Principles in antimicrobial

therapy: The ABCs

Benjamin G. Co, MD, FPPS, FPSECP

Professorial lecturer in Antimicrobial Therapy, Graduate School
University of Santo Tomas
Executive Director, Center for Drug Research Evaluation and
Studies, Inc.
At the Research Institute for Tropical Medicine
 Disclosure
• Medical Director, Otsuka Philippines
Pharmaceuticals Inc.
• Honorarium received as Speaker for: Abbott
Pharmaceuticals, Astellas Pharmaceuticals, GSK
Vaccines, MSD Vaccines, Natrapharm-Patriot
• Advisory Board: GSK Vaccines (PHiD-CV), MSD
Vaccines Regional Advisory Board
• No CME activities in any form have been received
by the speaker
 Is there anything beyond BE?
• Four important parameters should be
observed before writing an antibiotic
prescription:
– SAFETY
– AFFORDABILITY
– NEED/SUITABILITY
– EFFICACY
 YES THERE IS!

AND IT SIMPLY MEANS WE GO BACK

TO BASICS…THE A B C OF ANTIBIOTIC
THERAPY
 Objectives
• 1. Review the basic principles in selection of
optimal antimicrobial therapy in pediatrics
• 2. Provide an update on the epidemiologic
basis for antibiotic selection
• 3. Provide guidelines for SANE-based
prescription in the current scenario of generic
equivalents
 Selecting Optimal Antimicrobial Therapy
(adapted from Principles of Anti-infective Therapy by John Bradley and Sarah Long in
Principles & Practice of Pediatric Infectious Diseases)

Questions pertinent to choosing antimicrobial therapy appropriately

1. What is the clinical syndrome/site of infection? Pathogens are predictable by site

2. Does the child have normal defense mechanisms (in which case causative agents
are predictable) OR are they impaired by underlying conditions, trauma, surgery, or a
medical device (in which case causative agents are less reliably predictable)?

3. What is the child’s age? Pathogens are predictable by age

4. What clinical specimen(s) should be obtained to guide empirical/definitive therapy?

5. Which antimicrobial agents have activity against the pathogens considered, and
what is the current range of susceptibilities for each antibiotic against these pathogens
in the practitioner’s hospital or clinic?
 Selecting Optimal Antimicrobial Therapy
(adapted from Principles of Anti-infective Therapy by John Bradley and Sarah Long in
Principles & Practice of Pediatric Infectious Diseases)

Questions pertinent to choosing antimicrobial therapy appropriately

6. What special pharmacokinetic and pharmacodynamic properties of a
therapeutic agent are important regarding the site of the infection host?
7. For any given infection site, what percent of children require effective
antimicrobial therapy with agents first selected for treatment? Bacterial
meningitis requires 100%, whereas 75% may be acceptable for impetigo.
8. What empiric therapy and what definitive therapy would be optimal?
Agents with a broad spectrum of activity may be appropriate for empiric
therapy, whereas those with a narrow spectrum of activity are preferred for
definitive therapy.
9. What special considerations exist regarding drug allergy, drug interaction,
route of administration, cost, alteration of flora, or selective pressure in an
environment?
 Step 1: Predicting the infection
organism
• Bacteria are tropic for tissues locally following
invasion; certain species have a proclivity for
causing serious infections; while others can be
dismissed in some infections when the site is
already identified
– Examples:
• Meningitis: N. meningitidis, grp B strep, S. pneumoniae, Hib
(?)
• AOM: S. pneumoniae, H. influenzae, M. catarrhalis
• Cellulitis, pyogenic arthritis, osteomyelitis: S. aureus, S.
pyogenes
Acute Otitis Media

Macrolides or b-lactams?
 Step 2. Consider host defense
mechanism
• If the host is healthy with intact immunity and
normal integumental barriers to infection, the
causative pathogens are predictable
• If the host is healthy with intact immunity but
with trauma to skin, mucous membranes, recent
surgical procedure, or indwelling medical device,
a variety of relatively nonpathogenic commensals
can be causative pathogens, mandating therapy
with broader spectrum antibiotic
• If the host is immunocompromised – REFER!
 Step 3. Consider the age of the child
• Predictability based on child’s age and age-specific
exposures
– Newborn period (L. monocytogenes, GBS, E. coli)
– Developmental maturity of immune system provides
improved recognition of polysaccharide-encapsulated
pathogens (S. pneumoniae, Hib) as infants approach 3 y/o.
– Group childcare exposures in young infants are linked to
carriage of, and infection by, antibiotic-resistant strains of
S. pneumoniae
– School-related exposure to S. pyogenes and older children
to atypical pathogens (low in young infants)
– Adolescent exposure to STIs
 Step 4. Perform diagnostic tests
• Every effort should be made to prove the
etiology of the infection and obtain an isolate
for susceptibility testing ESPECIALLY when you
need to prescribe an antibiotic (particularly
very broad spectrum coverage which can
result in altered culture findings later on)
• Difficult in the local setting, but try to DELAY
having to start antibiotic therapy, unless
warranted clinically.
Step 5. Consider antibiotic susceptibilities
of suspected pathogens

• Antimicrobial Resistance Surveillance

(Jan. – Dec. 2008)
Research Institute for Tropical Medicine
Antimicrobial Resistance Surveillance Pattern
Antimicrobial Resistance Surveillance
(Jan. – Dec. 2008)
 Enteric Patogens

90
80
Percent Resistance

70 Ampicillin
60 Chloramphenicol
50 Ciprofloxacin
40 Cotrimoxazole
30 Tetracycline
20 Nalidixic Acid
10
0
Salmonella Nontyphoidal Shigella Vibrio
typhi Salmonella cholera

%R (Number Tested)
Ampicillin Chloramphenicol Ciprofloxacin Cotrimoxazole Tetracycline Nalidixic Acid
Salmonella typhi 0.4 (252) 0 (248) 0.9 (219)
Nontyphoidal Salmonella 18.3 (71) 4.6 (65) 0 (74) 13.9 (36)
Shigella 83.3 (12) 46.2 (13) 7.7 (13) 54.5 (11) 0 (12)
Vibrio cholera 1.1 (89) 1.1 (90) 0 (89)
 ARI Pathogens

50 Ampicillin
40 Cefuroxime
% Resistance

Chloramphenicol
30
Ciprofloxacin
20 Co-amoxiclav
10 Cotrimoxazole
Erythromycin
0
Penicillin
Streptococcus Haemophilus Moraxella
pneumoniae influenzae catarrhalis Amp-sulbactam

%R (Number Tested)
Ampicillin Chloramphenicol Co-amoxiclav Cotrimoxazole Erythromycin Penicillin
Streptococcus pneumoniae 5.3 (113) 22.6 (115) 0 (116)
Haemophilus influenzae 10.3 (97) 15.4 (91) 22 (82)
Moraxella catarrhalis 23.3 (437) 16.1 (453) 46.4 (425) 36.8 (459)
 Staphlococci and Enterococci

100
90
80 Ampicillin
Benzylpenicillin
%Resistance

70
60 Ciprofloxacin
50 Cotrimoxazole
40 Erythromycin
30 Oxacillin
20
Vancomycin
10
0
Staphylococcus Staphylococcus Enterococcus
aureus epidermidis faecalis

%R (Number Tested)
Ampicillin Benzylpenicillin Ciprofloxacin Cotrimoxazole Erythromycin Oxacillin Vancomycin
Staphylococcus aureus 94.3 (1115) 7 (969) 5.2 (993) 8.9 (1140) 31 (1141) 0 (1132)
Staphylococcus epidermidis 92.7 (341) 43.1 (320) 52.2 (343) 54.8 (332) 0 (349)
Enterococcus faecalis 3.4 (179) 0 (225)
 Enterobacteriaceae

Amikacin
90
80 Ampicillin
70 Ampi-sulbactam
% Resistance

60 Cefuroxime
50 Ciprofloxacin
40 Ceftriaxone
30 Cephalothin
20 Gentamicin
10 Cotrimoxazole
0 Cefepime
E. coli Klebsiella Enterobacter
Imipenem

%R (Number Tested)
Amikacin Ampicillin Ampi-sulbactam Cefuroxime Ciprofloxacin Ceftriaxone
E. coli 8.7 (2433) 77.7 (2825) 24.6 (2259) 13.9 (1590) 36.2 (2595) 21.1 (2435)
Klebsiella 11.8 (1943) 28 (1538) 21.2 (1092) 24.6 (1992) 19.2 (1929)
Enterobacter 12.4 (1429) 23.2 (1416) 26.6 (1400)
Cephalothin Gentamicin Cotrimoxazole Cefepime Imipenem
E. coli 38.6 (1361) 24.7 (2561) 65 (2504) 13.1 (2365)
Klebsiella 45.3 (1065) 21.9 (1975) 7.8 (1858) 0.6 (2085)
Enterobacter 78.7 (863) 28.9 (1452) 13.2 (1360) 2.3 (1374)
 %R (Number Tested)

Gram negative, non-fermentative bacilli Pseudomonas aeroginosa

Amikacin
12.4 (1828)

30 Amikacin
Cefepime
13.1 (1710)

25 Cefepime Ceftazidime
15.4 (1709)
% R e s i s ta n c e

Ceftazidime Ciprofloxacin
20
28.3 (1709)
Ciprofloxacin Gentamicin
15
Gentamicin 24.1 (1707)
Imipenem
10 Imipenem 15.9 (1696)
Netilmicin
5 Netilmicin
14 (344)

0 Piper-Tazo Piper-Tazo
10.8 (928)
Pseudomonas aeroginosa Tobramycin Tobramycin
21.8 (1692)
 Neisseria

90
80 Cefixime
70 Ceftriaxone
% Resistance

60 Ciprofloxacin
50
Ofloxacin
40
30 Penicillin
20 Spectinomycin
10 Tetracycline
0
Neisseria gonorrhea

Number Tested
Cefixime Ceftriaxone Ciprofloxacin Ofloxacin Penicillin Spectinomycin Tetracycline
Neisseria gonorrhea 0 (75) 0 (82) 47.8 (69) 54.1 (74) 70.7 (75) 0 (70) 81.4 (70)
 Step 6. Consider PK/PD properties of
drugs
• Critical information to guide the selection of
both drug and drug dosage in antimicrobial
therapy:
– 1. route of administration
– 2. absorption
– 3. tissue distribution of antibiotic at site of
infection
– 4. drug elimination characteristics
 PD antibacterial effect of antimicrobial agents by
primary bacterial target and by antibiotic class
Primary target Antibacterial class Pharmacodynamics Intracellular
activity
Cell wall B-lactams Bactericidal Not generally
- penicillins Time-dependent effective
- cephalosporins PAE only against
- monobactams G(+) organisms
- carbapenems Carbapenems PAE
Glycopeptides against G(+) & G(-)
- vancomycin organisms
- teicoplanin
Cell membrane Lipopetides Bactericidal Not known
- Daptomycin Concentration-
Polymyxins dependent
- Polymyxin B Long PAE
- Colistin (Daptomycin)
PAE (polymyxins)
 PD antibacterial effect of antimicrobial agents by
primary bacterial target and by antibiotic class

Primary target Antibacterial class Pharmacodynamics Intracellular

activity
Ribosome Macrolides, Bacteriostatic or –cidal Yes
azalides, ketolides (ketolides)
Time- and
concentration-
dependent
Long PAE
Tetracyclines, Bacteriostatic Yes
glycylcyclines Time-dependent
Long PAE
Lincosamides Bactericidal or –static Yes
(Clindamycin) Time-dependent
PAE
 PD antibacterial effect of antimicrobial agents by
primary bacterial target and by antibiotic class

Primary target Antibacterial class Pharmacodynamics Intracellular

activity
Ribosome Aminoglycosides Bactericidal Not effective
Concentration- partially
dependent
PAE
Oxazolidinones Bacteriostatic (except Not effective
against S. pneumoniae) partially
Concentration-
dependent
PAE
Rifamycins Bactericidal Yes
Long PAE
 PD antibacterial effect of antimicrobial agents by
primary bacterial target and by antibiotic class

Primary target Antibacterial class Pharmacodynamics Intracellular

activity
Ribosome Quinolones Bactericidal Yes
Concentration-
dependent
Long PAE
Streptogramins Bactericidal (except Yes
against Enterococcus
faecium)
Concentration-
dependent
PAE
 PD antibacterial effect of antimicrobial agents by
primary bacterial target and by antibiotic class

Primary target Antibacterial class Pharmacodynamics Intracellular

activity
Nucleic Acid Metronidazole Bactericidal Yes
Concentration-
dependent
PAE
Sulfamethoxazole- Bactericidal Yes
trimethoprim Concentration-
dependent
PAE – postantibiotic effect OR the observation of delay in
regrowth of organisms following removal of antibiotic from the
media
 PK/PD basis of optimal antibiotic therapy
(adapted from Michael N. Neely and Michael D. Reed in Principles & Practice
of Pediatric Infectious Diseases, 2008)
Drug disposition in specific patient populations
Schematogram of sites of action for various
antibiotics
 Time vs concentration-dependent
antibiotics
• PD of antibiotics are based on:
– 1. kinetics of bacterial killing
– 2. post-antibiotic effect (PAE)
– 3. post-antibiotic leukocyte enhancing effect
(PALE)
– 4. inoculum effect
 Time vs concentration-dependent
antibiotics
• Concentration-dependent antibiotics
– Exhibit a concentration-dependent killing:
• The higher the concentration of the drug, the greater
the bactericidal effect
– PAE: the time period after an exposure to and
removal of an antimicrobial agents during which
inhibition of bacterial growth persists
– In vivo PALE: enhanced leukocyte phagocytosis
and intracellular killing of bacterial during the
drug-free period
 Time vs concentration-dependent
antibiotics
• Concentration-dependent antibiotics
– Aminoglycosides: goal is to attain maximum serum
concentrations exceeding the MIC of the organism
tenfold (10)

– Fluoroquinolones: ratio of the area under the

cure/MIC (AUIC) should be greater than 125

– GIVE TOTAL DAILY DOSE LESS FREQUENTLY

 Time vs concentration-dependent
antibiotics
• Time-dependent antibiotics
– Bactericidal effect is dependent upon the length
of time that the bacteria are exposed to serum
concentrations which exceed the MIC of the
bacteria by at least 4x.
– All drugs exert PAE vs S. aureus but not all drugs
exert PAE against G(-) bacilli.
– Goal is to attain serum concentrations of at least
4x MIC of the infecting agent for at least 60% of
the dosing time interval.
 Time vs concentration-dependent
antibiotics
• Time-dependent antibiotics
– Most cost-effective means of attaining this is:
• 1. administering the drug by constant infusion following
an initial bolus or loading dose

• 2. OR, choosing the drug with the longest half-life

Time-dependent vs. Concentration-dependent
antibiotics
Clinical use of PK/PD correlates
Step 7. Consider target attainment
• In treating any child, the practitioner must
assess the seriousness of the infection, and
the risk or injury or death if the antibiotic is
not effective.
– Infections that are bothersome (e.g., impetigo)
but non-life-threatening, a cure rate of 70-80%
with a safe and inexpensive antibiotic is
acceptable, especially if alternative is using a drug
with a 98% success rate but has excessive risk of
toxicity or high cost.
Step 7. Consider target attainment
• In treating any child, the practitioner must
assess the seriousness of the infection, and
the risk or injury or death if the antibiotic is
not effective.
– Infections with degree of suffering or risk or organ
damage (e.g., pyelonephritis or AOM), cure rate of
80-90% is desirable.
– Infections that are life-threatening or serious (e.g.,
meningitis, sepsis), a 100% cure rate is mandatory
Step 7. Consider target attainment
• No formal list of “approved” cure rates or
“target attainments” exists.
• Accepted target attainment may differ
between diseases, physicians, families and
societies.
• Risk/Benefit ratio must always be considered
• Setting targets can help clarify decision-
making regarding relative merits, risks, and
cost of management.
Step 8. Separate empiric and definitive
therapeutic decisions
• Empiric therapy is selected based on:
– 1. presumed pathogens at the site of infection
– 2. local resistance patterns of the presumed
pathogens
– 3. desired cure rates selected by the clinician

IN GENERAL, THE SICKER CHILD DEMANDS

TREATMENT DOSAGES AND ANTIBACTERIAL
ACTIVITY ASSOCIATED WITH A HIGHER RATE OF
CURE.
Step 8. Separate empiric and definitive
therapeutic decisions
• Once the pathogen is identified, a narrow-
spectrum agent can frequently provide the
same degree of bacterial eradication and
clinical efficacy with:
– 1. decreased toxicity
– 2. decreased selective pressure
– 3. decreased cost
Step 8. Separate empiric and definitive
therapeutic decisions
• Switch therapy or definitive convalescent
outpatient therapy of serious infections
initially treated in the hospital can be
acceptable if:
– 1. risks of complications of the infection are
negligible
– 2. parents and child can adhere to well defined
management plans
– 3. follow-up or return to hospital quickly for any
infection- or therapy-related problems is not a
problem
 Step 9. Special considerations
• 1. drug allergy for a particular agent, agents of
the same type or agents in the same class
impact selection
• 2. cost considerations have become a greater
issue on health insurers and government
agencies and the public with knowledge in
doctors having “conflicts of interest” with the
pharmaceutical industry
 Step 9. Special considerations
• 3. Acceptable risk of failure needs to be
determined by the treating physicians and
medical advisors to the health plan
formularies to allow families to achieve
acceptable cure rates and continue to have
confidence in their healthcare providers.
 Take home message
• The armamentarium against bacterial
infections is within our reach. The challenge
to the physician is his/her ability to rationally
use these drugs so that we do not create bad
bugs and resort to more expensive treatment
options. It is wise to remember that Bad Bugs
are more often than not created by Bad use of
Drugs.
Thank you for your kind
attention