Antimicrobials

IT1 96006
Dr Helen Benson
BPharm PhD AACPA MPS Adv PP(II)
Consultant Pharmacist
 Be able to describe
• the role of antimicrobial therapy in the
treatment of infections
• Understand the factors involved in selecting
an appropriate antimicrobial
Learning • List commonly used anti-bacterials and their
classes
Outcomes • Identify antibiotics which should be used in
infections
• Understand information on specific groups of
antibiotics
 Principles of antimicrobial use

Classes

Lecture Antibacterials
Outline Antifungals

Antivirals

Clinical applications
Principles
• Microbes
• Fungi, yeasts, moulds (example
tinea)
• Bacteria (example, bacterial
pneumonia)
• Viruses, (examples, Herpes simplex,
influenza, COVID-19)
Normal Flora
• Normal flora reside throughout the
body
• Flora are known as ‘commensal’
meaning to the benefit of one organism
without effecting the other
• They protect the body from infection,
prevent pathogens penetrating
endothelium, help absorption of vitamins
and can digest fatty acids in the gut.
• Movement of normal flora from its
home location to another location in the
body can cause infection.
Pathways to infection
• Ingestion
• Inhalation
• Internal perforation
• Trauma
• Iatrogenic
• Surgical intervention
• Barrier nursing/ hand washing failure
• Communal wards
Vulnerable
populations
• Which patients do you think are more
prone to infection?

• What can we do about it?

Considerations when
choosing antimicrobials
• Source of infection
• Microbiology
• Patient centred considerations
(renal function, drug interactions,
convenience of treatment.)
• Recent travel
• Prophylaxis versus treatment
• Duration of treatment
• I.V. compatibility
Considerations when choosing
antimicrobials

• Length of treatment
• Single dose?
• Short Course< 5days?
• Longer Course 5-10 days
• Extended Course> 10 days
Antibiotics
Substances that kill or inhibit the
growth of bacteria
Considerations
when choosing
antibiotics
Bacterial Drug Targets

Source: Targeting virulence: a new paradigm for antimicrobial therapy

Anne E Clatworthy, Emily Pierson & Deborah T Hung. Nature Chemical Biology 3, 541 -
548 (2007)
Characteristics of Bacteria Gram Positive and Gram Negative

Gram negative cells Gram positive cells

Outer membrane No outer membrane

Prevents uptake of
gram stain Take up gram stain
Prevents penetration by
some antibacterial
agents

Benzylpenicillin, macrolides, rifampicin, fusidic acid, vancomycin are

unable to penetrate the outer membrane and are therefore ineffective
against gram negative organisms
Different bacteria are associated with
different infections
Genus Morphology Species Disease

Gram-negative
Bordetella Cocci B.pertusis Whooping cough
Campylobacter Spiral rods C.jejuni Food poisoning
Escherichia Rods E.coli Septicaemia, wounds, UTIs
Pseudomonas Flagellated rods P.aeruginosa Septicaemia,
respiratory tract, UTIs
Gram positive
Staphylococcus cocci S.Aureus Wound, boils, septicaemia
Streptococci Cocci S.pneumonia Pneumonia, meningitis
cocci S.pyogenes Scarlet fever,
rheumatic fever,
cellulitis
 organism Transmission Outcome
Gram positive S.pneumoniae inhalation Typical
pneumonia
Different S.Pyogenes inhalation Typical
pneumonia

bacteria S.aureus inhalation,

post -
Typical
pneumonia

may cause B.anthracis

influenza
Inhalation Typical

clinically pneumonia,
anthrax

similar
Gram negative M.catarrhallis inhalation Typical
pneumonia
K.Pneumonia aspiration Typical
infections P.Aeroginosa Inhalation
pneumonia
Typical
or pneumonia
aspiration
Bacterial Spectrum
• Broad spectrum-active against a
range of organisms (gram positive and
gram negative)

• Narrow spectrum-limited activity and

target particular microorganisms

Source: http://amrls.cvm.msu. edu/pharmacology/ant imicrobials/

Bactericidal or
Bacteriostatic
• Bactericidal-kill microorganisms

• Bacteriostatic-inhibit or delay
bacterial growth and replication

Source: http://amrls.cvm.msu.
edu/pharmacology/ant
imicrobials/
Antibacterial drug
targets
Three main targets for antibacterial
drugs
Cell wall synthesis
Nucleic acid synthesis
Protein Synthesis

Source: Sahare, Moon, Shindes. International Journal of Scientific & Engineering

Research, Volume 4, Issue 9, September- 2013 806
Antibacterials that
disrupt the cell wall
Different agents have different
targets within the cell wall

• Beta-lactams and glycopeptides

• Cell wall peptidoglycan synthesis

• Polymixins
• Outer cell wall membrane
structure
 Benzylpenicillin Gram positive Bacterial meningitis
(penicillin G) Some gram negative Skin and soft tissue
phenoxymethylpenicillin (strep or staph)
(penicillin V) Pharyngitis (S.pyogenes)

Penicillinase-resistant penicillins: Staphylococcal infections Bone and joint

Flucloxacillin, dicloxacillin infections
(S.aureus)

Beta-lactam Skin and soft tissue (strep or

staph)

antibiotics Broad spectrum penicillins:

Amoxicillin, ampicillin
Gram positive and gram
negative species
Otitis media
(s.pyogenes, H.
influenza)

(penicillins) UTI (E.coli)

Antipseudomonal penicillins Serious Gram-negative P. aeruginosa

Piperacillin, ticarcillin
 Many susceptible to inactivation
by beta-lactamase

May be used in combination with

a beta-lactamase inhibitor
Beta-lactam • E.g. Amoxicillin or ticarcillin and
antibiotics clavulanic acid

(penicillins) • Piperacillin with tazobactam

Source: www.blad.co.in
 • Inhibit synthesis of bacterial cell wall
peptidoglycan
• Bind penicillin-binding proteins
• Inhibit transpeptidation enzyme
• Inactivate autolytic enzyme inhibitor
•
Beta lactam
Cell lysis
• Bactericidal

antibiotics • Wide volume of distribution

• Do not cross blood brain barrier

(penicillins) • Rapid renal elimination

• Hypersensitivity reactions (due to degradation products)
• Alter GI and Urogenital flora (Vomiting, diarrhoea and
thrush)
 • Same mechanism of action as penicillin
• Some resistance due to Beta-lactamase
• oral and parenteral
• Some cross blood brain barrier
• Cefotaxime, cefuroxime,
Beta-lactams ceftriaxone
• Mainly renal excretion
Cephalosporins • Hypersensitivity cross sensitivity with
penicillin (approx 10%)
• Similar adverse effects to penicillins
 First generation: Mainly gram Strep and staph
cephalexin, positive
cephazolin, Moderate
cefalotin spectrum

Second generation: Moderate spectrum Acute Otitis media

cefaclor, cefuroxime, Mainly gram positive, H.influenzae respiratory
cefoxitin some gram negative tract infections
Acute sinusitis

Beta-lactams Third generation:

cefotaxime,
Broad spectrum
limited gram positive,
good gram negative
Pneumonia
Septicaemia
Bacterial
Cephalsporins
ceftriaxone,
ceftazidine meningitis
Peritonitis
Fourth generation: Broad spectrum P.auroginosa
Cefepime, cefpirome Increased gram infections sepsis
negative
Fifth generation: Some MRSA Complicated skin and soft
Ceftaroline activity Gram tissue (MRSA)
positive Community acquired pneumonia

Fifth generation: Resistant gram negative

Ceftolazane
 Imepenem, Same mechanism of action as penicillins
Meropenem, Bactericidal
Ertopenem Broad spectrum

Gram positive
Beta-lactams and gram
Resistance an issue
negative,
Carbapenems anaerobes

May be
combined Similar adverse effects to other beta lactams
with cilastin
 Aztreonam

• Resistant to most beta-lactamases

• Plasma half life of 2 hours

• Parenteral only
Beta-lactams • Gram negative aerobes only
Monobactams N.meningitis, H. influenza

• No cross reactivity with other penicillins

 Vancomycin, (teicoplanin, daptomycin)

• Inhibit cell wall synthesis

• But not a beta-lactam

• Spectrum: Mainly for gram positive

Glycopeptides • Vancomycin for MRSA

• Vancomycin not absorbed from GIT

• Parenteral administration for
systemic use
 Therapeutic Use: Serious gram
positive infections (MRSA)
• Renally cleared
Therapeutic Drug Monitoring
Required (Severe ADRs)
Glycopeptides- • High trough levels are
Vancomycin associated with ototoxicity and
nephrotoxicity
• Red man Syndrome (associated
with rapid administration)
 tetracyclines

Antibacterials chloramphenicol
that affect
protein
aminoglycosides
synthesis

macrolides
 • Inhibit protein synthesis
• Bacteriostatic
• Administered via oral and parenteral routes
• issues with oral absorption for some agents
• Doxycycline and minocycline well absorbed
Tetracyclines orally
• Broad spectrum

• gram positive and negative, mycoplasma,

chlamydia, spirochetes, some protozoa

• Metabolised by the liver

Tetracyclines
• Resistance is an issue (plasmid
mediated, co-selection)
• Therapeutic use is broad
• Adverse effects:
GI-irritation and GI flora,
Vitamin B deficiency, deposit in
teeth and bones,
photosensitivity, hepatotoxicity
 • binds ribosomal 50s subunit

• inhibits bacterial protein synthesis

• used systemically and topically (eye
drops)

• spectrum: gram positive and negative

Chloramphenicol • resistance: plasmid mediated
• Bacteriostatic
• bactericidal for H. influenza
• good oral absorption
• peak approx 2 hours
• T ½ approx 2 hours
Chloramphenicol
• Therapeutic use

• topical (eye and ear)

• systemic reserved for serious infections

due to adverse effects

• Adverse effects

• Bone marrow depression and

pancytopenia, Grey baby syndrome,
Hypersensitivity,GI flora
 Gentamicin, Streptomycin, Tobramycin,
Neomycin

NOT vancomycin (remember it’s a

glycopeptide)
• Inhibit protein synthesis at multiple sites
• Resistance: different mechanisms
Aminoglycosides • Spectrum: mainly aerobic gram negative
• not orally absorbed
• do not cross blood:brain barrier
• plasma half life 2-3 hours
• renal excretion!!!!!!!!!!!! (accumulation in
renal impairment)
 Therapeutic use

• enteric gram negative infections

• sepsis

Adverse effects
Aminoglycosides
• Serious and dose related

• ototoxicity

• nephrotoxicity

TDM important
Macrolides
Erythromycin, Clarithromycin, Clindamycin, Azithromycin,
Roxithromycin
• macrolide structure

Source:tmedweb.tula ne.edu
 • affect ribosomal translocation
• compete with choramphenicol and
clindamycin to bind 50s subunit- can’t use
together
• spectrum: varied
• erythromycin similar to penicillin

Macrolides • azithromycin less gram positive, more active

H.influenza, legionella
• oral and parenteral
• do not cross blood:brain barrier
• metabolism varies by agent (erythromycin-
hepatic)
• some agents metabolized by P450
(interactions!!!!!!)
 • Therapeutic use​: varied

• Respiratory tract, legionnaires

disease,pertussis, campylobacter,
chlamydia
Macrolides
• Adverse effects​: GI​,
Hypersensitivity
(erythromycin)​,cholestatic jaundice
 • Lincosamides
(e.g.clindamycin)
• Fusidic acid (good bone
Other penetration)
antibacterials • Linazolid (I.V. administration,
important role in the
that affect management of resistant
protein synthesis infections)
 Ciprofloxacin, Norfloxacin, Ofloxacin, Moxifloxacin,
Nalidixic acid

Antibacterials Mechanism of Action: inhibit topoisomerase>> inhibiting

bacterial replication
that effect
• Bactericidal
nucleic acid
synthesis: • Good oral absorption

Quinolones • Accumulate in some tissues (kidney, prostate,lung)

• hepatic metabolism (P450-cipro, norflox>>interactions!!!)

• renal excretion
 Chemical inactivation by Al3+ and Mg2+

Spectrum: broad (mainly gram negative)

Therapeutic use​: varied

Quinolones including complicated UTI, Typhoid,
salmonella, bone and joint,
P.aeruginosa, prostatitis,
febrile neutropenia

Adverse effects​: usually mild and

reversible GI, rashes, CNS
Antibacterial drug
targets
Three main targets for antibacterial
drugs
Cell wall synthesis
Nucleic acid synthesis
Protein Synthesis
- Folate synthesis is an additional
target for antibacterials

Source: Sahare, Moon, Shindes. International Journal of Scientific & Engineering

Research, Volume 4, Issue 9, September- 2013 806
Antibacterials that effect folate synthesis:
Sulfamethoxazole and
Trimethoprim
• Sulfonamide drugs compete with
PABA for enzyme
• Competitive antagonism
• Can overcome the inhibition with
excess PABA
• Bacteriostatic
• Plasmid mediated resistance
common

Source Rang and Dale,

Pharmacology 2016
 Sulfamethoxazole- oral administration
• In combination with trimethoprim
• Widely distributed in the body
• Cross blood:brain barrier
• Metabolised in liver
Sulfonamides Targets -P.jirobecci, Toxoplasmosis,
MRSA (skin/ soft tissue)
• Adverse effects​: Hepatitis,
hypersensitivity, Steven-Johnson
syndrome, bone marrow depression​,
Acute renal failure (from metabolites)
 Mechanism of Action: Folate antagonist
with a high affinity for dihydroreductase
Bacteriostatic
Used to potentiate effect of
sulfamethoxazole
Co-trimoxazole
Trimethoprim • good oral absorption
• high volume of distribution
• elimination pH dependent
• Spectrum: broad (gram positive and
negative)
 • Therapeutic role:UTI (growing AB
resistance), prostatitis
• Co-trimoxazole-UTI, pneumonia,
otitis media, sinusitis
• Adverse effects: megaloblastic
Trimethoprim anaemia associated with folate
deficiency, GI flora
disruption,nausea, vomiting,
Hypersensitivity,rashes
Antifungals
• Substances that kill or inhibit
the growth of fungi
 Candida infection
• oral and vaginal thrush
• invasive candidiasis (infection in
bloodstream)
Common Fungal Aspergillus infection
• aspergillus pneumonia
Infections • invasive sinus disease
Cryptococcus infection
• rapidly progressive pneumonia
• chronic meningitis
Targets of antifungal
drugs
• Fungal cell membrane and cell
wall
• Cell membrane bilayer
 Azoles (examples fluconazole, clotrimazole,
itraconazole, poziconazole)
• topical azoles widely used for oral and vaginal
thrush
• systemic azoles are used for candidaemia,
aspergillosis and other invasive fungal infections
Azole • Many clinically significant drug interactions​:
azoles are CYP 3A4 inhibitors
antifungals • fluconazole prolongs the QT interval
• PPIs and H2 antagonists reduce the absorption
of itraconazole and poziconazole
• Adverse reactions include rash, headache,
dizziness, nausea, vomiting abdominal pain,
diarrhoea and elevated liver enzymes
 Nystatin
• Available as oral drops, lozenges, creams and
pessaries
• Used topically for candida (thrush) infections
Amphotericin
Nystatin, • Lipsomal amphotericin is the most common
Amphotericin formulation (it is very expensive) and long
courses ae often required

and • Used for cryptococcal meningitis and severe

systemic fungal infections
Echinocandins Echinocandins
• Examples include caspofungin, andulafungin,
micafungin
• Active against most candida strains including
those resistant to azoles and amphotericin
• Caspofungin also active against aspergilluss
strains
Antivirals
Substances that kill or inhibit the
growth of viruses
 Acute
• HSV encephalitis
• Influenza
• Respiratory syncytial virus (RSV)
Types of • Cytomegalovirus
Viral Chronic
Infections • HIV
• Hepatitis B
• Hepatitis C
 Inhibit viral polymerase and viral DNA synthesis
Examples: famciclovir, acyclovir,valaciclovir,
ganciclovir and valganaciclovir
Used for the treatment and prevention of herpes
simplex infections​, shingles, acute chicken pox
Antivirals: (varicella zoster) in immunocompromised
patients​,treatment/prevention of CMV disease in
Guanine immunocompromised patients
Adverse Reactions: nausea, vomiting, diarrhoea,
Analogues hallucinations, headache, encephalopathy,
injection site reactions
Ganciclovir is associated with causing blood
dyscrasias including neutropenia,
thrombocytopenia, anaemia and
granulocytopenia
 Decrease viral replication by
inhibiting neuraminidase, preventing
the release of new virus from the
cells
Examples: oseltamivir (Tamiflu)
Antivirals: Indicated for treatment of Influenza A
Neuraminidase and B
inhibitors Used for prevention of influenza in
selected at risk groups
Shortens duration of influenza if
taken within 48 hours (modest effect)
ADRS: nausea, vomiting, headache
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