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CHAPTER 2
Fig. 1: Overview of bacterial infections6,7,8
CHAPTER 2
can be either intrinsically resistant to certain antibiotics or of contracting C. difficile, a known causative agent for
can also acquire resistance to antibiotics.26 antibiotic associated diarrhoea.21 A study by Pepin J et al. 29
showed that administration of fluoroquinolones emerged
The legacy of the past decades in terms of antibiotic use
as the most important risk factor for Clostridium difficile-
and misuse has added to the development of bacterial
associated-diarrhea caused by a hypervirulent strain of C.
resistance towards multiple drugs.18
difficile.
SUPERBUGS AND SUPER-RESISTANCE β-lactam and Quinolone Resistant Enterobacter:
Many of the bacterial pathogens related with the epidemics Enterobacter is a genus of Gram-negative, facultative
of human disease, subsequent to antibiotic use, have anaerobic, opportunistic pathogens. They are mainly
evolved into multidrug-resistant (MDR) forms. The term known to exhibit antibiotic resistance through expression
“superbugs” refers to microorganisms with heightened of an extensive variety of extended spectrum β-lactamases
morbidity and mortality due to multiple mutations (ESBLs) and Carbapenemases including, Klebsiella
conferring high levels of resistance to the antibiotic classes pneumoniae Carbapenemase, Oxacillinases and several
specifically recommended for their treatment.1 metallo-β-lactamases (MBLs).21
Staphylococcus aureus (MRSA, VISA and VRSA): S. MDR Pseudomonas aeruginosa: P. aeruginosa is a gram-
aureus, a Gram positive, facultative anaerobic pathogen negative, facultative anaerobic, opportunistic pathogen.
with both hospital and community acquired strains, is one It naturally has a host of siderophores (Fe3+ carriers)
among the most notorious superbugs.1,21 Following the and pigments that allow it to evade the innate immune
discovery of Penicillin, it seemed that S. aureus infections system. Furthermore, it has particularly discriminating
were controllable; however, it proved to be a short- outer membrane porins that make its outer membrane
lived one. The landmark discovery and introduction of impermeable and thus naturally resistant to many
Methicillin was anticipated to be a sure defense against the antibiotics. It has a high propensity to form biofilms that
penicillinases, but the appearance of Methicillin-resistant can increase resistances to antibiotics by 100 to 1000 fold.
S.aureus (MRSA) within 3 years inexorably led to other P. aeruginosa also has an extremely comprehensive efflux
multiantibiotic-resistant variants.1 MRSA is resistant pump system. Upregulation of the efflux pumps results in
to certain antibiotics, such as Methicillin, Dicloxacillin, resistance to an array of antibiotics. 21 (Table 3)
Oxacillin, Cloxacillin, Nafcillin and closely related classes
of drugs, such as Cephalosporins. The use of more Resistant Escherichia coli: Antibiotic resistance of E. coli
powerful drugs than necessary for less serious infections has risen rapidly due to horizontal gene transfer. ESBL
could be a cause of MRSA expansion.27 The development positive strains in bacteraemias have shown high cross
of resistance has led to the frequent use of Vancomycin resistance to Cephalosporins, Fluoroquinolones and
to treat MRSA infections. This greatly increased selective Gentamicin. E.coli strains in multiple continents have also
pressure has resulted in the emergence of MRSA isolates acquired the New Delhi Metallo-β-lactamase-1 (NDM-1)
with reduced susceptibility to Vancomycin (Vancomycin enzyme from Klebsiella pneumoniae, which confers a
intermediate Staphylococcus aureus - VISA strains) and to broad resistance to all β-lactams including Carbapenems
the appearance of Vancomycin-resistant S. aureus (VRSA except for Monobactam and Aztreonam.21
strains) with high-level resistance to Vancomycin.28 MDR Acinetobacter, MDR and Pan-drug-resistant
Resistant Enterococci Including VRE: Resistant Klebsiella pneumoniae, Resistant Neisseria Gonorrhoeae
Enterococci primarily comprises of two species, E. & Mycobacterium tuberculosis (MDR-TBTB and XDR-
faecalis and E. faecium, both of which are Gram-positive, TBTB) are the other vital resistant bacteria dominating the
facultative anaerobic, opportunistic pathogens. Both E. headlines of alarming resistance.21
faecalis and E. faecium have high levels of resistance rates The growing numbers of antimicrobial-resistant
(30–50%) against the aminoglycosides Gentamicin and pathogens place a significant burden on healthcare
Streptomycin.21 systems and have important global economic costs. It
Streptococcus pneumoniae: S. pneumoniae is a Gram- results in high mortality and morbidity rates, increased
positive, aerotolerant, anaerobic, opportunistic pathogen. treatment costs, diagnostic uncertainties and lack of trust
10 infection by advising for a microbiological testing (staining
of secretions/fluids/exudates, culture and sensitivity,
serological tests and other tests).39 Microbiological testing
helps to identify the specific etiologic agent and provides
information about the in-vitro activity of antimicrobial
drugs against the microorganisms identified.40 It also
assists the clinicians to decide whether the patient should
be prescribed antibiotics, as they are often under pressure
from patients who believe they need antibiotics. A
negative microbiology test report can make it easier for the
clinician to refuse unnecessary prescription of antibiotic.
Additionally, if the patient needs treatment immediately,
the test results can help in choosing the most appropriate
INFECTION
agent.41
Fig. 2: Common illness which requires Antibiotic therapy38 Empirical therapy: Clinician should reserve empirical
therapy for critical patients, where time is inadequate
for identification and isolation of the infection causing
in orthodox medicine.30 Considering the complications bacteria.39 Empiric prescribing is based on the clinicians
associated with increasing antibiotic resistance, its high working knowledge or experience of what is most likely
time to promote judicious and optimized use of antibiotics to be the pathogen causing the patient’s condition. E.g.
worldwide. certain elements of the presenting illness (such as site
GUIDELINES FOR ANTIBIOTIC STEWARDSHIP of infection) can help the clinician to predict a broad
The rise of antibiotic-resistant bacteria, which represents group of pathogens such as: skin and soft tissue: Gram
a serious threat to public health, can be overcome by positive cocci, urinary tract: Gram negative bacilli, intra-
promoting the optimized use of existing antibiotic agents abdominal: Gram-negative, Gram-positive and anaerobic
and preventing transmission of drug-resistant organisms organisms.35 Therefore, a common approach can be
through control of infection.31,32 Rationalizing the use prescribing a broad-spectrum antibiotic agent as initial
of antibiotics is an important patient safety and public empiric therapy with an intention to cover multiple
health issue in addition to being a national priority.33 possible pathogens commonly associated with the specific
The following guidelines can help clinicians to ensure clinical syndrome.23
appropriate use of antibiotic therapy. Simultaneously, the clinician should ensure that the
Evaluate the infection by clinical diagnosis: The samples for microbiological testing are collected before
communication occurring within the consultation starting the empirical therapy.42 Once microbiological
influences the treatment decision both for and against results have aided in identifying the etiological agent,
antibiotic prescription.34 Initial clinical diagnosis of every attempt should be made by the clinician to narrow
an infection should always precede the clinician’s the spectrum of the antibiotic.23
decision to prescribe antibiotics.35 The clinician should Prophylactic therapy: Antibiotic prophylaxis should
always consider whether or not antibiotic therapy is be prescribed to susceptible patients to prevent specific
even necessary for the patient by weighing the benefits infections that can cause definite detrimental effects.39
(efficacy, rapid recovery and comfort of patient) against Susceptible patients include pre-surgical patients,
the risks (antibiotic resistance, adverse effects) and costs immunocompromised patients and patients with traumatic
of treatment. At the same instance, clinician should also injuries.23 The selection of an antibiotic for prophylaxis
keep in mind that many infections are self-limiting and should be based on known or likely target pathogens,
that most of the patients just require supportive therapy for a short duration of time. A single dose of antibiotic
to deal with the symptoms.36 It is of utmost importance should be recommended for surgical prophylaxis. Long-
to highlight that a clinician should never prescribe term prophylaxis should be administered only when
antibiotics for non-bacterial infections such as cold, flu & the benefits outweigh the risk of resistance selection or
sore throats. Antibiotics tackle bacteria and hence should propagation.42
be restricted for the treatment of bacterial infections
only.37,38 (Figure 2) Criteria for choosing an antibiotic drug: Appropriate
antibiotic selection is vital to facilitate successful
Select an appropriate antibiotic therapy: Following treatment of infections and minimize the development of
a proper clinical diagnosis, a clinician should decide antibiotic resistance.43 Once the etiology of an infection is
whether to direct a patient to a definitive therapy or an known, the clinician should recommend a most narrow
empirical therapy or a prophylactic therapy. spectrum antibiotic which is cost-effective and least toxic
Definitive therapy: When the etiology of the infection for the shortest duration possible.36 While prescribing
is known, the clinician should proceed with definitive an antibiotic, clinicians should consider the following
therapy. Firstly, the clinician should confirm the bacterial treatment guidelines:
EFFICACY (Vancomycin/Teicoplanin) and Sulphamethoxazole 11
• Narrow spectrum or broad spectrum: The + Trimethoprim.44
spectrum of the antibiotic selected by the clinician • When critically ill patients require empiric
should be the narrowest to cover known or likely therapy before bacteriological diagnosis:
pathogens. For instance, patients undergoing Combination therapy can be used in hospital-
procedures associated with high infection rates, associated infections to ensure that at least 1 of
those involving implantation of prosthetic material the administered antibiotic agents will be active
and those in whom the consequences of infections against the suspected organism(s). E.g. if a patient
are serious should receive perioperative antibiotics. hospitalized for several weeks develops septic
The prophylactic antibiotic(s) should cover the most shock and the blood culture reports the growth
likely organisms and be present in the tissues when of Gram-negative bacilli, it would be appropriate
the initial incision is made, with adequate serum to provide initial therapy with 2 agents that have
concentrations maintained during the procedure.
CHAPTER 2
activity against Gram-negative bacilli, particularly
In such situations, a single dose of a Cephalosporin P. aeruginosa, which is both a common nosocomial
(such as Cefazolin) administered within 1 hour pathogen and frequently resistant to multiple
before the initial incision is appropriate for most agents. Thus in this scenario, a combination of an
surgical procedures; this practice targets the most antipseudomonal β-lactam with a fluoroquinolone
likely organisms (i.e., skin flora), while avoiding or aminoglycoside could be advisable.23
unnecessary broad-spectrum antimicrobial
therapy.23 • To extend antibiotic spectrum during
polymicrobial infections: When infections are
However, in scenarios where the causative agent is caused by polymicrobes (more than one organism),
not known and a delay in initiating therapy would a combination therapy can be preferred as it would
be life-threatening or risk serious morbidity, broad extend the antimicrobial spectrum beyond that
spectrum antibiotics, based on the likelihood of achieved by a single agent. Most intra-abdominal
the pathogen(s), should be prescribed.44 Clinician infections are usually caused by multiple organisms
should also make it a point to de-escalate the with a variety of Gram-positive cocci, Gram-negative
regimen as soon as the etiological agent is known.35 bacilli and anaerobes. Antimicrobial combinations,
• Monotherapy or combination therapy: In order to such as a third-generation Cephalosporin or a
evade antagonism between drugs and undesirable Fluoroquinolone plus Metronidazole, can be used
side effects of several antibiotics, it is prudent to as a potential treatment option in these cases
use a single agent wherever possible in antibiotic and can sometimes be more cost-effective than a
treatment.44 However, there are situations when comparable single agent (e.g., a Carbapenem).23
the use of an antibiotic combination is desirable. Bronchiectasis, peritonitis, urinary tract infections
The situations are: and otitis media are the conditions considered as
polymicrobial infections.39
• To achieve synergistic effect against the infection:
Synergy of antimicrobial agents infers that the • To prevent the development of bacterial resistance
combined effect of the agents is greater than with long term therapy: The development of
the sum of their independent activities when resistant mutants in a bacterial population is the
measured separately. For instance, in the treatment result of selective pressure from antibiotic treatment.
of serious infections for which rapid killing is While combining antibiotics with 2 different
essential, the combination of certain β-lactams mechanisms of action, the chance of a mutant
and aminoglycosides exhibits synergistic activity strain being resistant to both antimicrobial agents
against a variety of Gram-positive and Gram- is much lower than the chance of it being resistant
negative bacteria (e.g. combination of Penicillin to either one. Additionally, use of combination
and Gentamicin to treat endocarditis caused by therapy prevents the resistant mutant population
Enterococcus species). The addition of Gentamicin from emerging as the dominant strain and causing
to Penicillin has been shown to be bactericidal, therapeutic failure. This is the reason why,
whereas Penicillin alone is only bacteriostatic and combination therapy is considered as a standard
Gentamicin alone has no significant activity.23 for the treatment of infections like tuberculosis
and the human immunodeficiency virus, where
• Combination therapy also shortens the course of treatment duration is prolonged, resistance can
antibiotic therapy, e.g. combination of Penicillin or emerge relatively easily and therapeutic agents are
Ceftriaxone with Gentamicin for 2 weeks results in limited.23
more rapid clearance of the infecting microorganism
as compared to Penicillin or Ceftriaxone alone for 4 • Efficacy at the site of infection & tissue penetration
weeks.23 Other combinations that act synergistically – An antibiotic which is effective at the infected
are as follows: β–lactam antibiotic + β–lactamase site and exhibits adequate target tissue penetration
inhibitor, β–lactam antibiotic + Glycopeptide should be the preferred therapy.45 Antimicrobial
12 concentrations attained at some sites (namely,
Daptomycin
ocular fluid, cerebrospinal fluid (CSF), abscess
Good
Good
Poor
Poor
cavity, prostate and bone) are often much lower
than serum levels. For example, first- and second-
generation Cephalosporins and Macrolides are
not recommended for central nervous system
Linezolid infections as they do not cross the blood-brain
Good
Good
Good
Good
barrier. Fluoroquinolones are preferred oral agents
for the treatment of prostatitis because they achieve
high concentrations in the prostate. Daptomycin, an
excellent bactericidal agent against Gram-positive
Meropenem Vancomycin
Good
Poor
Good
Good
Good
zole
Good (in
Good (if
normal
cosides
GFR)
Poor
Fair
Good
Good
Good
Good
Good
Fair
clav
Good (in
CHAPTER 2
Fig. 3: Summary algorithm for rationale prescription of antibiotic therapy
remind patients to avoid sharing of medications with 10. Antibiotics: One of the Greatest Discoveries of the 20th
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An example of the rationale usage of antibiotic is
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CONCLUSION
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