Antimicrobial Drugs

Andi Alfia Muthmainnah T

Departemen Farmakologi
Fakultas Kedokteran
Universitas Tadulako
 Antibiotic vs Antimicrobial
Antibiotic
Kimia yang dihasilkan oleh mikroorganisme yang
membunuh atau menghambat pertumbuhan
mikroorganisme lain
•
Antimicrobial
Kimia yang membunuh atau menghambat pertumbuhan
mikroorganisme
•
 The Classification of Antimicrobial Drugs

Antimicrobials

Antibact Antifung Antiprot Anthel-

Antiviral
erials al ozoal mintics
 (FK, Mekanisme Kerja, Penggunaan Klinis,
Efek Samping)
• Klp 1: Penisilin
• Klp 2: Carbapenem
• Klp 3: Cefalosporin generasi 1&2
• Klp 4: Cefalosporin generasi 3&4
• Klp 5: Aminoglikosida
 Case
• A 62-year-old man with history of poorly
controlled Diabetes, HTN, and Hyperlipidemia
presents with worsening left lower extremity
pain. Physical exam reveals cellulitis and
possible wound infection, with concern for
osteomyelitis.
 Factors to Consider When Choosing
Antibiotics
patient's recent antibiotic therapy

hospital flora

presence of underlying diseases

available culture data – current AND past

risk for drug resistant pathogens:

• receipt of antibiotics within the preceding 90 days
• current hospitalization of ≥5 days
• antibiotic resistance in the community
• immunosuppressive disease and/or therapy
• presence of risk factors for resistance
 Choosing An Antibiotic

Think about Location:

• Where did the patient become ill? Travel?
Exposure?
• Where did the infection anatomically originate?
• Where in the body, has or will the infection
spread to?

Think about the bug you are treating

1. Consider your
bugs!

2. What are you

treating or
covering
empirically?
 Antibiotics Actions

Bactericidal
• Kills bacteria, reduces bacterial load

Bacteriostatic
• Inhibit growth and reproduction of bacteria

All antibiotics require the immune system to work

properly
• Bactericidal appropriate in poor immunity
• Bacteriostatic require intact immune system
Modes of Antimicrobial Action
 Cell Wall Synthesis Inhibitors

Beta Lactams
• Penicillins (PCN)
• Cephalosporins
• Carbapenems
• Monobactams

Vancomycin

Bacitracin

Polymyxin
 Beta Lactams

• B-lactams inhibit
transpeptidase.

• Only effective against rapidly

growing organisms that
synthesize peptidoglycan
(Ineffective against
mycobacteria.)

• Spectrum of activity: very

wide, anaerobes
 ß-Lactams
ß-Lactams
Penicillin
Narrow Spectrum
Cephalosporin •Benzylpenicillin (Penicillin G)
• Cefazolin, •Phenoxymethylpenicillin (Pen V)
Cefadroxil, Broad Spectrum
Cefalexin •Amoxicillin/Co-amoxiclav
• Cefuroxime •Ampicillin
• Cefixim,
Cefoperazon,
Carbapenem
Cefotaksim, •Meropenem
Cefpirom,
Cefpodoksim
proxetil,
Ceftazidim,
Ceftriaxon
• Cefepim
 Penicillins
• Derived from Penicillium chrysogenum.

• PCN G and PCN V are unaltered products of Penicillium

fermentation

• Semi-synthetic penicillins are formed by addition of R groups

to the main 6-aminopenicillanic acid ring.

• Should be given 1-2 a.c/p.c

 Adverse Reactions
• 5% of patients will develop a
hypersensitivity reaction (penicilloic acid).

• Rashes - most common reaction. 50% do

not have a recurrent rash.

• Ampicillin - rash in 50-100% of patients

with mononucleosis.

• Anaphylaxis – 1/10000 patients

– Urticaria, angioedema, rhinitis, asthma, and
anaphylaxis.
– 10% mortality rate.
– Anaphylaxis possible after negative skin
testing.
– Avoid all other B-lactams.
Natural Penicillins
• PCN G (IV/IM)
• PCN V (Oral)
• Active against Strep.,
peptostreptococcus, B
anthracis, Actinomycosis,
Corynebacterium, Listeria,
Neisseria & Treponema.
• Used for common oral
infections.
 Aminopenicillins
• Ampicillin (Oral, IV)
• Ampicillin/sulbactam (Unasyn; IV)
• Amoxicillin (Oral).
• Amoxicillin/clavulanate (Augmentin)
• Sulbactam and clavulanic acid increase activity against B-
lactamase producing organisms.
• Extended antimicrobial spectrum.
– Gram negatives: E. coli, Proteus, Salmonella,
Haemophilus, M. catarrhalis, Klebsiella, Neisseria,
Enterobacter, Bactoroides.
• Used as first line therapy for acute otitis media and
sinusitis.
 Resistance Mechanisms
• B-lactamase – hydrolyze the B-lactam ring.
– H. flu (7-24%)
– M. cat (93-100%)
– Penicillinase – Staph
• Alteration of penicillin-binding protein (PBP)
affinity. (Strep. Pneumo., MRSA)
 Cephalosporins
• Semisynthetic B-lactams
derived from chemical side
chains added to 7-
aminocephalosporanic
acid.

• Generally more resistant to

B-lactamases.
 Cephalosporins
• Adverse reactions.
– 5-10% cross-sensitivity with
pcn allergic pts.

– 1-2% hypersensitivity
reactions in non-pcn allergic
pts.

– Broader spectrum leads to

opportunistic infections
(candidiasis, C. difficile
colitis).
 Cephalosporins
First Generation Second Generation
• Cefazolin (Ancef; IV), • Cefuroxime (Ceftin; IV; Oral)
Cephalexin (Keflex; Oral) • Increased activity against H. flu,
enterobacter, Neisseria, proteus, E.
coli, klebsiella, M. catarrhalis,
• Spectrum: Most gram anaerobes and B. fragilis.
positive cocci (Strep, S.
aureus), E. coli, Proteus,
• Not as effective against S. aureus
Klebsiella. as the 1st generation.

• Use: S. aureus infection, • Cefpodoxime and Cefuroxime

surgical prophylaxis. active against intermediate level
resistant strep pneumo
 Cephalosporins
Third Generation Fourth Generation
• Spectrum: gram negative > • Cefepime (IV)
gram positive. • Active against Strep, Staph
• Ceftriaxone (IM/IV;), (mssa), aerobic gram
Cefotaxime
negatives (enterobacter, e.
– Useful for meningitis.
coli, klebsiella, proteus and
– Ceftriaxone used for highly pseudomonas)
resistant and multi drug
resistant strep pneumo
along with vancomycin.
• Ceftazidime active against
pseudomonas.
 Carbapenems
• Broadest spectrum B-lactam.
– Staph (not MRSA), Strep (highly resistant), Neisseria, Haemophilus,
Proteus, Pseudomonas, Klebsiella, Bacteroides, anaerobes (excluding
C. dif)
– Double coverage of Pseudomonas is recommended when using
imipenem.
• Toxicities:
– PCN allergy cross reactivity.
– Seizures noted in Imipenem studies.
Important Points for Betalactamase

• Beta lactams need frequent dosing for successful

therapeutic outcome
– Missing doses will lead to treatment failure
• Beta lactams are the safest antibiotics in renal
and hepatic failure
– Adjustments to dose may still be required in severe
failure
Other Inhibitors of Cell Wall Synthesis

Polypeptide antibiotics
– Bacitracin
• Topical application
• Against gram-positives
– Vancomycin
• Glycopeptide
• Important "last line" against antibiotic resistant S.
aureus
Bacitracin
• Inhibits regeneration of phospholipids receptors
involved in peptidoglycan synthesis.
• Originally isolated from debris in a pt’s wound.
• Active against gram positives and negatives.
• Topical use only (nephrotoxicity).
• Adverse effects.
– Contact dermatitis – top 10 allergen.
– Reports of anaphylaxis.
• Dermatology study showed no increase in wound
infection when clean surgical wounds were
dressed with white petrolatum vs. bacitracin.
• Combinations
– Neosporin – neomycin, polymyxin B, bacitracin
– Polysporin – polymyxin B, bacitracin
 Vancomycin
• Inhibits synthesis of cell wall phospholipids and prevents cross-
linking of peptidoglycans at an earlier step than B-lactams.
• Used in treatment of MRSA and highly resistant Strep. Species
• Resistance: changes in permeability and decreased binding
affinity.
• Adverse effects.
– Fever, chills, phlebitis and red man syndrome.
• Slow injection and prophylactic antihistamines.
– Ototoxic – may potentiate known ototoxic agents.
• Renal excretion (90-100% glomerular filtration).
– Normal half-life 6-10 hours.
– Half life is over 200 hours in pts with ESRD
 Polymyxin
• Bacillus polymyxa
• Decapeptide that disrupts the phospholipid layer
in cell membranes.
• Limited spectrum.
– Decreased gram positive coverage.
– Active against Pseudomonas, Proteus, Serratia, E. coli,
Klebsiella and Enterobacter.
• Cross reaction with bacitracin.
 Protein Synthesis Inhibitors

Target the bacterial ribosome.

• Bacterial – 70S (50S/30S)
• Mammalian – 80S (60S/40S)

50S binders
• Macrolides, Clindamycin, Chloramphenicol

30S binders
• Aminoglycosides, Tetracyclines
 Macrolides
Irreversibly bind the 50S subunit.
• Binding site is in close proximity to the binding sites of
lincomycin, clindamycin and chloramphenicol.
Erythromycin (Oral)
• Gram positives: Staph.(MRSA is resistant), Strep., Bordetella,
Treponema, Corynebacteria.
• Atypicals: Mycoplasma, Ureaplasma, Chlamydia

Clarithromycin (Oral)
• Similar to erythromycin.
• Increased activity against gram negatives (H. flu, Moraxella)
and atypicals

Azithromycin (IM, Oral)

• Decreased activity against gram positive cocci.
• Increased activity against H. flu and M. cat.
 Macrolides
Adverse effects.
• 10-15% of pts do not finish the prescribed course of erythromycin
because of GI distress.
• Jaundice
• Ototoxic (high doses)

Drug interactions
• Oxidized by cytochrome p-450.
• Inhibits other substrates and increases their serum concentrations.
• Theophylline, warfarin, astemizole, carbemazepine, cyclosporine,
digoxin, terfenadine.

Resistance
• Efflux mechanism (msrA)
 Clindamycin
Clindamycin (oral;IV).
• Irreversibly binds the 50S subunit

Antibiotic spectrum
• Strep species, Staph (some MRSA), B. fragilis, anaerobes

Use
• Used for deep neck space infections, chronic tonsillo-pharyngitis,
odontogenic abscesses, and surgical prophylaxis in contaminated wounds.
• Concomitant use of macrolides or Chloramphenicol adds no benefit

Adverse effects
• Pseudomembranous colitis
• GIT discomfort, rash
 Aminoglycosides
Kanamycin, Gentamicin, Streptomycin, Amikacin.

Binds the 30S subunit.

Synergism with cell wall inhibitors is seen because they
increase the permeability of the cell.
Antibacterial spectrum:
• Gram negatives: Pseudomonas, Proteus, Serratia, E. coli, Klebsiella
• Neomycin
• S. aureus and Proteus, Pseudomonas and Strep are resistant
Resistance
• decreased uptake, decreased binding affinity, enzymes (plasmids)
 Aminoglycosides
• Adverse effects:
– Ototoxic – associated with high peak levels and
prolonged therapy. Pts on loop diuretics,
vancomycin and cisplatin are at higher risk.
• Cochlear and vestibular.
• Concentrates in endolymph and perilymph.
– Nephrotoxic.
• Proximal tubule damage.
Important Points of Aminoglucosaids
Aminoglycosides should be given as a large single dose
for a successful therapeutic outcome
• Multiple small doses will lead to treatment failure and
likely to lead to renal toxicity

Aminoglycosides are toxic drugs and require monitoring

• Avoid use in renal failure but safe in liver failure

• Avoid concomitant use with other renal toxic drugs
• Check renal clearance, frequency according to renal
function
 Tetracyclines
Mechanism of Action
• Bind reversibly to bacterial 30S ribosomal subunits  bacteriostatic

Spectrum of Activity
• Mycoplasmas, Chlamydiae, Rickettsiae, Protozoa

Adverse Effects
• Oesophageal ulceration
• Photosensitivity reaction
• Incorporate into foetal and children bone and teeth

Avoid in pregnancy and children

Very good tissue penetration

 Folate Antagonists
• Bacteria must synthesize folate in order to form
cofactors for purine, pyrimidine and amino acid
synthesis.
• p-aminobenzoic acid (PABA) agonists.
– Substrates for dihydropteroate synthetase.
– Sulfonamides
• Sulfamethoxazole (SMP)
• Sulfasoxazole
• Dihydrofolate Reductase Inhibitors.
– Inhibits activation of folate to its active form,
tetrahydrofolate.
– Trimethoprim (TMP)
 Folate Antagonists
• Antibacterial spectrum.
– H. flu, Strep. pneumo, Neisseria species, S. aureus, and
Pneumocystis carinii
• Co-trimoxazole (trimethoprim + sulfamethoxazole)
– MRSA, UTI’s, Pneumocystis pneumonia prophylaxis.
– 97% of UTMB outpt Staph. aureus isolates are susceptible
to Bactrim.
 Folate Antagonists
• Dermatologic: Rashes are
common, ranging from
photodermatitis to Stevens-
Johnsons syndrome.
• Hematologic: Hemolytic anemia
(G6PDH deficient pts.),
neutropenia and
thrombocytopenia (up to 80% of
HIV pts)
• Drug interactions: Warfarin,
phenytoin, methotrexate.
 Miscellaneous

• Fluoroquinolones
• Rifampin
• Metronidazole
 Fluoroquinolones
• Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin
• Synthetic derivatives of nalidixic acid.
• Inhibits DNA gyrase, causing permanent DNA cleavage.
• Resistance:
– DNA Gyrase mutations
– Cellular membrane efflux mechanisms.
– Decreased number of porins in target cells.
• Wide distribution - CSF, saliva, bone, cartilage
 Antibiotic Spectrum
Effective vs. gram +, gram -, atypicals, and Pseudomonas.

Decreased activity against anaerobes.

Respiratory quinolones (levofloxacin).

• Active against Strep (including penicillin-resistant forms), S. aureus (including MRSA), H. flu, M. cat
(including penicillin-resistant strains), and atypicals.
• Used in AOM, sinustiis, pharyngitis

Antipseudomonas quinolones (ciprofloxacin/ofloxacin)

• Active against Pseudomonas, H. flu, M. cat.
• Strep pyogenes, Strep pneumoniae, and MRSA are resistant.
• Used in children with Cystic Fibrosis.
• Topicals used for otitis media.
Levofloxacin and Moxifloxacin have increased Staph activity even against cipro-
resistant strains.
 Fluoroquinolones

Adverse effects.
• Headache, dizziness, nausea, lightheadedness
• Limit use in pregnancy, nursing mothers, and children <
18.
• Drug interactions: may increase levels of theophylline,
warfarin, caffeine and cyclosporine.
• Absorption decreased when taken with cations.
• Arthralgias - 1%.
• Prolonged QT interval
 Fluoroquinolones in children.
• Only one approved indication in children  cystic
fibrosis
• Animal studies show joint/cartilage damage in wt
bearing joints of young animals.
– Dose and animal dependent.
• All fluoroquinolones have demonstrated this toxicity
– Short term use – no acute arthritis or serious adverse effects
(>1700 pts in general database review).
– No radiographic evidence of joint changes in any study
 Rifampin
• Interacts with the bacterial DNA-dependent RNA polymerase,
inhibiting RNA synthesis.
• Antibacterial spectrum
– Mycobacteria, gram positives, gram negatives.
– Used to treat carriers of meningococci or H. flu.
• Resistance.
– Develops rapidly during therapy. Should use in combination with other
drugs to decrease resistance rates.
– Decreased affinity of the polymerase.
• Metabolized in liver and may induce the cytochrome p-450
system.
 Metronidazole
• Metronidazol (oral;IV;ovula)
• Forms cytotoxic compounds by accepting electrons on its
nitro group.
• Distribution: nearly all tissues, including CSF, saliva, bone,
abscesses.
• Antibacterial spectrum: anaerobes, amoebicide and
parasites.
• Used for C. difficile and other anaerobic infections
(abscesses).
What is antimicrobial resistance?

Antimicrobial resistance (AMR) occurs when bacteria, parasites,

viruses or fungi change to protect themselves from the effects
of antimicrobial drugs designed to destroy them.
Why are antibiotics and antimicrobial resistance important?

Antibiotics decreased mortality from infections caused by resistant

bacteria
• Currently, antibiotics reduce post-operative infection rates to below 2.0%
• Without effective antibiotics, this could increase to around 40% to 50%. Up to 30%
of these patients could die from resistant bacterial infections

Modern medicine, especially surgery and cancer treatments,

depends on effective antibiotics to minimise the risk of infection

Antimicrobial resistance could cause significant loss of life

Antimicrobial resistance results in substantial financial cost for

patients and healthcare systems.
How has antimicrobial resistance developed?

• Antimicrobial resistance is a natural phenomenon

• Overuse, misuse and inappropriate use of antibiotics
• The delivery of more complex health care requiring longer
use of antibiotics
• Prolonged hospitalisation
• The implications of surgical procedures undertaken overseas
• Resistant pathogens can now spread easily
− during hospitalisation if infection prevention is poor
− potential for cross-border transmission through increased travel.
Source: Centers for Disease Control and
 Decline in antibiotic production
• Very few antibiotics
have been
developed in the
last 20 years
• Most ‘new’
antibiotics are
variations of existing
antibiotics
• Only 5 novel classes
have been
developed in the
last 20 years, e.g. 1
for TB. Source: Butler M, Blaskovich M, Cooper M. Antibiotics in the clinical pipeline in 2013.
Antimicrobial Resistance Requires a Global Response

Improve awareness and understanding of antimicrobial

resistance

Strengthen the knowledge and evidence base

Reduce the incidence of infection

Optimise the use of antimicrobial medicines

Develop the economic case for sustainable investment.

Thank You