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OVERVIEW OF
ANTIMICROBIAL THERAPY
By
AWADH ALANAZI, MD
1
Infectious Diseases (ID) Leading Cause of
• Morbidity & Mortality Worldwide
• Ability of bacteria, mycobacteria, viruses,
fungi, protozoa, chlamydiae, richettsia,
mycoplasmas, spirochetes & helminths to
cause infection is balance between:
a. Inoculume size, virulence and
b. Adequacy of host defenses.
• Despite of ability Antimicrobials to
Augment normal host defenses and
prevent/control infection, prescribing errors
are common, including:
2
1.
2.
3.
4.
5.
6.
Treating Colonisation
Suboptimal empiric theraphy
Inappropriate combination theraphy
Dosing and duration errors
Mismanagement of apparent ABX failure
Inadequate Consideration of ABX Resist
Potential
7. Tissue penetration
8. Drug interaction, S.E., Cost
• These Limit Antimicrobial Effectiveness
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I. Factors in Antibiotic Selection
A. Spectrum
•
ABX with “Concentration Dependent”
Kinetics (e.g. Quinolones and
Aminoglycosides) display increasing
killing with increasing concentration
above organism MIC. But
•
ABX with “time-dependent” Kinetics
(e.g. beta-Lactams and vancomycin)
DONOT.
B. Tissue penetration
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C. ABX Resistance
• Bacterial Resist: Natural/Acq.
Relative/Absolute
• Natural/Intrinsic R: pattogens not covered
by usual ABX spectrum e.g. 25% of S.
pneumoniae naturally resist to Macrolides
• Acquired Resist: amp. H. inflenzae
• Organism with intermediate/relative res.
Show increases in MIC, but remain
subsceptible to ABX at achievable
serum/tissue conc. (e.g. pen. R.S. pneum.)
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• Organisms with high/absolute resist. Show no
increase in MIC, thus cannot be overcome with
higher ABX doses (e.g. genta. Resist. P.
aerogenosa)
• Resist. Not related to volume or use duration
• Successful ABX Resist. Control strategies:
a. Eliminating ABX from animal feeds
b. Early detection of resistance by screening
c. Infection control precaution
d. Restricted ABX formulary = i.e. Controlled use
of ABX with high resist potentials
c. Preferential use of ABX with low resist
potentials by clinicians
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• Unsuccessful Strategies:
a. Rotating formularies
b. Restricted use of certain ABX classes
e.g. Quinolones, third generation
cephalosporius
e. Use of combination therapy
• In choosing between similar ABX select
with low Resist. Potential: a. ceftaz. Assoc.
with MRSA prevalence, b. vanco. Assoc.
with URE prevalence
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D. Safety Profile
•
Cost: single most important cost saving
early shift from I.V. to po. bec. cost of
adm. I.V. alone $10/dose. (i.e. may
exceed ABX cost itself)
•
Monotheraphy vs. combination
•
ABX SE, outbreaks of Resist. Organism
•
Prolonged Hospitalization
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II.
A.
•
•
•
a.


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Factors in Antibiotic Dosing
Renal Insufficiency and Dosing Adjustment
ABX with wide “Toxic-To-Therapeutic” Ratio
and Creati Clearance.
ABX with narrow toxic-with-therapeutic ratio
Patients with pre existing renal disease or
receiving other nephrotoxics.
Loading and maintenance dosing in renal insuff.
Initial/Loading unchanged, but maint. dose
modified
Moderate R.I. (Crcl 50-80 ml/min): M.D.
halved but dosing interval unchanged

Severe R.I. (Crcl 10-50 ml/min): M.D.
halved and dosing interval doubled
 Selected ABX with similar spectrum, but
eliminated by hepatic route.
b. AMG Dosing
 SDS. Not in Enterococcal IE.
 AMG induced Tubular Dysfunction:
Best assessed by
 Serum creatinine
 Renal tubular cast counts in urine
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Q: Which is mere accurately reflects AMG
nephrotoxicity
B. Hepatic insufficiency
• More problematic than R.I…………?
• Dosing Adj usu. Not required for Mild or
Moderate H.I.
• Severe H.I. Adjust ABX with hepatoxic
potentials
• Select ABX with Renal route of elimination
C. Combined Renal and Hepatic Insuff:
• No dosing Adj. Guidelines
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•
If R.I. worse than HI: ABX eliminated by
liver given at half total daily dose.
• If HI worse than RI: Renally eliminated
ABX Admn. according to Renal function
D. Mode of ABX and Excretion/Excretory
organ toxicity.
• Mode of elimination/Excretion does not,
per se, predispose to excretory organ
toxicity e.g. Nafcillin, though eliminated
by Liver, but not hepatotoxic.
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Table 1. Major Route of
Elimination
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HEPATABILITY
RENAL
Chloramphinicol
Nafcillin
Most B-Lactams
Gemifloxacin
Cefoperazone
Linezolid
AMG
Vancomycin
Doxycycline
INH/RIF/EMB
Monobactams
Nitrofurantoin
Minocycline
PZA
Carbapenems
Fluconazole
Moxifloxacin
Itraconazole
Polymycin B
Acyclovir
Macrolides
Caspofungin
Colistin
Valacyclovir
Telithromycin
Micafungin
Ciprofloxacin
Famciclovir
Clindamycin
Anidulafungin
Ofloxacin
Valgaciclovir
Metronidazole
Ketoconazole
Levofloxacin
Tetracycline
Tigecycline
Voriconazole
Gatifloxacin
Flucytosine
Amantadine
Daptomycin
Rimantadine
Quinupristin/
dalfopristin
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Posaconazole
• Hepatic insuff
Decrease dose of ABX by 50% in clinical
severe liver dis.
Alternative: Use ABX of renal elimination
• Renal Insuff
Crcl 40-60 ml/min: decrease dose by 50%,
maintain dosing interval
Crcl 10-40 ml/min: decrease dose by 50%
and double dosing interval
Alternatively use Hepatilly eliminated route
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III.
A.
•
•
B.
•
•
•
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Microbiology and Susceptibility Testing
Overview
S
Testing informative about microbial sens. of
pathogen to various ABX thus guiding
theraphy.
Assess in-vitro results consistency with clinical
situation
Limitation of Microbiol Suscept. Testing
In-vitro data donot diff. coloniser and
pathogens
Treat patient not Lab. Results
Differentiate between pathogen and coloniser
• In-vitro results Donot necessarily mean invivo efficacy
• In-vitro testing depends on microbe,
methodology and ABX concentration
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Table 2: ABX organisms combination in which
in-vitro suscept. unreliable
ABX
“Sensitive” Organism
penicillin
H. Influenzae, yersinia pestis
TMP-SMX
Klebsiella, Enterocci, Bartonella
Polymyxin B
Proteus, salmonella
imepenem
Stenotrophomonas maltophilia
(f.pseudo)
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gentamicin
MTB
vancomycin
Erysipelothrix rhusiopathiae
AMG
Streptococci, salmonella, shigella
clindamycin
Fusobacteria, clostridia,
enterococci and listeria
macrolides
p. multocida
1st, 2nd gen. cephalos
Salmonella, shigella, bartonella
3rd, 4th gen. Cephalos
Enterococci, listeria, bartonella
All ABX except vauco, linezolid,
tigecycline, minocycline
quinupristin/dalfopristin
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MRSA
• Unusual susceptibility patterns
Organisms have predictable S patterns
In case of unusual S pattern of an isolate,
further testing should be performed by
micro. Lab. and expanded suscept. testing
needed.
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Table 3: Unusual S. patterns
requiring further testing
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organism
Unusual S. pattern
Unusual S. pattern
N. Meningitidis
Penicill. R.
Penicill. S.
staphylococci
Vanco/clinda. R, but erylhro S.
Vanco. S.
Viridans strep.
S. Pneumoniac
Beta-hem. Strep
Enterobacteriacae
and klebsiella
Vanco. I/R
Vanco I/R
Pens I/R
Imipenem R
Vanco S.
Vanco S.
Penc. S.
Imipenem S.
Enterobater and
serratia
Amp/Cefazolin S.
Amp/cefazolin R.
Morganella and
providencia
Amp/Cefazolin S.
Amp/cefazolin R.
klebsiella
p. aeroginosa
Cefotetan S , ceftaz
Amk R , genta/tobra
Stenotrophomonas
maltophilia
TMP/SMX R
Imipenem S
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R
S
Cefotetan R , ceftaz S
Amk S ,genta/tobra R
TMP/SMX S.
Table 4: Screening for extended-spectrum BetaLactamase (ESBL)Activity
Palhogen
Positive Screening Result (MIC)
k. Pneumoniae
k. Oxytoca, E. coli
Cefpodoxime  4mcg/ml
Ceftaz  1mcg/ml, aztreonam  1mg/ml
Cefotaxime  1mcg/ml, cefriaxone  1mcg/ml
p. mirablis
Cefpodoxine  4mcg/ml, ceftaz  mcg/ml
Cefotaxime  1mcg/ml
NB1 positive test for ESBL imp therapeutic implicaton
NB2 confirm ESBL requires 2 fold or more decrease in MIC for
either:- ceftaz + clavulanic acid or cefotaxime + clav. acid
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Summary
• In-vitro suscept. Testing useful but should
not be followed blindly
• Suscept. is conc. dependent thus
• IV-to-po switching using ABX of same
class, best made using po. ABX that can
achieve similar blood/tissue levels as I.V.
ABX.
* e.g. cefazolin lg 200 mcg/ml to cephalexin
500 mg 16 mcg/ml
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IV. Other Consideration in Antimicrobial
Therapy
A. Bactricidal vs. Bacteriostatic Therapy
•
For most infections Bacteriotastic and
Bactericidal ABX inhibit/kill organisms
at same rate, thus should not be factor in
ABX selection
•
Bactricidal ABX have advantage in
certain infections: IE, meningitis, febrile
neutropenia
B. Monotheraphy vs. Combination Theraphy
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Table 5. Combinations Theraphy and ABX Resistance
* Examples of ABX combination preventing resistance
• Anti-psedomenal penicillin [carben, cillin] + AMG
[genta, tobra, AMTC]
• Rif + INH, EMB, PZA
• 5-flucytosine + Ampho B
* Examples of ABX combinations not preventing resist
TMP-SMX
AMG+imipenem
aztreonam+ceftaz.
most other ABX
Cefepime+Cipro
combinations
NB: These combinations often prescribed to prevent
resist., when, infact they DONOT.
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C. I.V. vs. PO. switch therapy
• Patients adm.to hospital usu. Started on
IV. ABX then switched to equivalent PO.
after clinical improvement (usu 72 hr).
• Advantages of early IV-to-PO include:
- Reduced Cost
- Shorter hospital stay
- Less need for home I.V.
- Elimination of I.V. line infections
- Drugs suitable for IV-to-PO switch or
entirely by PO adm. include:
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





Doxycycline, minocycline
Clindamycin, metronidazole
Amoxicillin, chloramphinicol
TMP/SMX, Quinolones
Linezolid
Some penicillins and cephalosporins unusefule for
IV-to-PO switch bec. limited bioavailability
• Most infectious diseases should be treated orally
unless:
 Patient critically ill
 Cannot take PO
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 No equivalent oral ABX
 If patient can take PO, there is no difference in
clinical outcome using IV or PO, thus: •




Think in terms of:
ABX spectrum
Rather than: Route of admn.
Bioavailability
Tissue penetration
Nearly all non-critically ill patients should be
treated in part or entirely with PO ABX
 When switching from IV to PO, oral ABX should
achieve same blood tissue levels as the equivalent
I.V.
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Table 6. Biovailability of Oral Antimicrobials
Bioavailability
Antimicrobials
Excellent > 90% ie PO gives equiv.
Blood/tissue levels as same IV dose
(PO = IV)
Amox, TMP, linezolid, cephalexin,
TMP-SMX, fluconazole, cefadroxil,
minocycline, rifamp. Clindamycin,
chloramphinicol, INH Quinolones,
metronidazole, PZA EMB,
cycloserine
Good: PO < IV
Mostbeta-lactams, cefuroxime, EMB,
5 FCU cefixime, valacyclovir,
famciclovir, cefactor, cefpodoxime,
valgonaclovir, telithromycin,
ceftibuten, posaconazole,
itraconazole, macrolide
Poor: PO results in adequate
blood/tissue levels
Vancomycin, cefdinir, cefditoren
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D. Duration of Therapy
• Most bacterial infections in normal host
treated with ABX for 1-2 wks.
• ABX therapy may be extended in patient
with:
 Impaired immunity: DM, SLE,
neutropenia, diminished splenic function
 Ch. bacterial infections: IE, osteomyelitis
 Ch. viral and fungal inf.
 Certain intracellular pathogens
 Infections as HIV, CMV in compromised
host
require
life
long
suppressive
theraphy
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 ABX should ordinary not be more than 2
wk even if low grade fevers persist
 Prolonged theraphy offers no benefit rather
increases risk of SE, drug interactions and
superinfections.
32
Table 7. I.D. Requiring
Prolonged Antimicrobial Therapy
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THERAPY DURATION
3 wks
Lymphogranuloma venereum (LGU) syphilis
(late latent)
4 wks
Ch. O.m, ch. Sinusitis, ac. Osteomyelitis, ch.
Pyelonephritis, brain abscess, SBE (vividans
strept) legionella
6 wks
Ac. bact. endoc. (S. aureus, Enterococcus), H.
pylori.
3 months
Lung Abscess, ch. prostatitis
6 months
PTB, EPTB (usu > 6M), actinomycosis,
nocardia, ch. osteomyelitis
12 months
Whipple’s deisease
More than 12 months
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INFECTIOUS DISEASES
Lepromatous leprosy, bartonella, CMV, HIV
(lifelong), prosthetic-related, ch. Suppressive
therapy for PCP
NB
• Lung Abscess: treat until resolved or CXR
remained unchanged
• Actino: treat till resolved
• Nocardia may need prolonged treat. in
compromised hust
• Osteomyelitis: require adequate surgical
debridement for cure
• Prosthetic-related infections: may need
removal, if not need prolonged suppressive
theraphy, but clinical failure is the rule.
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V.
•
•
•
•
•
36
Imperic ABX Therapy
Susceptibility results usu. Not available
prior to treatment
Direct imperic ABX against most likely
pathogens
Mildly ill patients, inpatient, or
ambulatory: may be treated with oral
ABX with high bioavailability
Moderely or severely ill pateint usu
treatment with I.V.
Obtain spp. For micro diagnism (stains,
cultures) prior to starting ABX
VI.
•




37
Antibiotic Failure
Many causes for apparent AB failure:
ABX unresponsive infections
Febrile non-infectious disease
Drug fever
Most common ERROR in managing
apparent ABX failure is changing/adding
additional ABX rather than attempts to
determine the cause.
Causes of Apparent /Actual ABX Failure
1. In-vitro suscept. but inactive in-vivo.
2. ABX tolerance with GPC
3. Inadequate coverage/spectrum
4. Inadequate blood levels
5. Inadequate tissue levels:• Undrained abcess
• Foreign body related infection
• Protected focus (eg. CSF)
• Organ hypoperfusion: reduced blood
supply, eg. ch. osteo. in DM.
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6.
•
•
7.
8.
9.
10.
•
•
11.
•
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Drugs induced interactions
ABX inactivation
ABX antagonism
Decreased ABX activity in tissue
Fungal super infection
Treating colonisation not infection
Non-infectious Diseases
Midical disorder mimiking infection (eg. SLE)
Drug fever
Antibiotic unresponsive infectious disease
Most viral infections
VII. Drug Fever
Clinical Features of Drug Fever
History:
- Many but not all patients atopic
- Patients on sensitising medications
for days or years “without problem”
Physical Exam
•
Fever low or high-grade, but usually between
38.9 – 40.7 ºC (102º - 140ºF) may exceed
41.1ºC (106ºF)
•
Patient appears “inappropriately well” for
degree of fever.
•
Relative brody cardia
NB: second, CHB, pacemaker-induced rhythm beta
blocker, diltiazem, verapamel treatment
40
• Appropriate Temp.-pulse Rate
Pulse (beat/min)
Temp
150
41.1ºC (100ºF)
140
40.6ºC (105ºF)
130
40.1ºC (104ºF)
120
39.4ºC (103ºF)
110
38.9ºC (102ºF)
Lab Tests
• High WBC (usu. with left shift)
• Eosinophils present, but eosinophilia
uncommon
41
•
•
•
High ESR in majority of cases
Early, transient, mild elevation of
transaminases
Negative blood cultures
VIII. Pitfalls in ABX prescribing
1. Use of ABX to treat non-infectious diseases
(e.g. viral infections) or colonisation
2. Overuse of combination therapy
3. Use of ABX for persistent fevers:
42
• Reassess your patient, if faced with
apparent ABX failure (ie persistent fever
despite being on ABX regimen)
• Causes of prolonged fevers:
- undrained septic foci
- non-infectious medical disorder
- drug fever
- undiagnosed causes of leukocytosis/lowgrade fevers shouldnot be treated with
prolonged ABX courses
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4. Inadequate surgical therapy
- infected prosthetic materials or fluid
collections (eg Abscesses) often require
surgical therapy for cure.
- for infections like ch. osteomyetitis
surgery is only way (if feasible) to cure
infection, while ABX useful only to
suppress or to prevent local infection
complications
5. Home I.V. therapy: Less needed in view of
available excellent oral ABX, [eg
Quinolones and Linezolid].
44