Aminoglycosides &

Spectinomycin
 Outline of presentation
• Aminoglycosides
Streptomycin, Neomycin, Kanamycin,
Amikacin, Gentamicin, Paromomycin,
Tobramycin, Netilmicin
• Fluroquinolones
Ciprofloxacin, Moxifloxacin, Sparfloxacin,
Gatifloxacin, Enofloxacin, Ofloxacin,
Norfloxacin, Lomefloxacin, Levofloxacin
• Antimycobacterial Drugs
 Aminoglycosides
Streptomycin (the oldest drug)
Neomycin
Kanamycin
Amikacin
Gentamicin
Paromomycin
Tobramycin
Netilmicin

09/15/20 Chemotherapy 3
 Aminoglycosides
• Aminoglycosides are hydrophilic, polycationic,
amine containing carbohydrates that are
usually composed of three to five rings.
– The polycationic nature of aminoglycoside results
in a binding both
• to the anionic outer bacterial membrane and
• to anionic phospholipids in the cell membranes of
mammalian renal proximal tubular cells.
 Mechanism of action
The aminoglycosides are rapidly bactericidal.
• First, the positively charged aminoglycoside
binds to negatively charged sites on the outer
bacterial membrane, thereby disrupting
membrane integrity.
• Second, they irreversibility bind with 30s
ribosomal subunit and inhibit protein synthesis.
 Mechanism of action cont...
• Aminoglycosides inhibit protein synthesis at
least in three ways.
1. Interfere with the "initiation complex" of peptide
formation.
2. Induce misreading of mRNA, which causes
incorporation of incorrect amino acids into the
peptide, resulting in a nonfunctional or toxic
protein;
3. Cause a breakup of polysomes into nonfunctional
monosomes.
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 Pharmacokinetics
• They are very poorly absorbed from GIT (20%).
So, it must be given parentally to achieve adequate
serum concentration.
• After intramuscular injection, aminoglycosides
are well absorbed.
• They do not readily enter cells and also eyes
and CNS because of its highly polar nature.
• But all drugs of this group can cross the
placental barrier.
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 Pharmacokinetics cont...
• The concentration of these drugs is
predominant in renal cortex, endolymph-
perilymph of internal ear.
• Not metabolized
• Mainly excreted by glomerular filtration in the
kidney.
– Its excretion is directly proportionate to creatinine
clearance.

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 Antimicrobial spectrum
• Aminoglycosides are active against
– Aerobic gram negative bacilli
• such as Escherichia coli and Klebsiella pneumoniae, and
Proteus, Serratia, Acinetobacter,Citrobacter, and
Enterobacter spp
– Staphylococci
– Mycobacteria
– Protozoa
• But, have weak activity against anaerobes.

09/15/20 Chemotherapy 9
 Cont...
• Although they are not active against
enterococci or Listeria monoctogens, the
addition of aminoglycosides to penicillin G,
ampicillin, or vancomycin is often synergetic
and usually results in bactericidal effects.

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 Clinical uses of Gentamicin, Amikacin
• Used against wide range of serious infection
– such as septicemia, UTI, Pneumonia, menngitis,
enocarditis, bone and soft tissue infection caused by
pseudomonas aurugnosa, E.Coli, serratia, klebsiella,
enterobacteriaceae, proteus.
• In combination with penicillin in enterococcal
endocarditis.
• In methicillin resistant staphylococcal infection.
• Creams, ointments, or solutions of gentamicin
sulfate are for the treatment of infected burns,
wounds, or skin lesions.
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 Clinical uses of Streptomycin
• For tuberculosis – now days this drug is rarely used
because of
i. Less degree of activity
ii. Greater toxicity
iii. To be given intramuscularly
iv. Availability of other highly effective tuberculocidal drug.
• Plague
• Tularemia
• Brucellosis (in combination with tetracycline)
 Clinical uses of Neomycin
• It is not given parentally because of greater
toxicity and lower efficiency. It is given orally or
topically.
• Oral use
– To reduce the facultative flora of the gut (to reduce the
intestinal load of enterobacteriaceae in hepatic coma).
– Preoperative in colorectal surgery for gut sterilization
(in combination with Erythromycin).
– Ophthalmologic preparations of gentamicin available
for the treatment of eye infections.
• Topical Use:
– In combination with bacitracin & Polymixin-B.
 Clinical uses of Paromomycin
• Neomycin and kanamycin are too toxic for
parenteral use and are now limited to topical
and oral use.
• Paromomycin has been effective in intestinal
amebiasis.
 Adverse effects
Ototoxicity
•As a result of both cochlear and vestibular division
of the 8th cranial nerve.
– Cochlear dysfunction – the hearing capacity is lost
which is noted with high frequency tone.
– Vestibular dysfunction – vertigo, ataxia, loss of balance.
•Neomycin, kanamycin, and amikacin are the most
ototoxic agents.
•Streptomycin and gentamicin are the most
vestibulotoxic.
 Adverse effects
Nephrotoxicity
•Mild renal impairment to severe tubular
necrosis occurs.
•The drug is retained inside the tubular cell and
disrupts Ca++ madiated transport process.
•results in rising serum creatinine levels or
reduced creatinine clearance.
– Treatment is either to stop the drug in serious
case or adjustment of dose in low toxicity.
 Adverse effects
Neurotoxicity
•In very high doses aminoglycosides can
produce a curare like effect with neuromuscular
blockage that results in respiratory paralysis.
 Contraindications
• Ototoxic drugs
• Nephrotoxic drugs
• Muscle relaxants
• Myasthenia gravis
 Spectinomycin
• an aminocyclitol antibiotic that is structurally
related to aminoglycosides.
• Spectinomycin is used almost solely as an
alternative treatment for drug-resistant
gonorrhea or gonorrhea in penicillin-allergic
patients.

09/15/20 Chemotherapy 19
 Cont …
• Rapidly absorbed after intramuscular
injection.
• A single dose of 2 g (40 mg/kg) is given.
• There is pain at the injection site and
occasionally fever and nausea.

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 Nucleic acid Synthesis Inhibitors
• Fluroquinolones
• Rifampin

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 Quinolones
• These are old generation drugs.
• They did not achieve systemic antibacterial
levels so they have limited clinical values.
• Due to its rapid emergence of resistant strains
its use is limited in UTI.
o Nalidixic acid
o Cinoxacin
 Fluroquinolones
• New generation drug (no natural source)
• More activity and better penetration power.
• Bactericidal
• Inhibit DNA synthesis
• Exhibit concentration dependent killing
• Have excellent oral bioavailability
• Slow development of resistance
 Fluroquinolones
Members:
Ciprofloxacin
Moxifloxacin
Sparfloxacin
Gatifloxacin
Enofloxacin
Ofloxacin
Norfloxacin
Lomefloxacin
Levofloxacin
 Mechanism of action
• Fluroquinolones block the DNA synthesis by
inhibiting the enzyme DNA gyrase or
topoisomerase-II.
– DNA-gyrase is responsible for super-coiling of DNA.
• Fluroquinolones by inhibiting the DNA-gyrase
prevent negative super-coiling and relaxation
of DNA.
Ultimately there is no DNA synthesis and
transcription of DNA.
 Pharmacokinetics
• Well absorbed after oral administration.
• Absorption is impaired by divalent cations such
as anticids (Mg, Ca).
• It is widely distributed throughout the body fluid
and tissue.
• It is extensively metabolited
• excreted mainly by tubular secretion and by
glomerular filtration.
• All fluoroquinolones accumulate in renal failure.
 Antimicrobial spectrum
• Ofloxacin and ciprofloxacin inhibit gram-negative
cocci and bacilli, including Enterobacteriaceae,
Pseudomonas, Neisseria, Haemophilus, and
Campylobacter.
• Many staphylococci also are sensitive to these
drugs.
• Intracellular pathogens such as Legionella,
Chlamydia, M tuberculosis and M avium complex,
are inhibited by fluoroquinolones.
• It has no activity against anaerobes
 Clinical use
• Most of the drugs are effective UTI even when caused
by multidrug resistant bacteria (pseudomonas)
• In typhoid and paratyphoid cause by S. typhi and S.
paratypi
• also effective for bacterial diarrhea caused by
salmonella, shigella, toxigenc E.coli, campylobacter
• Soft tissue and bone infection, respratory tract
infection, intraabdominal infection, joint infection.
• Gonococcal infection (Ofloxacin)
• Legionnaires disease
 Clinical use
• Some of the atypical mycobacterial infections
(Ofloxacin, Ciprofloxacin)
• Chlamydial urethritis (Ofloxacin)
• Mycobacterium leprae (Ofloxacin)
 Adverse Effects
• Nausea, vomiting, diarrhea, dizziness,
headache, insomnia.
• Skin rush
• Photosensitivity (Lomefloxacin, Pefloxacin)
• Arthropathy (damage growing cartilage)
• Concomitant administration of theophylline
and quinolones can lead to elevated levels of
theophylline with the risk of toxic effects,
especially seizures.

09/15/20 Chemotherapy 30
 Contraindications
• Drug – theophylline (it increases the
concentration), antacid (it decreases the
absorption).
• Children under 18 years of age
• Lactating mother
• Pregnant mother
Antimycobacterial drugs

32
 Antimycobacterial Drugs
• Mycobacterial infections are the most difficult of
all bacterial infections to cure due to
– Mycobacteria are slowly growing organisms (can also
be dormant).
– The lipid-rich mycobacterial cell wall is impermeable
to many agents.
– A substantial proportion of mycobacterial organisms
are intracellular, residing within macrophages, and
inaccessible to drugs that penetrate poorly.
– notorious for their ability to develop resistance to any
single drug.

33
Cont …
• Therefore, combinations of drugs are required
to overcome these obstacles and to prevent
emergence of resistance during the course of
therapy.
• Anti-mycobacterial chemotherapy is slow
– treatment must be administered for months to
years depending on which drugs are used.

34
Cont …
• Antimycobacterial drugs can be divided into
three groups:
– Drugs used in the treatment of tuberculosis
– Drugs used in the treatment of atypical
mycobacterial infection
– Drugs used in the treatment of leprosy.

35
 Drugs Used in Tuberculosis

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 Drugs Used in Tuberculosis
• Drugs used in the treatment of tuberculosis
can be divided into two major categories:
– "First-line" drugs and

– "Second-line“ drugs

09/15/20 Antimycobacterial Drugs 37

Cont …
First-line drugs
• Superior in efficacy and possess an acceptable
degree of toxicity.
– Isoniazid
– Rifampin
– Pyrazinamide
– Ethambutol / Streptomycin

09/15/20 Antimycobacterial Drugs 38

 Cont …
Second-line drugs
• More toxic and less effective
• Indicated only when the mycobacteria
tuberculosis organisms are resistant to the first-
line agents.
– moxifloxacin or gatifloxacin
– Ethionamide
– aminosalicylic acid
– Cycloserin
– amikacin, kanamycin, capreomycin
– rifamycins (rifapentine, rifabutin)
– linezolid

09/15/20 Antimycobacterial Drugs 39

 Isoniazid (INH)
• Most active drug for the treatment of
tuberculosis caused by susceptible strains.
• Isoniazid is a prodrug which is structurally
similar to pyridoxine.
• bactericidal for actively growing tubercle bacilli.
• Able to penetrate into phagocytic cells.
– active against both extracellular and intracellular
organisms.

40
 Cont …
• Isoniazid inhibit synthesis of mycolic acids
which is an essential components of
mycobacterial cell wall.
• Not effective for dormant mycobacterial. It is
bactericidal in actively growing mycobacteria.
• Narrow spectrum of action limited to
mycobacteria.
• Low resistance

41
 Cont...
• Readily absorbed from the GIT.
• Diffuses readily into all body fluids and tissues.
• Metabolized by acetylation in the liver.
– N-acetyltransferase, genetically determined
– The dose need be adjusted in severe hepatic
insufficiency.
• Metabolites and a small amount of unchanged
drug are excreted mainly in the urine.

42
 Clinical Uses
• Used in the treatment and prevention of
tuberculosis.

43
 Adverse Effects
Hepatitis
• Isoniazid-induced hepatitis is the most frequent major
toxic effect.
• Characterized by loss of appetite, nausea, vomiting,
jaundice and histologic evidence of hepatocellular
necrosis.
• Can be fatal if the drug is not discontinued rapidly.

• Risk of INH-hepatitis is greater in geriatrics, alcoholics and

possibly during pregnancy and the postpartum period.

09/15/20 Antimycobacterial Drugs 44

Cont …
Peripheral Neuropathy
• Is observed in 10–20% of patients given
dosages greater than 5 mg/kg/d but is
infrequently seen with the standard 300 mg
adult dose

• Isoniazid promotes excretion of pyridoxine,

resulting in a relative deficiency  peripheral
neuropathy.
09/15/20 Antimycobacterial Drugs 45
Cont …
• Pyridoxine, 25–50 mg/d is recommended for
those with conditions predisposing to
neuropathy.

• Predisposed: slow acetylators, patients with

malnutrition, alcoholism, diabetes, AIDS.

09/15/20 Antimycobacterial Drugs 46

Cont …
CNS toxicities
• May precipitate convulsions in patients with
seizure disorders
• Muscle twitching, dizziness, ataxia,
paresthesias, stupor, and toxic
encephalopathy
• Pyridoxine prevents in general all nervous
system toxicities

09/15/20 Antimycobacterial Drugs 47

Cont …
Other adverse effects
• Allergic reactions such as fever and skin
rashes
• Hematologic abnormalities, tinnitus,
pyridoxine deficiency anemia and
gastrointestinal discomfort.

09/15/20 Antimycobacterial Drugs 48

 Drug interaction
• Aluminum-containing antacids inhibit INH
absorption.
• INH inhibits metabolism of Phenytoin,
carbamazepine, diazepam and Warfarin.

09/15/20 Antimycobacterial Drugs 49

 Rifampin
• Rifampin binds bacterial DNA-dependent RNA
polymerase and thereby inhibits RNA synthesis.
– Rifampin is bactericidal for mycobacteria.

• It readily penetrates most tissues and penetrates

into phagocytic cells.
– It can kill organisms that are poorly accessible to
many other drugs, such as intracellular organisms
and those sequestered in abscesses and lung cavities.

50
 Cont...
• Rifampin is well absorbed after oral
administration and excreted mainly through
the liver into bile. It then undergoes
enterohepatic recycling.
• It is a cyp450 enzyme inducer
– The serum concentration of protease inhibitors,
Nevirapine, ketoconazole and warfarin decreased
by 50% on co-administration.

51
 Cont...
• Administered together with INH, ethambutol,
or another antituberculous drug.
– This is to prevent emergence of drug resistant
mycobacteria.
• It is an alternative to INH for prophylaxis in
patients who are unable to take INH.
• Adverse effects:
– Red-orange discoloration of different body fluids.
– Flu-like syndrome (fever, chills, ataxia)
– Hepatitis, jaundice
52
 Ethambutol
• Inhibits synthesis of mycobacterial cell wall.
• well absorbed from the gut.
• accumulates in renal failure.
• crosses the blood-brain barrier only if the
meninges are inflamed.
• hydrochloride salt is given as a single daily
dose in combination with INH or rifampin for
the treatment of tuberculosis.

53
Cont …
• The higher dose is recommended for treatment
of tuberculous meningitis.
• The most common serious adverse event is
retrobulbar neuritis, inflammation of the optic
nerve which makes objects appear blurred.
– causing loss of visual acuity and red-green color
blindness is a dose-related side effect.
– relatively contraindicated in children too young to
permit assessment of visual acuity and red-green
color discrimination.

54
 Pyrazinamide(PZA)
Pyrazinamide
• relative of nicotinamide, stable, slightly
soluble in water.
• Drug is taken up by macrophages and kills
bacilli residing within this acidic environment.
• well absorbed from the gastrointestinal tract
and widely distributed in body tissues,
including inflamed meninges.

55
 Cont...
• Pyrazinamide requires an acidic environmentto
exhibit its tuberculocidal activity.
• Thus, pyrazinamide is highly effective on
intracellular mycobacteria.
• Pyrazinamide is a prodrug.
– The mycobacterial enzyme pyrazinamidase
converts pyrazinamide to pyrazinoic acid, the
active form of the drug.

56
Cont …
• The specific drug target is unknown, but
pyrazinoic acid disrupts mycobacterial cell
membrane metabolism and transport
functions.
• Major adverse effects of pyrazinamide include
– hepatotoxicity, nausea, vomiting, drug fever, and
hyperuricemia.
• Hyperuricemia may provoke acute gouty
arthritis.
57
• Pyrazinamide is an important front-line drug
used in conjunction with isoniazid and
rifampin in short-course (ie, 6-month)
regimens as a “sterilizing” agent active against
residual intracellular organisms that may
cause relapse.

58
 Streptomycin
• Penetrates into cells poorly.
• active mainly against extracellular tubercle bacilli.
• crosses the BBB and achieves therapeutic
concentrations with inflamed meninges.
• employed principally in:
– individuals with severe, possibly life-threatening
forms of tuberculosis (meningitis and disseminated
disease)
– treatment of infections resistant to other drugs.

59
Combination Chemotherapy of Tuberculosis
• The duration of therapy for a patient with
tuberculosis depends upon
– the severity of the disease
– the organ affected and
– the combination of agents.
• There are two phases in the treatment of
tuberculosis
– the intensive phase, which lasts 8 weeks,
• makes the patients noninfectious.
– The continuation phase, which lasts 6 months or more
and
• at least two drugs should be taken.

60
Cont …
• Four types of drug regimen are currently
employed in Ethiopia
– Directly Observed Treatment Short Course (DOTS)
– Re- treatment Regimen
– Short course Chemotherapy
– long course chemotherapy (LCC)

61
 Directly Observed Treatment Short
Course (DOTS)
• Used in:
– new Pulmonary TB smear positive patients
– new Pulmonary TB smear negative and
Extrapulmonary TB patients who are seriously ill
– TB in children < 6 years.
• It consists of: (2S (RHZ)/6(EH)
– intensive phase
• 8 weeks of treatment with Streptomycin, Rifampicin,
Isoniazid and Pyrazinamide
– Continuation phase
• 6 months of Ethambutol and Isoniazid or
• 4 months of rifampin and isoniazid (RH).

62
Cont …
• Children <6 years receive 4 months of Rifampicin
and INH (RH) in the continuation phase.

• Drugs have to be collected:

– daily during the intensive phase of DOTS and taken
under direct observation by the health worker.
– every month and self-administered by the patient
during the continuation phase

63
 Re- treatment Regimen

• Used for patients previously treated for more

than one month with short course chemotherapy
(SCC) and Long course chemotherapy (LCC) and
are still smear positive.
• These patients are: -
– Relapses
– Treatment failures
– Returns after default who are pulmonary tuberculosis
positive.

64
Cont …
• consists of: [2SE (RH) Z/1E (RH) Z/5E (RH) ]
– 2 months of treatment using Streptomycin, INH,
Ethambutol, Rifampicin and Pyrazinamide then
– the intensive phase
• 1month of INH, Ethambutol, Rifampicin and
Pyrazinamide
– Continuation phase
• 5 months of ethambutol, Rifampicin and INH.

65
Cont …
• Streptomycin should not be included in the
retreatment regimen for pregnant women.

• The drugs should be taken under direct

observation of the health worker throughout
the duration of Retreatment including the
continuation phase.

66
 Short course Chemotherapy

• Is recommended for:
– new patients with smear negative pulmonary TB
– new patients with extra pulmonary tuberculosis
– TB in children of 6 years and older.
• consists of: 2(RHZ)/6(EH)]
– intensive phase
• 8 weeks of treatment with Rifampicin, Isoniazid and
Pyrazinamide
– Continuation phase
• 6 months of Ethambutol and Isoniazid.

67
 Long course chemotherapy (LCC)

• to be prescribed in all cases of TB in

regions/Zones where the DOTS program is not
yet started.
• Consists of:
– intensive phase
• 2 months of Streptomycin, Ethambutol and INH
– Continuation phase
• 10 months of Ethambutol and INH.

68
 Drugs Active against
Atypical Mycobacteria

69
 Drugs Active against Atypical
Mycobacteria
• Disease caused by atypical mycobacteria is
often less severe than tuberculosis and not
communicable from person to person.

• M. avium complex is an important and

common cause of disseminated disease in late
stages of AIDS.

70
Cont …
• treatment of disseminated disease
– Azithromycin/clarithromycin + ethambutol
• effective and well-tolerated regimen
• Some authorities recommend use of a third
agent, ciprofloxacin or rifabutin.
– Rifabutin in a single daily dose of 300 mg has been
shown to reduce the incidence of M avium complex
bacteremia in AIDS.
– Clarithromycin also effectively prevents MAC
bacteremia in AIDS patients.

71
Drugs used in Leprosy

72
 Drugs used in Leprosy

• Leprosy is caused by mycobacterium leprae.

• can be treated with dapsone, rifampin,
clofazimine, ethionamide, etc.
• Because of increasing reports of dapsone
resistance, treatment of leprosy with
combinations of the drugs is recommended.

73
 Dapsone
(diaminodiphenylsulfone)
• most widely used drugs in the treatment of
leprosy
• inhibits folate synthesis.
• Resistance can emerge in large populations of M
leprae.
– the combination of dapsone, rifampin, and
clofazimine is recommended
• well absorbed from the gut and widely
distributed throughout body fluids and tissues.
• Excretion into urine is variable, and most
excreted drug is acetylated.
74
 Side effects
• usually well tolerated.
• Gastrointestinal intolerance, fever, pruritus,
and rashes occur.
• Erythema nodosum often develops during
dapsone therapy in lepromatous leprosy.
– Erythema nodosum leprosum(ENL) may be
suppressed by corticosteroids.
• Hemolysis and methemoglobinemia can occur.

75
 Rifampin

• effective in lepromatous leprosy.

• given in combination with dapsone or another
antileprosy drug.
– Because of the probable risk of emergence of
rifampin-resistant M leprae

76
 Clofazimine

• absorption from the gut is variable

• major portion of the drug is excreted in feces.
• stored widely in reticuloendothelial tissues and
skin.
• given for sulfone-resistant leprosy or when
patients are intolerant to sulfone.
• A common dosage is 100 mg/d orally.
• The most prominent untoward effect is skin
discoloration ranging from red-brown to nearly
black.

77
 Treatment regimen, MDT
 PB Adult
(6 blister packs) to be taken monthly within a maximum period
of 9 months
 Rifampicin 600 mg once a month
 Dapsone 100 mg every day
 MB Adult
(12 blister packs) to be taken monthly within a maximum period
of 18 months
 Rifampicin 600 mg once a month
 Clofazimine 300 mg once a month
 Clofazimine 50 mg and dapsone 100 mg every day

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Multi Drug Therapy
09/15/20 Chemotherapy 80