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PHARM 213 Infectious Diseases > 4. Antibacterials > Flashcards

4. Antibacterials Flashcards

1
Q

Antimicrobials

A

Substances that kill or inhibit bacteria

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2
Q

Antibiotic

A

Substances produced by micro-organisms that kills other micro-organisms

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3
Q

History of antibacterials/infection

A
  • Pre antibiotics:
    + Immune response
    + Civilisations using mouldy bread or soil compressed on wounds
  • Germ theory in 19th century - identifies microorganisms ad the cause of infection
  • Ehrlich uses dyes to cure infections including syphillis - development of Salvarsan in 1910
  • 1928: Fleming discovers penicillin from Penicillium mould on staphylococci
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4
Q

Antibacterial development

A
  • 1932: Domagk discovers the active component in a dye - Protonsil (Bayer) the 1st sulphonamide
  • Florey & Chain purify penicillin from mould broth
  • Further compounds from soil bacteria are isolated & repurposed for human use e.g. streptomycin, tetracycline, & erythromycin
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5
Q

Drug targets

A

Ideally unique bacterial targets not present in mammalian cells & usefully therapeutic with minimal mammalian damage

Unique bacterial targets:

  • Cell wall
  • Cell membrane
  • Protein synthesis apparatus
  • DNA/RNA transition apparatus

Semi-unique targets:
- Metabolic folate pathway

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6
Q

Development to resistance

A
  • Identification of resistance
  • Fleming predicted inappropriate use of penicillin would lead to antibiotic resistance in 1945
  • Resistance is identified in nature before ‘development’ as many drugs are repurposed natural defence mechanisms, but resistance then proliferates in clinical isolates
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7
Q

Slowing innovation

A
  • Development slowed/stopped while resistance is increasing
  • Larger economic returns on chronic diseases & societal willingness to pay for cancer treatments
  • University lead research > pharma
  • Antibiotics not drug like:
    + Large molecules, reactive moieties, solubility = hard to formulate
    + E.g. Opposite properties for Gram negatives
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8
Q

Antimicrobial PK/PD

A

MIC: Min inhibitory concnetration
MBC: Min concentration to kill organism

  • PKPD targets are specific for the bacteria + antibiotic + clinical condition
  • Streptococcal cellulitis - Penicillin 30-40 % T > MIC
  • Streptococcal endocarditis - Penicillin 90-100% T > MIC
  • Different strategies can achieve equivalence depending on target
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9
Q

Bioavailability (BA/F)

A
  • Proportion of given dose in blood/serum
    + IV = 100% or 1F
    + PO ≤ 100% (usually less) limited by tolerability
  • Benefits of IV:
    + Ensures predictable high concentrations
    + Important in sepsis with reduced flow to site of absorption
- Benefits of PO:
\+ Practical for administration
\+ Reduced costs
\+ Reduced length of stay
\+ Reduced length of infection from cannula
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10
Q

Distribution

A
  • Critical for access to infection sites
  • Tissue penetration higher with lipophilic drugs
  • High Vd suggests penetration > extracellular fluid
  • Eyes, prostate & brain have pores
    + Difficult access so lipophilic better
    + Inflammation changes barrier permeability
  • Further issues may arise at site of infection e.g. increased pH, biofilms, prosthesis, intracellular pathogens
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11
Q

Metabolism

A
  • Least critical component for infection PK
  • Some antibiotics are formulated as pro-drugs for increased absorption or half life
  • Will the drug be activated if used in a non-standard administration route e.g. direct injection in CNS or inhaled?
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12
Q

Elimination

A
  • Excretion is important in determining length of treatment effect for T > MIC or AUC:MIC
  • Influences dosing regimens & TDM monitoring
  • Elimination also forms part of the distribution pathway for urinary tract or gut lumen
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13
Q

Post-antibiotic effect (PAE)

A
  • Phenomena of PAE when persistent suppression of bacterial growth after exposure of antibiotic (concentration below MIC) in absence of host defences
  • Postulated that:
    + Persistence of antibiotic at bacterial binding sites (relative to systemic concentration)
    + Non-lethal damage by antibiotics
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14
Q

Killing effect - Bactericidal or bacteriostatic?

A
  • Theoretical concern which has no influence on practice
    + ‘cidal’ - MBC:MIC within 4 dilutions
    + ‘static’ MBC: MIC > 4 dilutions difference (usually»)
  • In practice innate immune system has a role - concern in immunosuppression
  • Systematic review shows no difference in outcomes
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15
Q

Synergy

A
  • When 2 antibiotics achieve better killing together (> 100% inclusive) than either agent alone
  • Beta lactam & aminoglycoside
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16
Q

Antagonism

A
  • Controversial & limited evidence to support

- Competitive similarly located binding sites e.g. chloramphenicol & macrocodes

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17
Q

Antibiotic spectra

A

Broad/narrow terms used to help choose the best antibiotics to reduce effect on commensal flora

ALL RELATIVE:

  • Penicillin narrow vs co-amoxiclav broad
  • Co-amoxiclav narrow vs meropenem broad
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18
Q

Mechanisms of resistance

A
  1. Alter antibiotic targets
  2. Antibiotic-degrading enzyme
  3. Enzyme binding to antibiotic
  4. Efflux pumps
  5. Alter permeability
  6. Increased targets
  7. Remove the necessity for target enzyme
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19
Q

Cell wall - Key differences

A
  • Outer membrane layer
  • Thickness of cell wall
  • Porins
20
Q

Beta-lactams (Penicillins, cephalosporins, carbapenems & monobactams)

A
  • Peptidoglycan cross links to strengthen cell wall
  • Transpeptidase (PBP):
    + Mediated by PBP
    + Recognises side chain (D-ala-D-ala)
    + Cross links to second peptide chain or forms a glycine bridge
    + Different PBPs by bacterial species
  • Core structure is beta-lactam ring
  • Interactions with transpeptidase as a mimic of the D-ala-D-ala residue
  • Beta-lactam sterically strained & rapid catalytic reaction
  • Enzyme is reversibly inactivated
  • Inhibition of cell wall replication or remodelling:
    + Autolysins released (help break down cell wall)
    + Osmotic instability
    + Cell death
  • Side chains (R1 R2):
    + Provide steric protection from beta-lactamases
    + Allow penetration through porins
    + Confer pharmacological stability
    + Reduce acid lability (improve bioavailability)
21
Q

Main types of resistance to Beta-lactams (Beta-lactamases)

A
  • Penicillinase (S. aureus) - flucloxacillin developed using R1 to prevent binding
  • Use of beta-lactamase inhibitors e.g. clavulanic acid (weak inhibition & slowly hydrolysed)
  • Extended spectrum beta-lactamase (ESBL)
  • Metallo-beta-lactamase

PKPD target beta-lactams is fT > MIC

22
Q

Penicillins

A
  • Naturally purified from mould (naturally…) – activity against many organisms but many now produce beta-lactamases
  • Anti-staph – R1 modified to treat staphylococci (penicillinase)
  • Amino – added amino group increases hydrophilicity allowing increased porin transfer (more Gram-negative activity)
  • Extended spectrum penicillins – bigger side chains prevent more beta-lactamases’ activity and allows greater porin transfer
  • Beta-lactamase inhibitors are generally added to Amino/ES penicillins to confer greater coverage
23
Q

Cephalosporins

A
  • The added ring makes the compound more resistant to degradation by enzymes
  • “Generations” relate to staged development of cephalosporins with different activity & chemistry
  • 1st & 2nd generation relatively ‘narrow’ spectrum
  • 3rd R1 side chain allows increased penetration for Gram-negatives, had increased affinity for PBPs & increased resistance to beta-lactamases
  • 4th R1 & R2 side chains increase Gram-negative spectrum greatly
  • 5th MRSA activity due to R2 side chain binding not beta-lactam ring
24
Q

Carbapenems

A
  • Most broad-spectrum antibiotic class
  • Modified beta-lactam ring & significant side chain changes
  • Relatively small molecules with good porin access
  • Resistant to most beta-lactamases
  • Affinity for many if not all PBPs
  • Imipenem co-formulated with cilastatin (not an antibiotic) as it inhibits the destruction by dehydropeptidase I in the renal brush border
  • Meropenem chemically modified R1 so intrinsically resistant to DHP I – pharmacokinetics similar to imipenem
  • Ertapenem modified R2 group prolongs the half-life but confers weak activity against Pseudomonas
25
Q

Monobactams

A
  • Aztreonam – totally synthetic – drug shortages
  • Chemically designed to bind well to (has high affinity for) Gram-negative PBP3
  • Novel structure with dissimilar side chains shows no allergic cross-reactivity with other beta-lactams
    + Side chains hypothesis formed after this
26
Q

Manipulating beta-lactam PK/PD

A

Probenecid inhibits tubular secretion of weak organic acids including penicillins & some cephalosporins:

  • Prolongs serum half-life, increasing serum concentration
  • t1/2 from 1.6 hours to 2.7 hours, increases T > MIC
27
Q

Glycopeptides (Vancomycin & telicoplanin)

A
  • Same peptidoglycan pathway as beta-lactams but very different mechanisms – overcomes resistance in PBP
  • Binds to D-ala-D-ala dipeptide of the peptidoglycan side chain which prevents transpeptidase accessing due to the bulk of the drug
  • Resistance can easily occur (e.g. in staphylococci & enterococci)
    + D-ala-D-ala dipeptide enzymatically changed to D-ala-D-lac to reduced binding affinity
  • Large molecules with poor penetration – no Gram-negative activity
  • Very broad Gram-positive cover as no PBP involved
  • Vancomycin originally very toxic due to poor purification process now increased technique & reduced ADR profile
28
Q

Glycopeptide - Key ADRs

A
  • Renal toxicity
  • Infusion related “Red Man Syndrome”
    + Histamine release from mast cells
    + Speed of infusion related, reduced rates 10 mg/min to reduce likelihood
29
Q

Vancomycin PK/PD

A

PK/PD target AUC:MIC 400:
- Validated in MRSA pneumonia cohort (n = 103) with improved outcomes & bacterial resistance
- Trough concentration correlated to AUC:
+ 15 mg/L = ~400
- Loading doses used in practice to achieve therapeutic levels earlier (important in sepsis)

30
Q

Vancomycin - Therapeutic monitoring

A
  • Outcomes are related to concentrations we need to ensure adequate exposure
  • Serum levels (HPLC) measured at Css
    + t1/2 6 hours = 30 hours
  • Vancomycin clearance linearly related to CrCl – dose adjustment simple if clearance stable
  • Monitoring for efficacy so administration should continue whilst awaiting results
31
Q

Daptomycin

A
  • Novel cyclic polypeptide
  • Inserts lipid ‘tail’ into cytoplasmic membranes forming an ion conducting channel
    + 4 molecules aggregate to form
    + Potassium leaks out, depolarising membrane potential, leading to cell death
  • Gram-positive activity only as poor penetration
  • Concentration dependent - AUC:MIC 400 for stasis & 1000 for killing

Key ADRs:

  • Myositis so monitor Creatinine Kinase
  • Deactivated by pulmonary surfactant, so no use in pneumonia
32
Q

Polymyxins

A
  • Positively charged colistin binds to negatively charged lipopolysaccharides (LPS) in outer membranes (Gram-negative) displacing Ca2+ & Mg2+ stabilising ions
  • Fatty acid side chains inserts into outer membrane disrupting the LPS molecules increasing permeability
  • PK/PD fAUC:MIC 20-49
  • Initial drug dosing licensing found to less effective
    + Ongoing work to identify best approach using loading doses, maintenance dosing based on CrCl
  • Nephrotoxicity & neurotoxicity required close monitoring of patients
33
Q

Fosfomycin

A
  • Binds & covalently modifies cysteine residues inactivating bacterial cell wall enzyme MurA (MurA catalyses 1st step of peptidoglycan synthesis)
  • Efficacious for Gram positive & negative bacteria
  • Requires cAMP for active transport internally so no anaerobic activity
  • Useful for ESBL organisms as cell wall active but not beta-lactam related so unaffected by enzymes
  • Different AUC:MIC required but still concentration dependent - intracellular enzyme not in cell wall budding

2 different salts/formulations:

  • Trometal has good absorption & predominately urinary excretion (60%) so used as an oral mega-dose for UTI
  • Calcium/sodium used with IV dosing, lower urinary excretion (10%)
34
Q

Metabolic pathway inhibition [Sulpha drugs (sulfamethoxazole & dapsone)]

A
  • Microorganisms (except enterococci) do not absorb folate like humans & are reliant on synthesis from para-aminobenzoate (PABA)
  • Sulphanomides structurally similar to PABA & inhibit DHFR stopping
  • Trimethoprim inhibits DHFR stoppung conversion to active form required for DNA synthesis
  • No good PK/PD data on effect (1950s/1960s)
  • Has effect on creatinine (renal function marker)
    + Sulfa direct renal toxicity
    + Trimethoprim inhibits tubular secretion of Cr without an effect on GFR - expect to see an increase of 20% in Cr
  • Commonly causes dermatological toxicity from rash to SJS
  • Less commonly causes haematological toxicity & bone marrow suppression
35
Q

Protein production - ribosomal inhibition

A
  • Protein is inhibited by various antibiotic classes (mRNA to protein)

Key antibiotic targets on ribosomal subunits (30S + 50S = 70S)

  • Prevent assembly of the 70S ribosome
  • Block tRNA binding
  • Mismatch reading of mRNA & tRNA
  • Block exit of produced peptide
36
Q

Tetracyclines (Tetracycline, doxycycline, minocycline & tigecycline)

A
  • Binds to the 30S subunit & prevents tRNA binding to the A site
  • Tigecycline modified to overcome resistance from structural modification of the subunit, decreasing tetracycline binding
    + Also reduces efflux pump excretion
    + Very broad spectrum
  • PK/PD fAUC:MIC but limited data on targets
  • Tetracyclines highly protein bound & well distributed into tissue
    + Tigecycline is bound so well that increased mortality in sepsis due to no circulating antibiotic

Key ADRs:

  • Photosensitivity - c.f. malaria
  • Oesophageal ulceration & gastritis
  • Binding metals e.g. Ca2+ in mineralisation of children’s bone/teeth - lower concern with doxycycline
37
Q

Aminoglycosides (Streptomycin, neomycin, gentamicin, tobramycin, amikacin)

A
  • Amino group bound by glycosidic linkage to central 6 membered ring
  • Large molecule but smaller than vancomycin so penetrates Gram-negative well
    + Positive charge facilitates transition through the outer membrane by creating transient holes
    + Requires oxygen dependent transport through cytoplasmic membrane therefore poor anaerobic cover
    + Binds to the 30S subunit causing mismatching of mRNA & tRNA leading to protein mistranslation (junk proteins)
  • Resistance usually occurs from efflux pumps & degradation enzymes rather than ribosomal conformation
38
Q

Aminoglycoside PK/PD

A
  • Cmax:MIC target of 8-10
  • AUC:MIC pf 70-120 also associated with efficacy
  • Vd similar to ECF so changes in PK vastly when affected e..g burns & sepsis
  • Once daily dosing is utilised to achieve high Cmax compared to licensed dosing of q12 or q8 - also utilises PAE (increased rates of toxicity)
  • Limited resistance but use is restricted by toxicity

Penetrates human cells poorly except proximal renal tubules (&perilymph) where it concentrates

  • High rates (5%) of nephrotoxicity/AKL but usually reversible & often significant after prolonged therapy (≥ 5 days) with high Cmax
  • Ototoxicity with high frequency hearing loss & vestibular toxicity (mitochondrial weakness)
39
Q

Aminoglycoside TDM

A
  • Cmax (peak) - occurs 30 minutes post infusion after distribution to ECF (usually not measured as recommended daily dose are&raquo_space;> MIC)
  • 4 to 6 hours post dose - used to calculate an AUC or draw the ADME curve using software
  • Cmin (trough/pre-dose)
    + Offers little to no PK benefit for the patient
    + Used to check for clearance & reduces risk of toxicity
40
Q

Chloramphenicol

A
  • Broad spectrum but limited by toxicity - limited PK/PD data
  • Binds to 50S subunit in the peptide-transferase cavity:
    + Interacts with nucleotides & prevents transpeptidation reaction (peptide chain formation)
    + Resumes on discontinuation - reversible
  • May also bind to human mitochondrial ribosomes causing toxicity
  • Concentration dependent bone marrow suppression
  • Idiosyncratic aplastic anaemia (1 in 10-20,000)
  • Gray (baby) syndrome:
    + Seen in 1959 with neonatal mortality of 50%
    + Occurs predominately in neonates due to impaired glucuronidation & reduced renal excretion
    + Circulatory collapse from reduced myocardial function with hypotonia, ashen-grey colour, hypotension, hypoperfusion & acidosis
41
Q

Macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin & clindamycin)

A
  • Similar overlapping binding sites on 50S ribosome at peptidyl-transferase centre
  • Macrolides bind near the exit tunnel for the proteins but also interferes extension of the peptide chain like chloramphenicol
  • Clindamycin binds at A & P site preventing the path of the growing peptide chain (physical block)
  • Resistance is often enzyme mediated alteration of binding site so when macrolide resistance occurs it often confers clindamycin resistance or can easily develop
  • Clindamycin has some limited evidence of benefit in toxic shock syndromes (streptococci or staphylococci) by reducing protein production especially enterotoxins as an adjunct to beta-lactam therapy
  • Poor Gram-negative penetration so little activity
    + Slight differences in activity between agents
  • PK/PD target is fAUC:MIC 25-30 with PAE seen
  • Azithromycin is derived from erythromycin for better PK
    + Prolonged serum t1/2 & tissue t1/2 from high host cell tissue concentration
  • Shorter treatment durations & daily dosing
    + Pertussis 5 days vs 14 days
  • Prolonger sub-therapeutic concentrations for up to 30 days leading to AMR
  • Macrolides, especially azithromycin, being used for immuno-modulatory effects
  • No effect on Pseudomonas but may have indirect effects via immune system e.g. reduced ILs from macrophages & evidence shows reduced CF exacerbations & increased survival in panbronchiolitis
42
Q

Linezolid

A
  • Completely synthetic compound
  • Binds to 50S subunit preventing assembly of the 70S ribosome
  • Unique mechanism so low resistance
  • Good activity against Gram-positive organisms only
    + MRSA, VRE, MDRTB
  • Limited course length due to toxicity after weeks of therapy
    + Neuropathy & bone marrow suppression
    + MAO inhibitor
  • Could also be used as a toxin suppressor
43
Q

Fluoroquinolones (Ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin)

A
  • Chloroquine (antimalarial) modified to target more Gram-negative as quinolones - Fluorine added to enhance therapy
  • Inhibits 2 topoisomerases that regulate DNA supercoiling - DNA gyrase + Topoisomerase IV
  • Topoisomerase work in uncoiling DNA, replication, transcription, recombination & repair of DNA
  • FQs bind near the active enzyme site and create a highly stable complex with DNA at the point of strand breakage but before relegation, leading to double stranded DNA breakage & cell death

Different affinity for each enzyme leads to slight change in activity, but penetration & degradation are also factors:

  • Ciprofloxacin – Gram-negative predominance
  • Moxifloxacin – Gram-positive predominance

PK/PD fAUC:MIC 30 – 40 (+) or 80 – 100 (-), PAE seen:

  • Dosing differences needed to achieve these
  • Highly bioavailable, high tissue penetration (inc Vd) including sanctuary sites

Key ADRs (Infrequent due to dissimilar topoisomerases in humans)

  • <1% tendinopathies e.g. Achille’s tendon rupture
  • Irreversible peripheral neuropathy
  • Mental health conditions including delirium, confusion & agitation
44
Q

Rifampicin (also rifambutin, ridfapentine, rifaximin)

A
  • Inhibits RNA polymerase (an enzyme that produces mRNA or tRNA from DNA) by binding within the DNA/RNA channel & sterically blocks the RNA transcript at 2 – 3 nucleotides
  • Resistance can easily occur with single mutations in binding site - Always used in combination
  • Gram-positive & mycobacterial action, poor penetration through outer Gram-negative membrane
  • PK/PD AUC:MIC for killing but Cmax:MIC for reducing resistance development
  • t1/2 = 3 h but significantly PAE seen especially against mycobacteria
  • Zwitterionic at physiological pH (both +ve & -ve charges) gives good distribution & tissue penetration
  • Hepatically metabolised via CYP isoenzymes & large number of strong interactions as enzyme inducer - Can also cause hepatotoxicity

ADRs: Secretion staining – benign but scary ADR is unexpected:

  • Orange/red staining of all bodily fluids including urine, sweat & tears
  • Caution patients on clothing & contact lenses
45
Q

Nitrofurantoin

A

Unknown precise mechanism but postulated several mechanisms (explains low resistance):

  • Inhibit bacterial enzymes
  • Ribosomal blockage
  • Direct DNA damage
  • Active against most uropathogens (UTIs)

PKPD – none to speak of!

  • Rapid urinary excretion & tissue degradation (t1/2 = 20 minutes) so even with IV only urinary concentrations are measurable
  • 2 formulations – standard given QDS & macro-crystals which slow dissolve & are then absorbed slower given BD
  • ADRs are rarely seen due to low tissue concentrations but can be seen with chronic use & renal impairment
    + Pulmonary fibrosis & hepatoxicity
46
Q

Metronidazole (also tinidazole & ornidazole)

A
  • Unknown precise mechanism but small molecules diffuses into cells & is activated by reduction of the nitro group, leads to anionic free radical production causing DNA damage & cell death
  • Only occurs in anaerobic bacteria as oxygen re-oxidises the free radical back to the parent compound producing oxygen radicals instead which are easily scavenged
  • PKPD AUC:MIC (70) & Cmax:MIC both show best efficacy parameters
  • Well absorbed (>90%) & distributed widely with limited restriction
  • Intraluminal metronidazole (& active metabolite) levels of 0 – 15% with reducing levels as diarrhoea resolves
    + Low entero-hepatic recirculation but presumably direct secretion through inflamed mucosa

Key ADRs:
- Neuropathies seem with prolonged (e.g. 4 – 6 weeks) treatment & can be slow to resolve
- Often causes a metallic taste (systemic)
- ‘Disulfuram-like’ reaction with alcohol
+ Inhibition of aldehyde dehydrogenase increases levels of acetyl aldehyde leading to nausea, vomiting, flushing, palpitations
+ So no alcohol while on it – including washout period

PHARM 213 Infectious Diseases (13 decks)

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