4. The first consideration in selecting an
antimicrobial agent is whether it is
indicated.
6/26/2013 4amrhamdy MD FCCP
5. Antibiotics are antibacterial substances
produced by various species of
microorganisms (bacterial, fungi, and
actinomycetes) that suppress the
growth of the microorganisms.
6/26/2013 5amrhamdy MD FCCP
6. Common usage often exclude the term
antibiotics to include synthetic
antimicrobial agents, such as
sulphonamides and quinolones.
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7. Antibiotics have three general uses:
• Empirical therapy
• Definitive therapy
• Prophylactic or preventive therapy.
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8. When used as empirical or initial
therapy, the antibiotic should cover all
the likely pathogens because the
infecting organism(s) has not yet been
defined.
6/26/2013 8amrhamdy MD FCCP
9. Optimal and judicious selection of
antimicrobial agents for the therapy of
infectious diseases requires clinical
judgement and detailed knowledge of
pharmacological and microbiological
factors.
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10. The quinolones are a family of
synthetic broad –spectrum antibiotic
drugs.
6/26/2013 10amrhamdy MD FCCP
11. The first generation of the quinolones
began with the introduction of
nalidixic acid in 1962 for the
treatment of urinary tract infections
in humans.
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12. • There are simple quinolones and
fluoroquinolones.
• FQs are quinolone antimicrobials
having one or more fluorine
substituations.
6/26/2013 12amrhamdy MD FCCP
14. In the 1990s, compounds with additional
fluoro and other substitutions have been
developed (2nd generation FQs)- further
extending antimicrobial activity to gram
+ve cocci and anaerobes, and/ conferring
metabolic stability (long t1/2), and/ or
conferring metabolic stability (longer t1/2).
6/26/2013 14amrhamdy MD FCCP
16. Therapeutic uses of simple quinolones:
• Uncomplicated urinary tract
infection.
• Urinary antiseptic.
• Diarrhea casued by Proteus, E. coli.
Salmonella, Shigella (ampicillin
resistant).
6/26/2013 16amrhamdy MD FCCP
17. Fluoroquinolones are the only class of
antimicrobial agents in clinical use
that are direct inhibitors of bacterial
DNA synthesis.
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18. They inhibit two bacterial enzymes,
DNA gyrase and topoisomerase IV.
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20. FQ enter the host cells and are
therefore active against intracellular
pathogens, e.g. Mycoplasma spp,
and Chlamydia spp.
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21. Spectrum of Activity
The greatest activity of FQs is against
aerobic gm-ve bacilli, particularly
Enterobacteriaceae, and against
Haemophilus spp and gm-ve cocci
e.g. Neisseria spp and Moraxella
catarrhalis, and also against non-
enteric gm-ve bacilli such as Ps
aeruginosa and against
staphylococci.6/26/2013 21amrhamdy MD FCCP
25. Use in Pregnancy
• Not used during pregnancy.
• Not used in lactating mothers as it is
secreted in breast milk.
6/26/2013 25amrhamdy MD FCCP
26. Use in Children
Not recommended for routine use in
children less than 18 years of age
(arthropathy with erosions of the
cartilage in weight-bearing joints).
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27. Use in Children cont’d
• Used in cystic fibrosis?
• Complicated urinary tract infections
and pyelonephritis?
6/26/2013 27amrhamdy MD FCCP
29. Concentration in prostate tissue, stool,
bile, lung, and neutrophlis as well as
macrophages usually exceed serum
concentrations.
6/26/2013 29amrhamdy MD FCCP
30. Resistance
• Resistance to FQs has been slow to
develop.
• Increasing resistance has been
reported among
Salmonella, Pseudomonas, Staphyloc
occi, Gonococci and Pneumococci.
6/26/2013 30amrhamdy MD FCCP
31. Resistance cont’d
• The likelihood of developing
quinolone resistance is thought to be
related to the intensity and duration
of therapy.
• Resistance may occur via mutations
in chromosomal genes via mutations
in plasmids
6/26/2013 31amrhamdy MD FCCP
32. Resistance cont’d
• The use of the most potent FQ is a
logical choice if resistance has to be
avoided/ delayed.
• Previous exposure to an FQ in the
recent past precludes the use of a
member of this class for the
empirical treatment of CAP.
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33. Among “atypicals’, antibiotic resistance
is rare and very seldom responsible
for clinical failure.
6/26/2013 amrhamdy MD FCCP 33
35. Gastrointestinal
• Occurs in 3-17% of patients.
• Anorexia, nausea, vomiting, and
diarrhea.
• Abdominal discomfort.
6/26/2013 35amrhamdy MD FCCP
36. Nervous System
• In 0.9 -11%.
• Mild headache and dizziness.
• Insomnia.
• Alteration of mood.
• Hallucinations, delirium, seizures.
6/26/2013 36amrhamdy MD FCCP
37. Rash and other Allergic
Manifestations
• In 0.4-2.2 %.
• Photo toxicity.
6/26/2013 37amrhamdy MD FCCP
38. Arthropathy
• Arhtropathy with cartilage erosions
and non inflammatory effusions
occurs in the weight-bearing joints
(in animals).
• Tendinopathy and tendon ruptures
have been reported, mainly the
Achilles tendon, also rotator cuff,
hand, biceps, and thumb.
6/26/2013 38amrhamdy MD FCCP
39. Arrhythmia and QT Interval
Prolongation
Moxifloxacin, levofloxacin and
gemifloxacin should be avoided in
patients with known QT interval
prolongation and with
hypokalemia, hypomagnesemia and
use of anti arrhythmic drugs.
6/26/2013 39amrhamdy MD FCCP
41. • Known allergy to the drug.
• Epilepsy.
• QT prolongation.
• Pre-existing CNS lesions or
inflammation or stroke.
• With benzodiazepines
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42. In the USA, a “Black Box” warning of
increased risk of developing
tendonitis and tendon rupture in
patients of all ages. This risk is
further increased in individuals over
60 yrs, taking CS drugs, and have
received kidney, heart or lung
transplantations.
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43. May exacerbate weakness in patients
with myasthenia gravis due to their
neuromuscular blocking activity.
6/26/2013 amrhamdy MD FCCP 43
45. 1. For empirical therapy of an infection in
which the cause is unknown.
2. For treatment of polymicrobial
infections.
3. To enhance antimicrobial activity( i.e.
synergism) for a specific infection.
4. To prevent the emergence of resistance.
6/26/2013 45amrhamdy MD FCCP
48. Guidelines from the IDSA ( Infection
Disease Society of America)
recommend the following options for
empiric-second line treatment for
ABRS:
6/26/2013 48amrhamdy MD FCCP
52. Community-aquired LRTI is a very
common cause of acute illness and
probably the most common reason
for lost working time in adults.
6/26/2013 amrhamdy MD FCCP 52
53. The spectrum of disease ranges from a
mild mucosal colonization or
infection, an acute bronchitis or
AE/COPD to an overwhelming
parenchyma infection with the
patient presenting with a severe CAP.
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54. It is an acute illness (present for 21
days or less), usually with cough as
the main symptom, with at least one
other LRT symptom (sputum,
dyspnea, wheeze or chest
discomfort/pain) and no alternative
explanation (e.g. sinusitis or asthma).
6/26/2013 54amrhamdy MD FCCP
55. Definitive CAP
• Is an acute illness with cough and at
least one of new focal chest
signs, fever more than 4 days or
dyspnea/ tachypnea, and without an
obvious cause.
• Supported by chest radiograph
findings of lung shadowing that is
likely to be new.
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56. • CAP is a common and potentially
serious illness.
• It is associated with considerable
morbidity and mortality, particularly
in elderly patients and those with
significant co-morbidities.
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57. • Pneumonia, which is most often a
bacterial disease, should, in general,
be treated with antibiotics.
• A delay of more than 8 hours in
treatment is associated with
increased mortality.
6/26/2013 amrhamdy MD FCCP 57
58. Older quinolones, such as ciprofloxacin
and ofloxacin have rather poor anti-
pneumococcal efficacy and are not
recommended for the empirical
treatment of CAP.
6/26/2013 amrhamdy MD FCCP 58
59. Advantages of Respiratory FQ
• They exhibit broad spectrum coverage
including all common LRTI pathogens.
• They have a high bioavailability.
• They have good penetration resulting in
high intra-celullar concentrations.
• A long half-life permitting once or twice
daily dosing.
• Are rapidly bactericidal.
6/26/2013 amrhamdy MD FCCP 59
60. Respiratory quinolones are more likely
to result in treatment success than
the combination of a beta-lactam
plus a microlide for treatment of CAP.
6/26/2013 amrhamdy MD FCCP 60
61. AE/COPD
An event in the natural course of the
disease characterized by a worsening
of the patient’s baseline dyspnea,
cough and/or sputum beyond day-
to-day variability sufficient to
warrant a change in management
(chest radiograph shadowing
consistent with infection confirms
CAP)6/26/2013 61amrhamdy MD FCCP
62. The newer FQs have excellent intrinsic
activity against Str. Pneumonia, H.
influenzae, Moraxella catarrhalis
and the atypical respiratory
pathogens.
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63. • FQs may be used as mono-therapy to
treat high risk patients with
AE/COPD, for patients with CAP
requiring hospitalization, but not
admission to ICU.
• The newer FQs often achieve clinical
cure rates in more than 90 % of these
patients.
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64. Key factors to consider when selecting
Antibacterial Therapy for LRTIs
6/26/2013 64amrhamdy MD FCCP
77. • There appears to be an increase in
multidrug- resistant TB.
• It was estimated that in 2004 half a
million new cases of MDR-TB cases
were diagnosed world wide.
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78. Of the new compounds being tested
for their efficacy in TB treatment, the
FQ are the first novel drugs since the
development of rifamycins to have
been shown to have significant
activity against M. tuberculosis.
6/26/2013 amrhamdy MD FCCP 78
79. • Multidrug-resistant TB (MDR-TB) is
defined as TB resistant to at least
isoniazid and rifampin.
• Extensively drug-resistant TB (XDR-
TB) is caused by MDR strains that are
also resistant to at least one FQ and
one or more injectable agents.
6/26/2013 amrhamdy MD FCCP 79
80. • The anti-TB activity of FQs has been
under investigation since the 1980s.
• FQs are novel anti-TB drugs to be
used when a patient is infected with
a MDR-TB strain.
6/26/2013 amrhamdy MD FCCP 80
81. Many are active in vitro but only a
few, including
oflaxicin, ciprofloxacin, levofloxacin,
sparfloxacin, levofloxacin and
lemofloxaxin, have been clinically
assessed.
6/26/2013 amrhamdy MD FCCP 81
82. • The choice of FQ should be based
not only on the in vitro activity, but
also on the long-term tolerance.
• The in vivo activity of FQs is
concentration dependent.
6/26/2013 amrhamdy MD FCCP 82
83. • The administration of FQ for CAP
patients with TB has been associated
with delay in diagnosis and increased
resistance and poor outcomes.
• Multiple FQs prescriptions for
undiagnosed TB were more likely to
have FQ resistant M. TB.
6/26/2013 amrhamdy MD FCCP 83
84. According to a recent meta analysis of 11
randomized controlled trials comprising a
total of 1,514 patients, no statistically
significant difference was observed in
relation to cure, treatment failure and
clinical and radiological improvement
when first-line drugs were replaced by a
FQ (ciprofloxacin, oflaxacin or
moxifloxacin).6/26/2013 amrhamdy MD FCCP 84
85. Thus, there is currently no justification
for the substitution of a FQ for first
line drugs or the addition of a FQ to
the standard regime.
6/26/2013 amrhamdy MD FCCP 85
86. Moxifloxacin at the recommended
daily dose of 400mg is the most
active FQ against TB, while
ciprofloxacin is the least effective.
6/26/2013 amrhamdy MD FCCP 86
87. Warning
The broad spectrum activity and
common use against many other
infections is also concern, since
widespread use of this class of
antibiotics may lead to a rapid
increase in already emerging
resistance problems.
6/26/2013 amrhamdy MD FCCP 87
88. It is wise not to use respiratory FQs as
a first-line therapy for LRTI, but to
reserve these drugs for selected
patients with CAP.
6/26/2013 amrhamdy MD FCCP 88
