoglycan chains, causing cell lysis
• Cephalosporins have a beta-lactam ring with a dihydrothiazine ring
• Different classes of beta-lactams: penicillinases, extended-spectrum beta-lactamases (ESBLs), metallo-beta-lactamases, cephalosporinases

Beta-Lactamase Inhibitors

• Have a lactam ring, but are weak antibiotics
• Must have higher affinity for inhibitor than drug
• Inhibitor must bind irreversibly to beta-lactamase
• Examples: clavulanate, sulbactam

Difference between Beta-Lactams and Vancomycin

• Beta-lactams bind to transpeptidase, while vancomycin binds to the growing peptidoglycan chain
• Autolysins break peptide bonds, but no further bonds are created with vancomycin

Polymyxins

• Disrupt inner and outer cell membranes, causing cell lysis
• Act only on Gram-negatives
• Examples: polymyxin B, polymyxin E (colistin)

Impact of Colistin Resistance

• First clinical infection caused by a colistin-resistant strain in the US in 2016
• Estimated 1.4% of E. coli and 0.7% of Klebsiella pneumoniae isolates in China are resistant
• Newer molecular measures are more reliable in detecting resistance

Importance of Preserving Antibiotics

• Despite Staphylococcus aureus resistance, penicillin remains important for treating:
  • Listeriosis
  • Meningitis
  • Streptococcal infections
  • Syphilis

Treatment of Meningococcal and Gonococcal Diseases

• Meningococcal disease:
  • Treated with IV antibiotics (benzyl penicillin or amoxicillin)
  • Rare occurrence of drug resistance
  • Maintenance therapy for shock (fluids, etc.)
  • Vasoactive treatments (IV adrenaline and steroids)
  • Experimental therapies (anti-cytokine and anti-endotoxin) have been investigated
• Gonococcal disease:
  • Developed resistance to all antibiotics introduced for treatment
  • 3rd generation cephalosporins (e.g. cefixime or ceftriaxone) are first-line treatments
  • Dual treatments (e.g. ceftriaxone and azithromycin) are now recommended due to the emergence of "superbugs" resistant to ceftriaxone

Urinary Tract Infections (UTIs)

• Can cause fever, loin pain, and ascending infection
• Secondary spread can lead to:
  • Renal abscess
  • Bacteremia
  • Pyelonephritis
  • Cystitis (exacerbated by urinary stasis)
  • Prostatitis
  • Urethritis
  • Epididymitis
• Contamination from faecal/perineal flora is a common cause of UTIs
• Aetiological agents of UTIs include:
  • E. coli (very common)
  • Klebsiella/Proteus spp. (less common)
  • Pseudomonas aeruginosa (hospital-associated)
  • Staphylococcus epidermidis (associated with catheterization or instrumentation)
  • Enterococcus faecalis
  • Chlamydia trachomatis (in sexually active people)
  • Neisseria gonorrhoea

Treatment Guidelines and Precautions for UTIs

• Uncomplicated lower UTI:
  • Trimethoprim and nitrofurantoin are recommended (concentrated in urine and remain active in the bladder)
  • Variations in dose for different patient groups
• Pregnancy:
  • Avoid quinolones and trimethoprim
  • Nitrofurantoin: avoid at term, use amoxicillin or cephalosporin instead
• E. coli with ESBL enzymes:
  • Increasing prevalence
  • Nitrofurantoin remains sensitive
• Renal impairment:
  • Caution when using antibiotics in this patient group
• Upper UTI (acute pyelonephritis):
  • Antibiotics are initially administered via IV route due to septicaemia risk
  • Cephalosporin, quinolone, and gentamicin are used
  • Pseudomonas aeruginosa has intrinsic resistance

Antibiotic Resistance and Consequences

• Antimicrobial resistance (AMR) compromises:
  • Organ transplant
  • Cancer chemotherapy
  • Diabetes management
  • Routine surgery (e.g. hip replacements, caesarians)
• Other impacts of AMR:
  • Longer hospital stays
  • Longer time intubated
  • Longer duration of antibiotic treatment
  • Greater financial costs
• Predicted deaths attributable to AMR are expected to surpass deaths from other causes by 2050

Importance of Preserving Antibiotics

• Despite Staphylococcus aureus resistance, penicillin remains important for treating:
  • Listeriosis
  • Meningitis
  • Streptococcal infections
  • Syphilis

Treatment of Meningococcal and Gonococcal Diseases

• Meningococcal disease:
  • Treated with IV antibiotics (benzyl penicillin or amoxicillin)
  • Rare occurrence of drug resistance
  • Maintenance therapy for shock (fluids, etc.)
  • Vasoactive treatments (IV adrenaline and steroids)
  • Experimental therapies (anti-cytokine and anti-endotoxin) have been investigated
• Gonococcal disease:
  • Developed resistance to all antibiotics introduced for treatment
  • 3rd generation cephalosporins (e.g. cefixime or ceftriaxone) are first-line treatments
  • Dual treatments (e.g. ceftriaxone and azithromycin) are now recommended due to the emergence of "superbugs" resistant to ceftriaxone

Urinary Tract Infections (UTIs)

• Can cause fever, loin pain, and ascending infection
• Secondary spread can lead to:
  • Renal abscess
  • Bacteremia
  • Pyelonephritis
  • Cystitis (exacerbated by urinary stasis)
  • Prostatitis
  • Urethritis
  • Epididymitis
• Contamination from faecal/perineal flora is a common cause of UTIs
• Aetiological agents of UTIs include:
  • E. coli (very common)
  • Klebsiella/Proteus spp. (less common)
  • Pseudomonas aeruginosa (hospital-associated)
  • Staphylococcus epidermidis (associated with catheterization or instrumentation)
  • Enterococcus faecalis
  • Chlamydia trachomatis (in sexually active people)
  • Neisseria gonorrhoea

Treatment Guidelines and Precautions for UTIs

• Uncomplicated lower UTI:
  • Trimethoprim and nitrofurantoin are recommended (concentrated in urine and remain active in the bladder)
  • Variations in dose for different patient groups
• Pregnancy:
  • Avoid quinolones and trimethoprim
  • Nitrofurantoin: avoid at term, use amoxicillin or cephalosporin instead
• E. coli with ESBL enzymes:
  • Increasing prevalence
  • Nitrofurantoin remains sensitive
• Renal impairment:
  • Caution when using antibiotics in this patient group
• Upper UTI (acute pyelonephritis):
  • Antibiotics are initially administered via IV route due to septicaemia risk
  • Cephalosporin, quinolone, and gentamicin are used
  • Pseudomonas aeruginosa has intrinsic resistance

Antibiotic Resistance and Consequences

• Antimicrobial resistance (AMR) compromises:
  • Organ transplant
  • Cancer chemotherapy
  • Diabetes management
  • Routine surgery (e.g. hip replacements, caesarians)
• Other impacts of AMR:
  • Longer hospital stays
  • Longer time intubated
  • Longer duration of antibiotic treatment
  • Greater financial costs
• Predicted deaths attributable to AMR are expected to surpass deaths from other causes by 2050

Learn about the history of antimicrobial chemotherapy, antibiotic drug classes, mechanisms of action and resistance, and understand recent trends in antimicrobial consumption.