Antibiotics in Respiratory tract

infections

KumaraswamyKademane@imu.edu.my
Twitter: @kumaraswamy16
Learning objectives

 Describe the common group of antibiotics

used in respiratory infection in terms of
 Indications
 Mechanism of action
 Major side effects
 Contraindications
Targets of antibacterial agents
Microorganisms causing RTI
 Ear infections: Otitis media
 Strep. pneumoniae, H. influenzae, and Strep. pyogenes
Upper respiratory tract infections:
 Bacterial pneumonia
 CAP (community acquired pneumonia): Strep.
Pneumoniae, H. influenzae, staph. aureus)
HAP (Hospital acquired pneumonia)
 Atypical pneumonia
mycoplasma, chlamydia, legionella,
 Viral (influenza, varicella etc.)
Antibacterials commonly used in RTI

 Beta-lactam antibiotics:
 Penicillins
 Cephalosporins
 Carbapenems
 Macrolides & Ketolides
 Tetracyclines
 Others
Beta-lactam antibiotics
Beta-lactams inhibit the cell wall synthesis
 Bacterial cell wall
 Rigid peptidoglycan layer, maintains cell shape and
integrity
 Peptidoglycan (polysaccharide and polypeptide)
 Cross linking of polypeptides (transpeptidase/PBP)
gives the rigidity
 Penicillins bind to and inhibit PBPs leading to halt in
peptidoglycan formation and cell death
Diagram of MOA of beta-lactams
Classification of Penicillins
 Natural penicillin: penicillin G
 Acid resistant alternative to PnG:
 Phenoxymethyl Penicillin (Penicillin V)
 Penicillinase resistant Penicillins: antistaphylococcal
penicillins
 Acid labile: Methicillin Recall [MRSA]
Methicillin Resistant
Staphylococcus Aureus
Classification of Penicillins
 Natural penicillin: penicillin G
 Acid resistant alternative to PnG:
 Phenoxymethyl Penicillin (Penicillin V)
 Penicillinase resistant Penicillins: antistaphylococcal
penicillins
 Acid labile: Methicillin, Nafcillin, Cloxacillin, Dicloxacillin
 Acid resistant: Flucloxacillin
 Beta-lactamase inhibitors:
 Clavulanate, sulbactam, tazobactam
Extended spectrum penicillin
 Aminopenicillins: G+ve and G-ve
 Ampicillin, Amoxicillin, Bacampicillin
 Carboxypenicillins: Pseudomonas, Enterobacter, and Proteus
 Carbenicillin, Ticarcillin
 Ureidopenicillins: Pseudomonas, lysteria
 Piperacillin, Mezlocillin, Azlocillin
 Amidino penicillins:
 Mecillinam, Pivmecillinam
Clinical uses of penicillin

 Pneumococcal pneumonia/meningitis
 Pharyngitis/recurrent rheumatic fever
 Syphilis (treponema pallidum)
 Gas gangrene (Cl. perfringens)
 Staphylococcal infections (penicillinase resistant
penicillins)
Clinical uses of penicillin contd..

 Extended spectrum penicillins

 RTI : otitis media, sinusitis, bronchitis, CAP
 Bite wound infections
 Antipseudomonal penicillins
 LRTI, intra-abdominal, skin, soft tissue, genito-urinary
infections
Betalactamase inhibitors

 Clavulanic acid: combined with amoxycillin (Moxclav)

 Sulbactam: combined with ampicillin
 Tazobactam: combined with piperacillin (Piptaz)
ADRs of penicillins
Generally well tolerated, except hypersensitivity
reactions
 Anaphylactic shock (0.05%),
 Serum sickness (urticaria, fever, joint swelling)
 Skin rash (ampicillin)
 Interstitial nephritis
 Diarrhoea & superinfections (ampicillin, amoxicillin)
Cephalosporins

 Mechanism of action similar to penicillins

 Inhibits transpeptidase and thereby cell wall synthesis
1st generation Cephalosporins

Parenteral agents Oral agents

Cephalothin • Cephalexin
• Cephradine
Cefazolin
• Cefadroxil

G+ve bacteria and Proteus, E coli, Klebsiella (PEcK)

2nd generation Cephalosporins

Parenteral agents Oral agents

 Cefaclor
Cefuroxime
 Cefuroxime axetil
Cefoxitin (B. Fragilis)

Includes H. influenzae, Enterobacter aerogenes, and

some Neisseria species (HENPEcK)
3rd generation Cephalosporins

Parenteral agents Oral agents

Cefotaxime • Cefixime
Ceftizoxime • Cefpodoxime
Ceftriaxone • Cefdinir
Ceftazidime • Ceftibuten
Cefoperazone

Enhanced activity against enterobacter spp, serratia

4th generation Cephalosporins

Parenteral agents

Cefepime
cefpirome

5th generation: ceftaroline (IV)

1st generation clinical uses

 Predominantly against G+ve & also Proteus, E-coli,

Klebsiella (UTI)
 Cefalexin, cefadroxil – CAP, UTI
 Cefazolin – agent of choice in surgical procedures
2nd generation clinical uses

 More G-ve coverage than first generation

 Especially beta lactamase producing H. influenzae
 Less active against G+ve
 Cefoxitin and cefotetan are active against B.fragilis
(colorectal surgery prophylaxis)
 In mixed anaerobic infections: peritonitis, diverticulitis
3rd generation uses
 Cefdinir and cefpodoxime proxetil are the best oral
agents against pneumococci and S. aureus.
 Cefotaxime and ceftriaxone are excellent for CAP
 Pneumococci, H. influenzae, S. aureus
 Meningitis (pneumococci, meningococci, H influenzae)
 Good penetration into CSF
 Ceftriaxone is the therapy of choice for all forms of
gonorrhea and for severe forms of Lyme disease
4th generation uses

 More resistant to betalactamases

 Mainly for serious G-ve infections: enterobacter,
citrobacter, serratia
 Infections of CNS
Adverse effects of cephalosporins

Adverse reactions
 Hypersensitivity reactions: anaphylaxis, fever, skin
rashes, nephritis, and hemolytic anemia
 Ceftriaxone: biliary sludging syndrome & cholelithiasis
 Contraindications:
Allergy (~1 to 20% cross-reactivity with penicillin)
Carbapenems
Imipenem
 Broad spectrum
 Gram +ve, G-ve aerobes, anaerobes
 Given by parenteral route
 Rapidly hydrolysed by renal dehydropeptidase – I
 Cilastatin – reversible inhibitor of enzyme
 Uses: severe hospital acquired infections, LRTI
 ADRs: propensity to induce seizures at higher doses
Newer agents: Meropenem, Ertapenem
Monobactam: aztreonam
Macrolides
 Macrocyclic lactone ring
 MOA: Binds to 50s ribosomal
subunit and Inhibits bacterial
protein synthesis
 Inhibits translocation of
peptidyl-tRNA
 Same binding site as
Chloramphenicol & Clindamycin
MOA of protein synthesis inhibitors
Indications: Azithromycin, clarithromycin
 Respiratory tract infections due to Streptococcus
pneumoniae, Haemophilus influenzae, and atypical
pathogens (Mycoplasma, Chlamydia, Legionella)
 Acute exacerbations of chronic bronchitis, acute otitis
media, acute streptococcal pharyngitis, and acute
bacterial sinusitis
 Chlamydial infections, diphtheria, pertussis,
Helicobacter Pylori infection, erysipelas and cellulitis
of skin
Adverse effects of macrolides

 Cholestatic jaundice
 GI disturbances: nausea, vomiting, diarrhoea
 QT prolongation and vent. Arrhythmia
 Enzyme inhibition
 Enhance the effect of warfarin, theophylline, digoxin,
CCBs
Tetracyclines
 Tetracycline, doxycycline, minocycline, tigecycline
 Binds to 30S subunit
and inhibit tRNA
binding to acceptor site
Clinical indications of tetracyclines

 Doxycycline: 100mg BD for 7days

 CAP due to S.pneumoniae, H influenza
 Mycoplasma, chlamydia
 Cholera, rickettsia, anthrax, C. trachomatis urethritis
 Adverse effects
 GI: epigastric burning, nausea, vomiting, diarrhoea
 Hepatotoxicity, Renal toxicity
 Fanconi syndrome with outdated tetracyclines
 Contraindicated in children, discoloration of teeth
 Vancomycin

Mechanism of Action
Vancomycin inhibit the synthesis of the cell wall in
sensitive bacteria by binding with high affinity to the
D-alanyl-D-alanine terminus of cell wall precursor units.
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Vancomycin indications

 I.V. 500 mg q 6h or 1g q 12h, rate @10mg/min

 Pneumonia when MRSA is suspected, (HAP or CAP with
risk factors for staphylococcal infection, e.g., influenza)
 Endocarditis
 Skin/soft tissue and bone/joint infections
 CNS infection
 Orally for Pseudomembranous colitis due to C. Difficile
[500 mg q.i.d. max]/d for 7-10 d]
Vancomycin adverse effects

 Allergy: anaphylaxis, macular skin rash, urticaria,

 Skin flushing: “red-neck” “red man” syndrome
 Ototoxicity: hearing impairment
 Nephrotoxicity: more with high dose
 Extra caution if used with aminoglycosides
 Quinolones

MOA: Inhibit formation of negative DNA supercoils by DNA gyrase.

 Gyrase enzyme binds to DNA (1), creating positive (+) superhelix.
 Then introduces a double-strand break in the DNA and passes the
front segment through the break (2).
 The break is then resealed (3), creating a negative (–) supercoil.
 Quinolones inhibit the nicking and closing activity of the gyrase and,
the decatenating activity of topoisomerase IV.
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Indications of quinolones

 Respiratory tract infections:

CAP (moxifloxacin > older quinolones)
Legionella pneumophila: levofloxacin (or azithromycin)
is the antibiotic of choice
 Urinary tract infections: norfloxacin
 Typhoid, dysentery (shigellosis),
 Bone and joint infections
Adverse effects of quinolones

 GI: mild nausea, vomiting, and/or abdominal

discomfort
 Pseudomembranous colitis (ciprofloxacin)
 Achilles tendon rupture or tendinitis
 Rashes, photosensitivity reactions
 CI in Children
 May damage growing cartilage and cause arthropathy
Anti viral drugs
Varicella (chicken pox) pneumonia
 Acyclovir 10–20 mg/kg every 8 h intravenously for 7–
10 days is the treatment of choice
 Acyclovir inhibits viral DNA synthesis.
 Major side effects include reversible hematological
toxicity, renal failure, and seizures or coma.
 Foscarnet 40 mg/kg every 8 h should be used in
patients who do not respond to acyclovir
Influenza
For influenza A
 Amantadine 100 mg b.d. orally
Side effects: confusion, tremor, seizures
For influenza A and B
 Zanamvir 10 mg (two inhalations) b.d. 5 days
SE: bronchospasm
 Oseltamivir 75 mg b.d. orally for 5 days
 SE: nausea, vomiting
Acute otitis media
Treatment (antibiotics + nasal decongestant)
 Amoxicillin (20–40 mg/kg/d) or Erythromycin (50
mg/kg/d) for 10 days
 Cefaclor (20–40 mg/kg/d) or amoxicillin-clavulanate
(20–40 mg/kg/d) combinations, for resistant cases
 Tympanocentesis for bacterial and fungal culture
 Myringotomy: for severe otalgia or when
complications (mastoiditis, meningitis) have occurred
Summary
 H.Influenzae epiglotitis: cefotaxime or chloramphenicol
 Exacerbation of chronic bronchitis:
amoxicillin or tetracycline or erythromycin
 Uncomplicated CAP
amoxicillin (or benzyl penicillin inj.) or
erythromycin/azithromycin if penicillin allergic
ADD:
# flucloxacillin if staph. infection suspected
# vancomycin if MRSA suspected
# azithromycin if atypical suspected
Summary contd..
 Severe CAP of unknown aetiology
cefuroxime or cefotaxime + erythromycin/azithromycin
ADD:
# flucloxacillin if staph infection suspected
# vancomycin if MRSA suspected
 Pneumonia possibly caused by atypical pathogen
Erythromycin/azithromycin
ADD ampicillin for severe Legionella infection
Tetracycline for chlamydial or mycoplasma
Summary contd..

 HAP
Cefotaxime or ceftazidime, or anti-pseudomonal
penicillin or quinolone

ADD aminoglycoside for severe illness

Thank You