Presentation is a review of an original article on principles to choosing an antibiotic in a specific scenario

1. Journal Club
Principles of Antibiotic
Therapy
By
Dr. Sayan Chakraborty
Final Year JR- MD Tropical Medicine
School of Tropical Medicine, Kolkata
E-mail: dr.sayan@gmail.com

2. Authors & Journal
AJ Varley BSc MB BS MRCS FRCA
Jumoke Sule MB ChB MRCP FRCPath
AR Absalom MB ChB FRCA MD
doi:10.1093/bjaceaccp/mkp035
Continuing Education in Anaesthesia, Critical Care & Pain |
Volume 9 Number 6 2009
© The Author [2009]. Published by Oxford University Press on
behalf of the British Journal of Anaesthesia.

3. Historical perspective
Microscopy:
• Magnifying glass: by Pliny in 1st century AD
• Modern microscope: in 1590 by Dutch spectacle maker Zaccharias
Jannsen
• 270x microscopes: by Antonie van Leeuwenhoek (1632–1723), first
to see & describe bacteria
Bacteria:
• Abu Ali ibn Sina: first to propose the presence of bacteria in
1020
• Louis Pasteur: demonstrated that fermentation is due to
microorganisms
• Robert Koch: proposed the ‘germ theory of disease’, received
nobel prize
• Hans Christian Gram: in 1884, developed Gram’s staining

4. Historical perspective
• Ancient Chinese, Greeks and Egyptians used moulds and
plants to treat infection Eg: Quinine for malaria
• Ernest Duchesme, first described the antibacterial
properties of Penicillium spp. in 1897
• Fleming developed penicillin in 1928
• Paul Ehrlich: Discovered the first true antibiotic,
Salvarsan, treatment for Syphilis, after his work on
arsenic and other metallic compounds in Germany, 1909.
• Gerhard Domagsk, a pathologist, discovered the
sulphonamides in the Bayer laboratories in 1932.

5. Pharmacology of antibiotics
• Defined as pharmacological agents that selectively kill or
inhibit the growth of bacterial cells, while having little or
no effect on the mammalian host
• Bacteriostatic antibiotics prevent replication of bacteria,
rely on an intact immune system to clear the infection
• Bactericidal antibiotics kill the bacteria
• Use of a bactericidal agent is mandatory when treating
infective endocarditis since the bacteria are protected
from host immune functions within valve vegetations
• Cidal activity can sometimes be achieved by a
combination of antibiotics

6. Pharmacokinetics &
pharmacodynamics
• Pharmacokinetic (PK), pharmacodynamic (PD) and microbiological
parameters are increasingly used to predict microbiological and
clinical outcome
• PK refer to absorption, metabolism, distribution, and elimination
• PD refer to the effects of the drug on the body or organism
• After bolus, peak concn depends on the dose and the initial volume
of distribution
• The rate of decline of drug concn depends on the rates of
redistribution, metabolism, or renal clearance.
• Most antibiotics are eliminated via the kidneys— glomerular
filtration or tubular secretion
• Exercise caution in impaired kidney function eg: Aminoglycosides

7. PK & PD parameters/Indices
Parameters:
• Peak concentration
• Minimum inhibitory concentration (MIC),
• Area under the concentration–time curve at steady state
over 24 h (AUC)
• Protein binding
• Post-antibiotic effect
Indices:
• Peak/MIC,
• Time/MIC,
• AUC/MIC

8. Concentration dependent
killing
Aminoglycosides and Fluoroquinolones
• Peak concentration/MIC and AUC/MIC best correlate with
efficacy
• Prolonged antibiotic effect after the serum level decreases
below the MIC
• Higher doses result in efficacy and once-daily dosing for
aminoglycosides maximizes the peak concentration/MIC
• Different ratios efficacious for different drug–bug
combinations
• Eg: for FQs, optimal AUC/MIC ratio for successful t/t of Strepto
pneumoniae is 25–35, whereas ratios >100 may be required
for successful t/t of Gram-negative bacilli.
• Higher AUC/MIC ratios less likely to be associated with
development of resistance

9. Time-dependent killing
• β-Lactams, erythromycin, clindamycin, linezolid
• Time/MIC being the most important index for
efficacy
• The proportion of time above MIC is the most
important parameter
• AUC/MIC correlates best with efficacy for
azithromycin, tetracyclines, glycopeptides, and
quinupristin–dalfopristin

10. Adverse reactions
Hepatic & Renal dysfunction:
• Most commonly: rashes, diarrhoea, nausea & vomiting,
headache
• Carbapenems associated with transient increase in
transaminases, which resolve after the cessation of therapy.
• Aminoglycosides can cause permanent nephrotoxicity (tubular
damage, even at safe levels) and ototoxicity if intracellular
accumulation occurs
• Aminoglycosides commonly used in patients with sepsis and
renal hypoperfusion, both independent risk factors for renal
dysfunction, so difficult to determine the 1° cause of toxicity.
• Once-daily dosing regimens proposed to reduce SE.

11. Adverse reactions
Allergic reactions
• Most common with β-lactams
• Allergic reactions in 1950-60s commonly caused by
contaminants, not present in modern formulations
• True allergy rate was 33% if an allergy documented
in the medical notes, whereas it’s only 7% when
based on self-reporting – One study
• In penicillin allergic patients, the incidence of cross-
reactivity to other β-lactam agents (including
cephalosporins and carbapenems) is 10%

12. Resistance
• Sulphonamides in 1935 and Penicillin in 1941
• In 1946, 14% Staph aureus cultures were resistant
• By 1948 only 20% of Neisseria gonorrhoeae isolates were
sensitive to sulphonamides
• Some bacteria may not be inhibited adequately by drug concn
that are safely achievable at the affected body site.
• Eg: penicillin remains effective for the t/t of pneumonia, but
not meningitis, caused by pneumococci with intermediate
susceptibility to penicillin
• Resistance -- intrinsic or acquired
• Intrinsic resistance arises if the drug target is not present in
the bacterium’s metabolic pathways or drug impermeability,
eg β-lactams have no effect against mycoplasma

13. Resistance
• Acquired -- by mutation or by transfer of genetic material
from resistant to susceptible organisms
• Mutations occur frequently with rifampicin and fusidic
acid
• Transfer of genetic material occurs via plasmids and
transposons, bacteriophages or direct conjugation
• Niederman defined 4 main factors driving microbial
resistance
excess antibiotic usage
incorrect use of broad spectrum agents
incorrect dosing
non-compliance

14. Principles of prescribing
Prophylaxis:
• Three principles:
High risk of infection
Likely infecting organisms and their susceptibilities
should be known
Prophylaxis to be administered at the time of risk
• Eg: Management of contacts of a case of meningococcal
meningitis, who should be offered chemoprophylaxis at
the time of greatest risk of developing the infection
(rifampicin or ciprofloxacin is commonly used)

15. Principles of prescribing
Surgical chemoprophylaxis:
Depends on the type of procedure to be performed and are as
follows:
• (i) clean: those that do not open body cavities, not associated
with inflamed tissue
• (ii) clean-contaminated: involve the opening of body cavities
like GIT or GU tract
• (iii) contaminated: procedures involving acute inflammation
or visible wound contamination;
• (iv) dirty: operations performed in the presence of pus,
previously perforated viscus or open injuries that are >4 hr old

16. Principles of prescribing
Surgical chemoprophylaxis recommendations:
• Clean operations (thyroidectomy): prophylaxis is
generally not recommended. Maintaining strict asepsis
and good surgical technique
• Large bowel surgery associated with heavy levels of
bacterial contamination & post-op infection rates higher
• Prophylaxis depends on faecal bacterial load by
mechanical means and the administration of systemic
antibiotics active against aerobic and anaerobic
organisms, administered at induction to ensure adequate
antibiotic levels at the start of surgery

17. Principles of prescribing
Surgical chemoprophylaxis recommendations contd:
• Foreign materials implanted have a higher risk of infection, may
require chemoprophylaxis. In orthopaedic procedures, skin
commensals mostly implicated in peri-prosthetic infections
• Procedures that cause a transient bacteraemia, usually cleared by RE
system, may result in endocarditis in at-risk patients (with
anatomical abnormalities, prosthetic valves, or sequelae of
rheumatic fever)
• Prophylaxis is not recommended for dental procedures or
procedures of the upper and lower GI, GU, respiratory tracts when
there is no evidence of infection at the site of the procedure (NICE
guidelines)
• Patients with repeated UTI, mainly due to anatomical abnormalities,
can be given permanent courses of trimethoprim or nitrofurantoin

18. Treatment of existing
infections
Choice of empirical therapy:
• Clinical assessment and a reasonable estimate of etiology
• Imp clinical factors include the severity of illness, immune
status, other co-morbidities, & infected prosthetic implants
• Before commencing antibiotic therapy, it is vitally important to
obtain appropriate samples for culture except in meningitis
Broad spectrum vs narrow spectrum:
• Broad-spectrum antibiotics such as β-lactam/β-lactamase
inhibitor combinations, third generation cephalosporins, FQs,
and carbapenems useful for initial empirical therapy in
critically ill patients
• More targeted therapy once C/S reports available

19. Treatment of existing
infections
Broad spectrum vs narrow spectrum:
• Broad-spectrum agents are more likely to lead to
selection of resistant organisms, including fungi
• Third-generation cephalosporins and FQs have the
propensity to cause antibiotic-associated diarrhoea
• Narrow spectrum agents (e.g. penicillin, trimethoprim
and flucloxacillin) are preferred, where possible, less
likely to develop resistance and less likely to be
associated with Clostridium difficile

20. Route of administration
• To be determined by the site and severity of the infection
• Eg: Mild impetigo affecting a small area of skin can be treated
by short-term topical antibiotics
• Choice of oral or IV therapy will depend on:
drug levels required at the site of infection
potential for absorption from the GI tract
severity of the disease process
• Eg: Ciprofloxacin has good bioavailability when taken enterally,
and results in similar blood levels and AUC values compared
with IV administration (absorption may be reduced by antacid
use)

21. Duration of treatment
• Continued until resolution of the infection is achieved.
• This can be judged by means of a clinical assessment, for
example:
improvements in gas exchange
resolving pyrexia
Decreasing secretions
resolution of infiltrates in CXR in VAP
• This clinical information supplemented with lab data such as:
decreasing white cell counts
C-reactive protein assays
• The duration of therapy required varies enormously between
different anatomical sites and organisms

22. Microscopy and culture
• Early microbiological information of appropriate body fluid
samples eg. blood, urine or CSF
• A count of white blood cells, red blood cells or epithelial cells
according to sample type allows an assessment of
inflammation and sample quality
• Gram’s staining allows an assumption of the likely organism
type, thus providing an early opportunity for the selection of
empirical antibiotic therapy
• Bacterial culture is integral to microbiological practice, since it
enables empirical treatments to be refined to agents that may
be less toxic, cheaper, or more effective
• Non-culture techniques, including nucleic acid amplification
tests, are now being performed to identify bacteria and their
resistance genes

23. Susceptibility tests
• Disc diffusion tests: Discs with known antibiotic concentrations
are applied to the agar plate and incubated in standard conditions
for 18–24 h. Interpretation of susceptibility is determined by
comparing the diameter of the zones of inhibition around the
antibiotic disc with published data for susceptible and resistant
organisms
• Broth and agar dilution methods: use a standardized amount of
organism incubated in doubling dilutions of culture media in
standard conditions for 18–24 h. The lowest concentration at which
no growth occurs is referred to as the MIC
• E-test: uses a pre-defined gradient of antibiotic within a plastic
strip; applied onto an agar plate inoculated with the test organism
and incubated. This test gives an accurate MIC comparable with agar
or broth dilution tests and is technically less demanding

24. Antibiotic assays
• Antibiotic serum levels are performed for:
to prevent the development of toxic levels
to ensure that levels are therapeutic
to assess compliance with drug regimes ( predominantly TB
treatment courses)
• Commonly performed during aminoglycoside therapy
• Alternatively, they can be more complex ‘microbiological
assays’ or ‘back-assays’ in which samples of a patient’s plasma
containing the administered antibiotics are combined with
standardized concentration of the infecting organism; rarely
performed because results are inconsistent and difficult to
interpret

25. Conclusion
• Understanding of the role of PK and PD parameters
allows for greater efficacy in the use of current
antibiotics and may reduce the development of
resistance
• Reductions in the amount of overall antibiotic use,
greater use of narrow-spectrum agents, and ensuring
compliance with therapy may also reduce the
development of resistance
• Use of routine chemoprophylaxis should be considered
carefully with reference to recognized guidelines
• Appropriate use of the microbiology laboratory is central
to correct antibiotic usage and guides the use of correct
agents and dosage to ensure efficacy and avoid toxicity