Use of antibiotics in oncology

1. Maj Sankalp Singh

2. NETILIMICIN
 Netilmicin is an aminoglycoside antibiotic
 It belongs to the Gentamicin family, which are compounds
derived from the actinomycete Micromonospora. The
difference in spelling (-micin) compared with the other
aminoglycoside antibiotics (-mycin) reflects this
difference in origin.
 Very similar in properties to Gentamicin
 It is a semisynthetic derivative of sisomicin.

3. Structure
 It contains two molecules of amino sugars (garosamine)
linked to a central hexose ring (2-deoxystreptamine) ring
by glycosidic bonds.

4. Mechanism of action
 Netilmicin is a rapidly bactericidal antibiotic
 It inhibits bacterial protein synthesis irreversibly by 3
mechanisms :-
 a)It binds to 30S and to some extent to 50S ribosomal
subunit of susceptible bacteria disrupting initiation complex
of protein synthesis
 b)It also causes misreading of the mRNA template and
incorporation of incorrect amino acids into the growing
polypeptide chains leading to formation of nonfunctional or
toxic proteins
 c) It causes break-up of mRNA bound polysomes to non-
functional monosomes.

5. Mechanism of action

6. Resistance
 Mechanism of resistance to netilmicin is by :
 a) Production of transferase enzymes which inactivate
drug by adenylation /acetylation/phophorylation.
 b) impaired entry of drug in cell due to
mutation/deletion of porin proteins
 c) receptor proteins on ribosomal 30s subunit may
undergo deletion/alteration due to mutation.

7. Pharmacokinetics
 Water soluble, more active at alkaline pH.
 highly polar cations and therefore very poorly absorbed
from the GI tract.
 absorbed rapidly & completely from intramuscular sites of
injection. Peak concentrations in plasma occur after 30 to
90 minutes of IM injection or IV diffusion.
 because of polar nature, does not penetrate into most cells
& tissues ( except renal cortex), the CNS & the eye.
 concentration is low in most body secretions.

8. Pharmacokinetics
 Excreted almost entirely in urine by glomerular filtration.
80% of a parenterally administered dose is excreted
unchanged within the first 24 hours. Half life in plasma
varies between 2 -2.5 hours in patients with normal renal
function.
 Dose adjustment must be made in a patient with renal
insufficiency.

9. Spectrum of action
 Active against Enterobacteriaceae and other aerobic gram-
negative bacilli (Pseudomonas, Proteus,Klebsiella,Serratia)
 little or no activity against anaerobic microorganisms
 though active against gram–positive bacteria, should not be
used as single agent to treat such infections as action against
them is limited
 active against some gentamicin-resistant strains as it is not
metabolised by aminoglycoside-inactivating enzymes
 useful for the treatment of serious infections owing to
susceptible gram-negative infections esp complicated UTIs,
sepsis & pneumonia.
 In combination with a cell wall-active agent, such as a
penicillin or vancomycin, an aminoglycoside produces a
synergistic bactericidal effect in vitro against enterococci,
streptococci, and staphylococci.

10. Dosage
 Adult: 4-6 mg/kg once daily or in 2-3 equally divided doses.
UTI: 150 mg as a single daily dose for 5 days.
Complicated UTI: 3-4 mg/kg daily in divided doses every 12
hr.
Child: Infants and neonates >1 wk: 7.5-9 mg/kg daily in 3
divided doses. Older children: 6-7.5 mg/kg daily in 3
divided doses.
All doses may be given as IM, slow IV (over 3-5 min) or as
a 50-200 ml infusion over 0.5-2 hr.
Treatment is usually given for 7-14 days.
Renal impairment: Dose reduction or lengthening of
interval between doses may be necessary.

11. Adverse effects
 Nephrotoxicity (5-25%) - Netilmicin may cause renal
dysfunction due to accumulation of the drug in the proximal
tubular cells. The most common significant finding is a mild rise
in plasma creatinine (5 to 20 mg/ml). Renal dysfunction is almost
always reversible as the proximal tubular cells have the capacity
to regenerate.
 Ototoxicity (1-5%) - Netilmicin may cause significant ototoxicity
though less than other aminoglycosides. Caused byProgressive
destruction of type I sensory hair cells of inner ear & maybe
irreversible. Vestibular toxicity (more common) may cause
headache, nausea, vomiting, vertigo & ataxia. A high-pitched
tinnitus often is the first symptom of cochlear toxicity.
 At high doses a ‘curare-like’ Neuromuscular blockade may occur
 Hypersensitivity reactions are infrequent.

12. TIMENTIN
(Ticarcillin + Clavulanic acid)
 Ticarcillin is an extended spectrum penicillin
(Carboxypenicillin) with increased activity against
Pseudomonas sp.
 It is similar to Carbenicillin but is better tolerated & has a
wider spectrum of action.
 It is a β-lactam based antibiotic & is susceptible to
hydrolysis by bacterial β-lactamase.
 Addition of β -Lactamase inhibitors such as clavulanic
acid extends the spectrum of ticarcillin against β-
lactamase producing organisms.

13. Structure
 All penicillins, consist of thiazolidine ring (a) connected
to a β-lactam ring (b)to which is attached a side chain
RNH(c).
 metabolic transformation or chemical alteration of β-
lactam ring causes loss of all significant antibacterial
activity.
 side chain determines many of the antibacterial and
pharmacological characteristics of a particular type of
penicillin.
Structure of Ticarcillin
sidechain

14. Mechanism of action
 bactericidal through inhibition of the final cross-linking
stage of peptidoglycan production by binding and
inactivating transpeptidases thus inhibiting bacterial cell
wall synthesis & causing cell death.

15. Resistance
 Mechanism of resistance to Ticarcillin is by
 a) β -Lactamase production – most common
 b) alteration in PBPs – seen in MRSAs
 c) impaired penetration of drug due to alteration in
porins/ efflux pump – seen in gram-negative organisms.

16. Pharmacokinetics
 Polar molecules. Not absorbed from GI tract. Well
absorbed by IM route. Peak plasma concentrations: 0.5-1
hr (IM).
 Widely distributed in body tissues & fluids. Protein-
binding: 50%. Plasma half-life: 70 min.
 Limited metabolism. 90% excreted unchanged in urine.
10% of renal excretion by glomerular filtration & 90% by
tubular secretion.

17. Spectrum of action
 Active against Gram +ve organisms & Gram –ve cocci.
 antimicrobial activity is extended to include gram-
negative rods like Pseudomonas & Proteus.
 activity against E.coli, salmonella & Enterobacter spp is
less
 susceptible to hydrolysis by β-lactamases.
 often administered with a β-lactamase inhibitor such as
clavulanate or sulbactam to prevent hydrolysis by broad-
spectrum β-lactamases .
 Indicated in severe Gram negative infections, hospital
aquired infections, peritonitis, septicemia, skin & soft
tissue infections, bone & joint infections, UTIs &
pneumonias.

18. Dosage
Serious gram negative infections -
 Adult: 200-300 mg/kg by infusion in divided doses every 4 or 6 hr
 Child: 200-300 mg/kg by infusion in divided doses every 4 or 6 hr.
 Renal impairment: Peritoneal dialysis patients: 3 g every 12 hr;
haemodialysis patients: 2 g every 12 hr plus an additional dose of 3
g after each dialysis session.
 Uncomplicated UTIs
Adult: 1 g IM/slow IV Inj every 6 hr.
Child: 50-100 mg/kg in divided doses every 6-8 hr.
 Complicated UTIs
Adult: 150-200 mg/kg daily by IV infusion in divided doses every
4 or 6 hr.
Child: 150-200 mg/kg daily by IV infusion in divided doses every
4 or 6 hr.

19. Adverse effects
 Hypersensitivity reactions which vary from anaphylaxis
(0.05% ) to skin rahes, urticaria, joint swelling, fever &
angioneurotic edema.
 pain at the inj site and phlebitis, dose-dependent
coagulation defect, hemorrhage & purpura, hemolytic
anemia & neutropenia.
 interstitial nephritis which is a autoimmune reaction
 pseudomembranous colitis
 haemorrhagic cystitis especially in cystic fibrosis patients.