Hospital acquired infection and antibiotic resistance

Question 1

Hospital acquired infections: list the reasons for the high rate of hospital acquired infection

Answer 1

1. Presence of pathogens
2. Very high density of very ill people – lots of pathogens
3. Crowded wards
4. People moving around – spreading (vectors)
5. Open wounds – easy portal of entry
6. Inserted medial devices – catheters, cannulas
7. Antibiotic therapy (may suppress normal flora)
8. Transmission by staff – contact with multiple patients

Question 2

Antimicrobial mechanisms: summarise the mechanisms of action of important antimicrobials, and recognise that antimicrobial therapy provides a selection pressure for the spread of antimicrobial resistance

Answer 2

Antimicrobial; Any chemical/substance that kills a microbe or stops it’s growth

1. Bactericidal – kills bacteria.
2. Bacteriostatic – stops bacteria growing.
3. Antiseptic – chemical that kills or inhibits microbes that is usually used topically to prevent infection.

“Selection pressure for the spread of antimicrobial resistance”

A resistant strain of bacteria appears shortly after the introduction of the antimicrobial

Important classes:

1. Beta-lactams:
   
   • Inhibit cell wall (peptidoglycan) synthesis
   • Penicillin, methicillin (bind to penicillin-binding proteins which catalyze synthesis of peptidoglycan)
   • bactericidal
   • Penicillin resistance works via drug inactivation (beta-lactamase) or altered target site
2. Tetracycline:
   
   1. Inhibits protein synthesis
   2. Bacteriostatic
   3. Tetracycline resistance is mediated by efflux/membrane pumps
3. Chloramphenicol:
   
   • Inhibit protein synthesis
   • Bacteriostatic but with Higher toxicity
4. Sulphonamides:
   • Sulpha-methoxazole
   • Bacteriostatic and are used in Combination therapy
   • ex. Protonsil (treats UTIs, bacteremia and prophylaxis for HIV+ individuals)
   • Sulfonamide resistance is conferred by blocking uptake/decreasing influx.
5. Aminoglycosides:
   
   • Bactericidal
   • Inhibit protein synthesis and cause damage to cell membrane
   • Toxicity has limited use, but resistance to other ABs has led to increasing use
   • Gentamicin, streptomycin

Quinolones:​

• Gram +ve infections
• Inhibits protein synthesis
• Synthetic, broad spectrum, bactericidal.
• Target DNA gyrase in Gm-ve and topoisomerase IV in Gm+ve.
• Resistance is associated with target site modification
• bactereicidal
  1. Macrolides:
  
  • Gram +ve infections (mainly)
  • Erythromycin, azithromycin.
  • Inhibits protein synthesis by targeting 50s ribosomal subunits
  • both bacteriostatic and bactericidal

Specific antibiotics examples:

1. Rifampicin
   
   • Bactericidal.
   • Targets RpoB subunit of RNA polymerase.
   • Spontaneous resistance is frequent.
   • Makes secretions go orange/red – affects compliance.
2. Vancomycin
   
   • Bactericidal
   • Targets Lipid II component of cell wall biosynthesis, as well as wall crosslinking via D-ala residues
   • Toxicity has limited use, but resistance to other antibiotics has led to increasing use e.g. against MRSA
3. Daptomycin
   
   • Bactericidal.
   • Targets bacterial cell membrane.
   • Gram-positive spectrum of activity.
   • Toxicity limits dose
4. Linezolid
   
   • Bacteriostatic.
   • Inhibits the initiation of protein synthesis by binding to the 50S rRNA subunit.
   • Gram-positive spectrum of activity

Question 3

Antimicrobial resistance: summarise the mechanisms of antimicrobial resistance, list important bacterial pathogens that are multi-drug resistant, and explain why antimicrobial resistance is associated with increased morbidity, mortality, length of hospital stay and cost

Answer 3

Simple explanation of Antimicrobial resistance

1. Colony of bacteria – some are resistant, some aren’t
2. Antibiotics given
3. Non – resistant are wiped out
4. Only left with resistant bacteria
5. No resource competition
6. Resistant strains flourish

Sources of antibiotic resistance genes

• Plasmids – extra-chromosomal circular DNA, often multiple copy. Often carry mutliple AB res genes – selection for one maintains resistance to all.
• Transposons. Integrate into chromosomal DNA. Allow transfer of genes from plasmid to chromosome and vice versa.
• Naked DNA. DNA from dead bacteria released into environment.

Mechanism – 4 pathways:

1. Altered target site;
   
   • Antibiotic can no longer bind to target site
   • Can arise via acquisition of alternative gene or a gene that encodes a target-modifying enzyme
   • Methicillin-resistant Staphylococcus aureus (MRSA) encodes an alternative PBP (PBP2a) with low affinity for beta-lactams.
2. Antibiotic inactivation; enzymatic degradation or alteration of the antibiotic before it has an effect. (ex, b-lactamase resistant to penicillin)
3. Altered metabolism; Increased substrate production outcompetes antibiotic target mechanism (e.g. increased production of PABA confers resistance to sulfonamides).or can switch to new metabolic pathways
4. Decreased drug accumulation; Decreased entry or increased efflux of antibiotic and Infectious dose is not reached

Morbidity – more exposure to hospital pathogens

Mortality – more exposure to hospital pathogens

Length of stay – more exposure to hospital pathogens, more illness

Cost –

• more drugs, cost of bed stay
• increased time to effective therapy
• Requirement for additional approaches – e.g. surgery.
• Use of expensive therapy (newer drugs).
• Use of more toxic drugs e.g. vancomycin.
• Use of less effective ‘second choice’ antibiotics

Multi drug resistant bacteria

1. Gram -ve
   
   • E. Coli
   • Salmonella
   • Neisseria gonorrhoeae
   • Pseudomonas aeruginosa
2. Gram +ve
   
   • Staphylococcus Aureus (MRSA)
   • Streptococcus pneumoniae
   • Clostridium difficile
3. Mycobacteria
   
   • Mycobacterium tuberculosis

Question 4

Treatment: summarise the main approaches used to prevent hospital acquired infections and the emergence of drug-resistant bacteria

Answer 4

Strategies;

1. Temporarily withdraw certain classes, tighter controls, use for only dangerous infections
2. Reduce use of broad-spectrum antibiotics
3. Identify resistant strains quicker
4. Combination therapy
5. Chemically adjust current antibiotics