C H A P T E R

Rational for Antibiotics – Guidelines

2 Mangesh Tiwaskar, Tanuja Manohar

AN OVERVIEW OF BACTERIAL INFECTION prevented or treated infections that occur in patients

Bacteria, ubiquitous in nature, play an important role in with chronic diseases such as diabetes, end-stage renal
maintaining the environment in which we reside. Only a disease or rheumatoid arthritis, complex surgeries
small percentage of the world’s bacteria cause infection such as organ transplants, joint replacements or cardiac
and disease. Bacteria are grouped as Gram positive and surgery and in patients with chemotherapy treatments.15
Gram negative based on the characteristics of their cell Studies with antibiotics have also shown unexpected non-
wall, as observed under a microscope after Gram staining antibiotic effects that indicate a variety of other biological
(developed by HC Gram in 1882). Some bacteria which activities. The results exhibited a significant number of
cannot be classified by Gram staining, e.g. Mycobacteria, additional therapeutic applications of “antibiotics” as
requires special staining. Bacteria can also be classified antiviral, antitumor or anticancer agents. In some cases,
as aerobes, obligate aerobes, facultative anaerobes and the alternative administrations have surpassed those of
obligate anaerobes, based on their need for oxygen to antibiotic activity in importance, such as in the treatment
grow.3 of cardiovascular disease or use as immunosuppressive
agents. Unfortunately, the enormous requirement of
Clinical manifestations of bacterial infections: The these valuable drugs had a significant downside.1
human body, which contains about 1013 cells, routinely
harbors about 1014 bacteria called as normal microbial ANTIBIOTIC RESISTANCE - MAGIC BULLETS AND MOVING
flora. 4 Though all of the human organs are susceptible TARGETS
to bacterial infection, most often microorganisms stay in The successful use of any therapeutic agent is always
harmony with the host through mutual or commensal followed by the potential development of resistance to
interactions.3,5 Each bacterial species has a predilection that agent from the time it is first employed.1 Alexander
to infect certain organs and not others. For e.g. Neisseria Fleming, who won a Nobel Prize for his discovery of
meningitidis usually infects the meninges of the central Penicillin, had warned about the perils of antibiotic
nervous system causing meningitis or can infect the lungs resistance.16 True to this prediction, resistance began to
causing pneumonia, however, it does not cause skin arise within 10 years of the large scale introduction of
infection.3 Penicillin.17 Initially, drug-resistant strains appeared in
Infectious disease is the clinically evident illness (viz. the hospitals, where most antibiotics were being used.
signs and symptoms) resulting from the infection, Streptococcus pyogenes resistant to Sulfonamide emerged
presence and growth of pathogenic bacterial agents in in military hospitals in the 1930s while Penicillin Resistant
an individual host organism.5 The list of microorganisms Staphylococcus aureus confronted London civilian
infecting different sites of the human body are mentioned hospitals shortly after the introduction of Penicillin in the
in Figure 1.6,7,8 1940s. Similarly, Streptomycin-resistant Mycobacterium
tuberculosis appeared in the community soon after
ANTIBIOTICS - A BOON TO MANKIND the discovery of this antibiotic.18 Over the years, more
Infection was a major cause of morbidity and mortality, and more microorganisms, exposed to more and more
prior to the development of antibiotics. The treatment antibiotics, eventually developed resistance to nearly all
of infections faced a great challenge during those antibiotics that have been developed.19 (Table 2 enlists the
periods.9 Later in 1928, the discovery of Penicillin, a beta resistance mechanisms of commonly used antibiotics1)
lactam antibiotic, by Alexander Fleming opened up the As a result, the optimism during the initial period of
golden era of antibiotics.10,11,12 It marked a revolution antibiotic discovery was tempered by the appearance of
in the treatment of infectious diseases and stimulated therapeutic resistant bacterial strains.18
new efforts to synthesize newer antibiotics. The period
between 1950s and 1970s is considered the golden era of FACTORS INTENSIFYING ANTIBIOTIC RESISTANCE
discovery of novel antibiotic classes, with very few classes Irrational use of antibiotics contributes to dramatically
discovered since then.11,13 Table 1 enlists the different increasing antibiotic resistance. Irrational antibiotic use
antibiotic classes with its mode of action and target is a worldwide problem that causes significant mortality,
infectious microorganisms.14 morbidity and increased health-care costs.20 Following
are some of the factors that drive antibiotic resistance:
Antibiotics have played a vital role in achieving major
advances in medicine and surgery. It has successfully Clinical over-prescription and public misconceptions:
 7

CHAPTER 2
Fig. 1: Overview of bacterial infections6,7,8

Table 1: Mode of action and target of antibiotic classes

Antibiotic class; example Mechanism of action Activity or target species
Sulfadrugs; Prontosil Inhibition of dihydropteroate Gram +ve bacteria
synthetase
β-lactams; Penicillin Inhibition of cell wall biosynthesis Broad-spectrum activity
Aminoglycosides; Streptomycin Binding of 30S ribosomal subunit Broad-spectrum activity
Chloramphenicols; Chloramphenicol Binding of 50S ribosomal subunit Broad-spectrum activity
Macrolides; Erythromycin Binding of 50S ribosomal subunit Broad-spectrum activity
Tetracyclines; Chlortetracycline Binding of 30S ribosomal subunit Broad-spectrum activity
Rifamycins; Rifampicin Binding of RNA polymerase β-subunit Gram +ve bacteria
Glycopeptides; Vancomycin Inhibition of cell wall biosynthesis Gram +ve bacteria
Quinolones; Ciprofloxacin Inhibition of DNA synthesis Broad-spectrum activity
Streptogramins; Streptogramin B Binding of 50S ribosomal subunit Gram +ve bacteria
Oxazolidinones; Linezolid Binding of 50S ribosomal subunit Gram +ve bacteria
Lipopetides; Daptomycin Depolarization of cell membrane Gram +ve bacteria
Fidaxomicin (targeting Clostridium Inhibition of RNA polymerase Gram +ve bacteria
difficile)
Dairylquinolines; Bedaquiline Inhibition of F1F0 – ATPase Narrow-spectrum activity
(Mycobacterium tuberculosis)
Gram+ve – Gram positive organism, S – Svedbergs unit, DNA – Deoxyribonucleic Acid, RNA – Ribonucleic Acid
Source: Kim Lewis14
 8
Table 2: Modes of resistance of commonly used antibiotics
Antibiotic class (examples) Mode(s) of resistance
β-Lactams (Penicillins, Cephalosporins, Penems, Hydrolysis, efflux, altered target
Monobactams)
Aminoglycosides (Gentamicin, Streptomycin, Phosphorylation, acetylation, nucleotidylation, efflux,
Spectinomycin) altered target
Glycopeptides (Vancomycin, Teicoplanin) Reprogramming peptidoglycan biosynthesis
Tetracyclines (Minocycline, Tigecycline) Monooxygenation, efflux, altered target
Macrolides (Erythromycin, Azithromycin) Hydrolysis, glycosylation, phosphorylation, efflux,
altered target
Lincosamides (Clindamycin) Nucleotidylation, efflux, altered target
INFECTION

Streptogramins (Synercid) C-O lyase (type B streptogramins), acetylation (type A

streptogramins), efflux, altered target
Oxazolidinones (Linezolid) Efflux, altered target
Phenicols (Chloramphenicol) Acetylation, efflux, altered target
Quinolones (Ciprofloxacin) Acetylation, efflux, altered target
Pyrimidines (Trimethoprim) Efflux, altered target
Sulfonamides (Sulfamethoxazole) Efflux, altered target
Rifamycins (Rifampin) ADP-ribosylation, efflux, altered target
Lipopeptides (Daptomycin) Altered target
Cationic peptides (Colistin) Altered target, efflux
Source: Davies J and Davies D 1

patients with non-bacterial infections, a practice

Table 3: Resistance mechanisms of P. aeruginosa
that has important repercussions
Upregulation Resistant to antibiotics
efflux pumps • Polypharmacy - Too many medicines are prescribed
per patient (Lack of trust in or delayed lab results,
MexEF-OprN Carbapenems and Fluroquinolones
fear of clinical failure)
MexCD-OprJ Fluorquinolones and some β-lactams
• Antibiotic injections are used where oral
MexAB-OprM Sulfonamides, β-lactams,
formulations would be more appropriate
Cephalosporins, Fluoroquinolones,
Macrolides, Novobiocin, • Prolonged prophylactic therapy
Tetracycline & Chloramphenicol
• Prolonged empiric antimicrobial treatment without
MexXY-OprM Aminoglycoside clear evidence of infection
Adapted from : Fair RJ et al21
• Failure to narrow antimicrobial therapy when a
There are a plethora of ways by which humans have causative organism is identified
inadvertently escalated the evolution of resistance.21 • Prescriptions do not follow clinical guidelines
Inappropriate prescriptions and over use of antibiotics
contributed to the promotion of bacterial resistance.15 • Patients self-medicate inappropriately
Worldwide, it has been evaluated that half of all medicines • Patients do not adhere to prescribed treatment
are prescribed, dispensed or sold inappropriately,
and that half of all patients fail to take their medicine Antibiotic overprescribing is associated with other
properly.20 An estimated two-thirds of global antibiotic problems, apart from spreading resistance, viz. Increased
sales occur without any prescription, while studies in medicalization of self-limiting infectious conditions,
Indonesia, Pakistan and India show that over 70% of increase of more severe diseases, length of disease, risk
patients are prescribed antibiotics. A vast majority - up of complications, mortality rate, healthcare costs, risk
to 90% - of injections are estimated to be administered of adverse effects and re-attendance due to infectious
unnecessarily.22 The determinants of irrational antibiotic diseases.25
use are mentioned below: 20,22,23,24 Misuse by the food Industry: The use of antibiotics in
• Very short consultation time - does not allow animal feed stocks has also aggravated the spread of
proper diagnosis resistance. Especially, their use for non-curative reasons
such as prophylaxis, metaphylaxis and growth promotion
• Prescription of antibiotics for non-bacterial accounted for up to 50% of all antibiotic consumption in
infections: Clinicians prescribe antibiotics to the early 2000s.21
Diminished pharmaceutical investment: Antibiotic It has a polysaccharide capsule that makes it naturally 9
development is no longer considered to be an economically resistant to phagocytes. About 40% of strains are no longer
wise investment for the pharmaceutical industry as susceptible to Penicillin, and its Penicillin resistance often
they are not as profitable as drugs that treat chronic correlates with resistances to Macrolides, Sulfamides,
conditions, such as diabetes, psychiatric disorders, older Tetracyclines and early generation Cephalosporins.
asthma or gastroesophageal reflux.15 Additionally, The strain is also resistant towards the third-generation
regulatory hurdles have also muted the interest of major antibiotics.21
pharmaceutical companies.21
Clostridium difficile: C. difficile is a Gram-positive, obligate
Human independent resistance: Though there is a anaerobic, spore forming opportunistic pathogen. C.
pronounced human contribution to the evolution of difficile can be community acquired, but has a particularly
bacterial resistance, there is also resistance that occurs in high rate of acquisition in hospitals. Patients hospitalized
nature in the absence of human interference.21 Bacteria for over four weeks have an approximately 50% chance

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

bacteria, is inactivated by the lung surfactant, hence

Good
Poor

Poor it is not useful for the treatment of pneumonia.23,35

Fair
INFECTION

The tissue penetration profile of a few antibiotics

are mentioned in the table below.35
• Bactericidal vs bacteriostatic therapy: An
high doses)
Good (in

antibiotic that is able to kill an organism instead

Good
Good
Good

of inhibiting its growth is preferred in few clinical

settings. These include infections where the
site of infection is not easily penetrated, e.g. in
infections such as meningitis, endocarditis and
Ertapenem

osteomyelitis. Immunocompromised patients, in

Good
Good
Good
Poor

particular neutropenic patients, are also usually

recommended for “cidal” therapy.46

DOSAGE, ROUTE OF ADMINISTRATION AND DURATION

Co-trimoxa-

• The clinician should consider pharmacokinetic

Good

Good
Good
Good
zole

and pharmacodynamic factors in determining the

drug dose.47 The dosage should be high enough to
ensure efficacy and minimize the risk of resistance
selection, and low enough to minimize the risk of
high doses)
Ciprofloxa-

Good (in

dose related toxicity.42

Good
Good
Good
cin

• The clinician should ensure the most appropriate

route of administration in antibiotic treatment. Oral/
enteral route of administration should be preferred
in patients with mild-to-moderate infections.35
Aminogly-

Good (if
normal
cosides

GFR)

When using oral therapy for invasive infections

Poor

Poor
Fair

(such as pneumonia, pyelonephritis, or abscesses),

clinicians should select an agent that has excellent
absorption and bioavailability (i.e., the percentage
CSF – Cerebrospinal Fluid, GFR – Glomerular Filtration Rate
high doses)
Ceftriaxone

of the oral dose that is available unchanged in the

Good (in

Good
Good
Good

serum). Examples of antibiotics with excellent

Table 4: Tissue penetration profile of few antibiotics

bioavailability are Fluoroquinolones, Doxycycline,

Linezolid, Trimethoprim-Sulfamethoxazole
and Metronidazole.23 Clinicians should reserve
intravenous antibiotics for severe infection or
Co-amoxi-

Good
Good

for certain sites such as the CSF, bacteraemia,

Poor

Fair
clav

endocarditis and bone & joint infections.35 New

microbiological or other information (e.g. fever
defervescence for at least 24 hours, marked clinical
high doses)

improvement; low C-reactive protein) should often

Ampicillin

Good (in

Source: Wasserman S et al35

Good
Good
Good

permit a switch to oral antibiotic(s), or switch to

an intravenous narrow spectrum alternative or
cessation of antibiotics (if no infection is present).44
• Antibiotic treatment should generally be continued
Soft tissue
Infection

for a maximum of 5 days or a shorter period if this

Urinary
site

is clinically appropriate; however, some specific

Lung

conditions require a longer course of therapy (viz.

CSF

endocarditis, osteomyelitis etc.)48

 13

CHAPTER 2
Fig. 3: Summary algorithm for rationale prescription of antibiotic therapy

PATIENT FACTORS with caution when benefits overweigh the risks.

The clinician should consider the age of the patient, Penicillins, Cephalosporins and Ethambutol are
immune status, pregnancy and lactation, associated safe in pregnancy. In lactating mothers, Sulfa,
conditions like renal and hepatic function, epilepsy etc. Tetracyclines, Metronidazole, Nitrofurantoin and
while choosing the antibacterial agent.49 Quinolones are contraindicated.39,49
• Age: Patients at both extremes of age handle drugs • Allergy or intolerance - Clinicians should routinely
differently, primarily due to differences in body obtain an evaluation of history of antibiotic allergy
size and kidney function.39 or intolerance.23
• Hepatic and renal function: Usually, dose is • Recent antibiotic use - Eliciting a history of
reduced to prevent accumulation and toxicity in exposure to antimicrobial agents in the recent past
patients with reduced renal or hepatic function. (approximately 3 months) can also help the clinician
However, sometimes doses might need to be in selecting an antimicrobial therapy. Because the
increased to avoid underdosing young healthy causative microorganism for a current episode of
patients with rapid renal elimination or those with infection emerged under the selective pressure of
rapid hepatic metabolism due to enzyme induction a recently used antimicrobial agent, it is likely to
by concomitant use of drugs such as Rifampin.23 be resistant to that drug and/or drug class, and an
alternative agent should be used.23
• Pregnancy and lactation: Human studies on
safety of antibiotics in pregnancy and lactation MONITORING RESPONSE TO THERAPY
are scarce, hence clinicians should prescribe The need for an antimicrobial therapy should be
it with utmost caution.23 Drugs with known reviewed on a daily basis by reviewing laboratory
toxicity or unestablished safety like Tetracyclines, evidence.44,35 Response to therapy depends on the nature
Quinolones, Streptomycin, Erythromycin and sensitivity of the agent, specificity of the drug,
and Clarithromycin are contraindicated in bioavailability and dosage. Longer the doubling time of
all trimesters while Sulfa, Nitrofurantoin and the organism, longer the time it takes to respond. Thus
Chloramphenicol are contraindicated in the last a Streptococcal pneumonia can respond within 24-48
trimester. Drugs with limited data on safety like hours, but tuberculosis may take 28 weeks to respond.
Aminoglycosides, Azithromycin, Clindamycin, The clinician should wait for the adequate period before
Vancomycin, Metronidazole, Trimethoprim, changing the drug (e.g. Streptococcal pneumoniae
Rifampicin and Pyrazinamide should be used infections 24-48 hours; E. coli 24-48 hours; Salmonella
 14 typhi 4-7 days; Mycobacterium tuberculosis 2-8 weeks user/medicine/MMI/Files/Bacteria_Table.pdf, viewed on
etc.). Drugs should be changed midway only when there August 27, 2016.
is absolutely no response or there is no expected response 7. Patras K. Polymicrobial Infections: Perhaps The Rule,
and the sensitivity report also suggests resistance.49 Since Not The Exception. 2013, Available at http://schaechter.
non-compliance is also one of the causes for treatment asmblog.org/schaechter/2013/08/polymicrobial-infections-
failure,50 the clinician should ensure patient adherence perhaps-the-rule-not-the-exception.html, viewed on
to the therapy. Treatment should be continued until all August 27, 2016.
pathogens are eliminated from the tissues or until the 8. Pathogen Regulation Directorate. Pathogen safety data
infection has been sufficiently controlled for the normal sheet-Infectious substances. 2011, Available at http://www.
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