Infectious Disease Pharmacology

This is still a work in progress!

Define selective-toxicity

toxic to the micro-organism, but not harmful to the cells of the host

What do antimicrobial agents target?

Antimicrobial agents target

* metabolic channels
* metabolic pathways
* structures present in the micro-organism, but not in the host

What is the difference between antibiotic and antimicrobial?

Antibiotic

* Substance produced by a micro-organism (natural origin)

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Antimicrobial

* Substance of natural, synthetic or semi-synthetic origin

What is a cytostatic / bacteristatic antimicrobial?

They inhibit the growth of the target organism/bacteria

What is a cytocidal / bactericidal antimicrobial?

They kill the target organism/bacteria

How are antimicrobial agents classified?

* Their target organism
* Cytostatic versus cytocidal
* Mechanism of action
* Spectrum of activity

What groups of organisms do antimicrobes target?

* Bacterias
* Fungi
* Viruses
* Protazoas

What is the mechanism of action of antibiotics?

* Inhibition of cell wall synthesis
* Inhibition of protein synthesis (translation)
* Inhibition of nucleic acid replication and transcription
* Inhibition of synthesis of essential metabolites
* Injury to plasma membrane

What are the two spectrums of antibacterial targets?

* Broad spectrum
* Narrow spectrum

What is a broad spectrum antibiotic + give examples?

Activity against a broad range of bacteria – Gram positive and Gram negative

* Carbapenems
* Fluoroquinolones
* 3rd and 4th generation cephalosporins

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The broader the spectrum, the more chance of antibiotic resistance

What is a narrow spectrum antibiotic + give examples?

Limited activity

* ^^Nitroimidazoles^^ active only against anaerobic bacteria
* ^^Glycopeptides^^ active only against Gram positive bacteria

What are the benefits of antimicrobial therapies?

* Reduced mortality
* Reduced morbidity
* Safer surgery
* Safer transplants

What are the downsides of antimicrobial therapies?

* Resistance
* Toxicity (to host)
* Secondary infection
* Hypersensitivity / allergic reactions

What is the steps of antimicrobial treatments?

Empiric treatment:

* Initial treatment, before causative organism identified
* It is the ‘Best guess’

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Definitive treatment:

* Targeted at identified organism

How do you select the type of antimicrobial agent?

* Site of infection
* Likely causative organism(s)
* Oral or intravenous therapy → also dependent on where patient gets treatment e.g. oral in GP practice?
* Pharmacodynamic characteristics of agent
* Therapeutic drug monitoring (TDM)

What is a minimum inhibitory concentration (MIC)?

Lowest concentration of the antimicrobial →

which results in inhibition of detectable growth of the organism

What are the 2 types of pharmacodynamics of antimicrobials?

* Time-dependent killing
* Concentration-dependent killing

What is a time-dependent killing pharmacodynamic + examples?

Bactericidal effect is dependent on the ^^length of time that the bacteria are \n exposed to concentrations of drug above the MIC^^

* Penicillins
* Cephalosporins
* Carbapenems

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A property associated with cell wall synthesis inhibtors

Bactericidal activity continues as long as the plasma concentration is greater than the minimum bactericidal concentration (or MIC).

What is a conc.-dependent killing pharmacodynamic + examples?

Bactericidal effect ^^increases with the concentration of the drug^^

* Fluoroquinolones
* Aminoglycosides

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The rate & extent of killing increases as the peak drug concentration increases

A property associate with drugs inhibiting protein or DNA synthesis

What are the host factors for antimicrobial therapies?

* Age
* Renal and hepatic function
* Underlying disease
* Antimicrobial allergy
* Genetic variation (e.g., G6PD deficiency)
* Pregnancy, breastfeeding
* Recent antimicrobial therapy
* Recent microbiology results

What are some complications of antimicrobial therapies?

* Development of antimicrobial resistance
* Drug toxicity
* Side effects (adverse reactions)
* Interactions with other medications
* Allergy (hypersensitivity reactions)
* Secondary infections
* Treatment failure

What are the types of allergy/hypersensitivity reactions?

* Immediate, IgE mediated, type 1
* Delayed, non-IgE mediated, usually type 4

What is a type-1 allergy reaction?

* It is immediate - Within 1 hour
* IgE mediated
* S/E: Urticarial rash, itch, flushing, wheeze, angioedema, hypotension, anxiety

What is a type 4 allergy reaction?

* Delayed - takes more than 1 hour
* Non-IgE mediated
* S/E: rash, fever, Stevens-Johnson syndrome

What is important to consider for allergic patients?

Detailed history important \n Need to distinguish:

* Nature of allergy
* Between allergy and side effect/intolerance (Type 1 or Type 4?)
* Groups of antibacterials that they had allergy / hypersensitivity / intolerance reactions to

Why can an antimicrobial treatment fail?

* Incorrect diagnosis
* Inappropriate choice of agent - e.g. doesn’t cross blood-brain barrier
* Suboptimal dose, frequency or duration
* Inadequate source control - e.g. if line is infected → remove the line as well as prescribing antibiotic!
* Drug resistance

What are the principles in prescribing antimicrobes?

* Treat only if evidence of infection
* Use as narrow-spectrum as possible
* Send appropriate microbiology samples, ideally prior to treatment
* Follow antimicrobial prescribing guidelines
* Use local guidelines if available
* Document indication and review/stop date
* Review with results
* Modify treatment, de-escalate if possible

What groups of drugs are inhibitors of bacterial cell wall synthesis + examples?

^^**Beta-lactam antimicorbials**^^

* Penicillins
* Cephalosporins
* Monobactams
* Carbapenems

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^^**Glycopeptides:**^^

* Vancomycin
* Teicoplanin

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**Bacitracin** \n

**Anti-**__**myco**__**bacterial agents:**

* Isoniazid
* Ethambutol

What is the structure of β-lactam antimicrobials + examples?

4-member core β-lactam ring + a side ring

* Penicillins have a 5 member side ring
* Cephalosporins have a 6 member side ring

Are β-lactams bactericidal or bacteristatic?

Bactericidal

How can β-lactams be modified?

By the modification of their side-rings

Why are β-lactams modified?

* To change antimicrobial activity
* To make resistance to β-lactamase enzymes
* Change their pharmacokinetics

What is the mechanism of action of β-lactams?

Cross-linking of newly formed peptide to glycan backbone is catalysed by \n ^^transpeptidase^^ (aka penicillin binding protein, PBP) → β-lactam antimicrobials ^^bind to transpeptidase and prevent formation of cross links^^ \n

* Inhibition of cell wall synthesis activates autolytic enzymes which trigger cell death
* Production of β-lactamase by bacteria can inactivate drug and confer resistance

How can a bacteria become resistant to β-lactam drugs?

Production of β-lactamase by bacteria can inactivate drug and confer resistance

What are the different classifications of Penicillins?

* ^^Natural penicillins^^
* ^^β-lactamase resistant penicillins^^
* ^^Aminopenicillins^^
* ^^Carboyxypenicillins^^
* Ureidopenicillins (not used clinically)
* ^^Penicillin and β-lactamase inhibitor combinations^^

What are the natural penicillin drug names?

* Penicillin G aka benzylpenicillin (IV)
* Penicllin V (oral)

What are the β-lactamase resistant penicillin drug names?

* ^^Flucloxacillin^^
* \[Methicillin\]
* \[Cloxacillin\]
* \[Nafcillin\]

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\[brackets\] = either not used in Ireland/UK or not used clinically

What are the aminopenicillin drug names?

* Ampicillin
* Amoxicillin

What are the carboxypenicillin drug names?

* ^^Temocillin^^
* \[Ticarcillin\]

What are the penicillin and Β-lactamase inhibitor drug combinations?

* Amoxicillin/clavulanate (aka coamoxiclav)
* Piperacillin/tazobactam (aka piptazobactam)
* \[Ampicillin/sulbactam\] - not used in IE/UK
* \[Ticarcillin/clavulanate\] - not used in IE/UK

What are the routes of administration for penicillins?

* Oral – penicillin V, amoxicillin, flucloxacillin
* IV – penicillin G, piperacillin, flucloxacillin
* IM – penicillin G

Which penicillin is has a higher bioavailability? Amoxicillin or Penicillin V?

Amoxicillin > Penicillin V

What reduces the absorption of penicillins?

* Food
* Acid pH

What is the protein binding of penicillins?

Variable

What is the distribution of penicillins like?

* Distributes in most tissues and fluids
* Crosses placenta
* Crosses blood-brain barrier (BBB) if inflamed e.g. meningitis

How is penicillin excreted?

* Predominantly renal excretion
* Tubular secretion >> glomerular filtration
* Dose reduction required in severe renal impairment (calc. eGFR)

What does the metabolism of penicillins look like?

Some hepatic metabolism

How much is nafcillin metabolised in the liver?

80% hepatic metabolism

What does probenecid do to penicillins? Why’s that useful?

* It inhibits the tubular secretion of penicillins
* Helps to lower daily intakes for patients (lower dosage, easier to manage/remember)

What are the side-effects of penicillins?

* GI - nausea, vomiting, diarrhoea, C. difficile infection
* Skin – rash, phlebitis
* Haematological – neutropenia, platelet dysfunction
* CNS – seizures, encephalopathy
* Nephrotoxicity – acute interstitial nephritis
* Hepatic effects – hepatitis, cholestasis
* Hypokalaemia
* Hypersensitivity type 1 and 4 reactions

What is the spectrum of activity of Penicillin V/G?

Narrow spectrum:

* Streptococci
* Neisseria meningitidis
* Treponema pallidum
* Clostridia

What is the spectrum of activity of Flucloxacillin?

Narrow spectrum:

*Staph. aureus*

What is the spectrum of activity of Amoxicillin?

Narrow spectrum:

* Streptococci
* Enterococci
* E. Coli
* Listeria

What is the spectrum of activity Amoxicillin/clavulanate (coamoxiclav)?

Broad spectrum:

* Gram negative bacilli
* streptococci
* Enterococci
* Staph. aureus
* Anaerobes

What is the spectrum of activity of Piperacillin/tazobactam (piptazobactam)?

Broad spectrum:

* Gram negative bacilli
* ^^**Pseudomonas aeruginosa - main use, in CF, burn patients, chemotherapy patients**^^
* Streptococci
* Enterococci,
* Staph. aureus
* Anaerobes

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What is are the clinical uses of Penicillin V/G?

* Streptococcal infections (pharyngitis, skin, soft tissue, pneumonia, bone, joint, endocarditis)
* Meningococcal meningitis
* Syphilis
* Diphtheria

What is are the clinical uses of Flucloxacillin?

Staph. aureus infections (skin, soft tissue, bone, joint, endocarditis)

What is are the clinical uses of Amoxicillin?

* Enterococcal infections (UTI, endocarditis)
* E. coli infections (UTI, intra-abdominal infections)
* Listeria infections

What is are the clinical uses of Amoxicillin/clavulanate?

* Intra-abdominal infections (usually polybacterial)
* Anaerobic infections
* Pneumonia

What is are the clinical uses of Piperacillin/tazobactam?

* Intra-abdominal infections,
* Anaerobic infections
* Hospital-acquired pneumonia (Pseudomonas aeruginosa)
* Neutropenic sepsis

How many groups are Cephalosporins classified into?

1st-5th Generations

What are the 1st gen. Cephalosporins?

* Cephalexin
* Cefazolin

What are the 2nd gen. Cephalosporins?

* Cefuroxime
* Cefaclor

What are the 3rd gen. Cephalosporins?

* Cefotaxime
* Cetriaxone
* Ceftazidime

What is the 4th gen. Cephalosporin?

Cefepime

\*Not used in IE

What is the 5th gen. Cephalosporin?

Ceftaroline

What are the routes of administration of Cephalosporins?

* Oral – cephalexin, cefaclor
* IV – cefuroxime, cefotaxime, ceftazidime, ceftriaxone
* IM – ceftriaxone

What is the bioavailability of Cephalosporins?

Cephalexin > cefaclor >> cefuroxime

What is the protein binding of cephalosporins?

Variable

What is the distribution of cephalosporins?

* Crosses most tissues and fluids
* Crosses the placenta
* ^^1st and 2nd generation do not cross BBB^^

How are cephalosporins excreted?

Predominantly renal excretion

Dose reduction required in severe renal impairment (calc. eGFR)

How are cephalosporins metabolised?

Some hepatic metabolism

What are the side effects of cephalosporins?

* GI – nausea, vomiting, diarrhoea, C. difficile infection
* Skin – rash, phlebitis
* Haematological – neutropenia, platelet dysfunction
* CNS – seizures, encephalopathy
* Nephrotoxicity – acute interstitial nephritis
* Hepatic effects – cholestasis
* Hypersensitivity type 1 and 4 reactions
* Estimated 10% cross reactivity with penicillins – likely \~1-2%

What is the spectrum of activity of 1st gen. cephalosporins?

* Streptococci
* Staph. aureus
* Some Gram negative bacilli

What is the spectrum of activity of 2nd gen. cephalosporins?

* Streptococci
* Staph. aureus
* Gram negative bacilli
* Haemophilus influenzae

What is the spectrum of activity of 3rd gen. (cefotaxime, cetriaxone) +4th gen. cephalosporins?

* Streptococci
* Staph. aureus (less than 1st or 2nd)
* Neisseria meningitidis
* Gram negative bacilli

What is the spectrum of activity of ceftazidime (also a 3rd gen., but has more activity)

* Streptococci
* Staph. aureus (less than cefotaxime, cetraixone)
* Neisseria meningitidis
* Gram negative bacilli
* ^^**Pseudomonas aeruginosa**^^

What is the spectrum of activity of 5th gen. cephalosporins?

* Enhanced Gram positive cover, including MRSA and enterococci
* No anti-pseudomonal cover

What is the clinical use of 1st gen. cephalosporins?

* Streptococcal and Staph. aureus infections (pharyngitis, skin, soft tissue)
* Uncomplicated UTI
* Some Gram negative bacteria

What is the clinical use of 2nd gen. cephalosporins?

* Intra-abdominal infections
* Surgical prophylaxis
* UTI
* Respiratory tract infection

What is the clinical use of 3rd gen. cephalosporins?

Broad spectrum

* Meningitis (N. meninigitidis, S, pneumoniae)
* Pneumonia
* Pyelonephritis
* Lyme disease
* Gonorrhoea
* Neutropenic sepsis
* Pseudomonal infections (^^ceftazidime^^ only)

Name a monobactam

Aztreonam

What are the targeted organisms of monobactams?

Active only against:

* Aerobic Gram negative bacilli, including P. aeruginosa

What is the benefit of monobactams?

Resistant to many β-lactamases

How are monobactams administered?

IV only

How are monobactams excreted?

Renal excretion – reduce dose in severe renal impairment

What are the side effects of monbactams?

* Rash
* Pancytopenia
* Suprainfections, including C. difficile
* Convulsions

What are the clinical uses of monobactams?

* Pyelonephritis
* Gram negative respiratory tract infections (cystic fibrosis)
* Intra-abdominal infections (in combination with other antimicrobials)

Give examples of cabapenems

* Ertapenem
* Meropenem
* Imipenem-cilastin
* Doripenem

What is the benefit of carbapenems>

Resistant to most β-lactamases (including extended-spectrum βlactamases, ESBL)

What is the spectrum of activity of carbapenems?

**Extremely broad spectrum cover**

* Gram negative bacilli
* Streptococci
* Listeria,
* Anaerobes
* Pseudomonas aeruginosa (not ertapenem)

When are carbapenems clinically used?

**RESERVE drug**:

* Used only for infections due to bacteria caused by resistant organisms
* Severe sepsis

How are carbapenems administered?

IV only

How are carbapenems excreted?

Renal excretion

Reduce dose in sever renal impairment

What are the side effects of carbapenems?

* Rash,
* Hepatic and haematological effects
* Seizures

How do glycopeptide antimicrobials work?

* Inhibit bacterial cell wall synthesis
* Interact with the terminal amino acids of the side chain → thereby interfering with the formation of cross links between chains

What are some examples of glycopeptide antimicrobials?

* Vancomycin
* Teicoplanin
* Oritavancin (single dose)
* Dalbavancin (weekly dosing)

What is the spectrum of activity of glycopeptide antimicrobials?

Narrow spectrum of activity

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**Gram positive organisms**

* Staph. aureus (including MRSA)
* Coagulase negative
* Staphylococci
* Enterococci
* Streptococci

Why can’t glycopeptide antimicrobials target gram negative bacteria?

Molecule too big to pass through the outer membrane of Gram negative bacteria

How are glycopeptide antimicrobials administered?

* IV use only as not absorbed orally
* Exception is the use of oral vancomycin for treatment of C. difficile infection (not absorbed, so available at intended site of action in bowel)
* IV dose based on weight and renal function