ALKAN HEALTH SCIENCE BUSINESS AND

TECHNOLOGY COLLEGE

Integrated Therapeutics IV (Cr. Hr =4hr)

By: Tsegaye Ababiya
(B.Pharm, MSc candidate in pharmacy practice)

Year IV& semester II

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Learning Objectives

Upon completion of this session, students will be able to:

Recognize about antimicrobial resistance after using it

Differentiate between microbial colonization and infection based on patient history,

physical examination, and laboratory and culture results

Major drug and patient specific considerations when selecting antimicrobial

therapy.

Common causes of patients failing to improve while on antimicrobials

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 1.Infectious diseases
1.1 Principles of Antimicrobials
Introduction
Antimicrobials are among the most widely used classes of drugs.

The use of antibiotics is the main driver in creating selective pressure for the
emergence of antimicrobial resistant pathogens.

Antimicrobials are different from other classes of pharmaceuticals because they

exert their action on bacteria infecting the host as opposed to acting directly on the
host.

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Introduction…..

Because antimicrobial use in one patient affects not only that patient but also
other patients if they become infected with resistant bacteria, correct selection,
use, and monitoring of clinical response are paramount ( e.g MDR TB)
There are two guiding principles to consider when treating patients with
antimicrobials:
(a) make the correct diagnosis and
(b) do no harm! (development of secondary infections can be caused
by selection of antimicrobial-resistant nontargeted pathogens)

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Introduction…..

Antimicrobials vary in their

spectrum of activity,

the ability to inhibit or kill different species of bacteria.

Broad spectrum vs Narrow spectrum

Antimicrobials that kill many different species of bacteria are called broad-
spectrum antimicrobials, whereas
Antimicrobials that kill only a few species of bacteria are called narrow-spectrum
antimicrobials.

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Introduction…..
Over all goal of Antimicrobial therapy

to cure the patient’s infection;

 limit harm by minimizing patient risk for adverse effects, including secondary
infections; and
 limit societal risk from antimicrobial-resistant bacteria.

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Normal Flora and Endogenous Infection

Many areas of the human body are colonized with bacteria—this is known as
normal flora.
 Infections often arise from one’s own normal flora (called an endogenous
infection).

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Normal flora…..mouth, URT,SKIN & ileum……

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Normal Flora……

Endogenous infection

May occur when there are alterations in the normal flora (eg, recent antimicrobial
use may allow for
 overgrowth of other normal flora) or

 disruption of host defenses (eg, a break or entry in the skin).

Knowledge of sites of microbial resides …

Norma anatomic sterile sites (CSF,blood,urine) …

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Colonization versus Infection

Infection refers to the presence of bacteria that are causing disease (e.g., the
organisms are found in normally sterile anatomic sites or in non-sterile sites with
signs/symptoms of infection).

Colonization refers to the presence of bacteria that are not causing disease.
• Only bacteria that cause disease should be targeted with antimicrobial therapy,
and
• non–disease-producing colonizing flora should be left intact.(R)

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Exogenously Acquired Bacterial Infections

Infections acquired from an external source are referred to as

exogenous infections.

These infections may occur as a result of

human-to-human transmission,

contact with exogenous bacterial populations in the environment, and

animal contact

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Exogenously Acquired Bacterial Infections………1

Resistant pathogens such as

methicillin-resistant Staphylococcus aureus (MRSA) and

vancomycin-resistant Enterococcus spp (VRE) may colonize hospitalized

patients or patients who access the health care system frequently.

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Exogenously Acquired Bacterial Infections………2

It is important to know which patients have acquired these organisms because
patients generally become colonized prior to developing infection, and

Colonized patients should be placed in isolation to minimize transmission.

Bacteria may produce toxins or possess characteristics that contribute to their

pathogenicity.

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Virulence Vs resistance

• Both are different microbial characteristics.

• Virulence refers to the pathogenicity or disease severity produced by an organism.

 For example, Streptococcus pyogenes, a common cause of skin infections, produces toxins
that can cause severe disease, yet it is very susceptible to penicillin.

Enterococcus faecium is a highly resistant organism but is frequently a

colonizing flora that causes disease primarily in the immunocompromised.

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Make correct diagnosis

Findings on physical examination, along with the clinical presentation, can help
identify the anatomic location of the infection (exogenous vs endogenous)

Fever is a host response to bacterial toxins

It often accompanies infection and is defined as a rise in body temperature above
the normal 37°C (98.6°F).

Oral and axillary temperatures may underestimate core temperature by at least

0.6°C (1°F), whereas rectal temperatures best approximate core temperatures.
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Correct diagnoses…..

Causes of fever
 Bacteria
 Virus
 Fungi
 Medications (eg, penicillins, cephalosporins, salicylates, and phenytoin),
 Trauma, or
 Medical conditions (eg, autoimmune, malignancy, pulmonary embolism, and
hyperthyroidism)

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Correct diagnoses…..

Some patients with infections may present with hypothermia (eg, patients with
overwhelming infection).

Elderly patients may be afebrile, as may those with localized infections (eg,
urinary tract infection).

 For others, fever may be the only indication of infection.

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Correct diagnoses…..

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Correct diagnoses…..

Imaging studies also may help to identify anatomic localization of the infection.

Radiographs are performed commonly to establish the diagnosis of pneumonia, as

well as to determine the severity of disease.

CT scans are a type of x-ray that produces a three-dimensional image of the
combination of soft tissue, bone, and blood vessels.

 In contrast MRI uses electromagnetic radio waves to produce two- or three-

dimensional images of soft tissue and blood vessels with less detail of bony structures

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 Non-microbiologic Laboratory Studies

WBC and differential………….(Increases in response to infection, but may be decreased owing to

overwhelming or long-standing infection).

Erythrocyte sedimentation rate (ESR),

C-reactive protein (CRP) and

Procalcitonin levels

Neutrophils in response to physiologic stress, leave the bloodstream and enter the tissue to “fight”
against the offending pathogens (ie, leukocytosis).

It is important to recognize that leukocytosis is nonspecific for infection and may temporarily occur

in response to noninfectious conditions such as acute myocardial infarction .

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Correct diagnoses…..

During an infection, immature neutrophils (eg, bands) are released at an increased

rate to help fight infection, leading to what is known as a “bandemia” or “left
shift”.

Some patients may present with a normal total WBC with a left shift (eg, the
elderly).

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Correct diagnoses…..

ESR and CRP

 are nonspecific markers of inflammation
 increase as a result of the acute-phase reactant response, response to inflammatory stimuli
such as infection or tissue injury.
 may be used as markers of infectious disease response because they are elevated when the
disease is acutely active and usually fall in response to successful treatment.
• Clinicians may use these tests to monitor a patient’s response to therapy in
osteomyelitis and infective endocarditis.
• These tests should not be used to diagnose infection because they may be elevated
in noninfectious inflammatory conditions.

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Correct diagnoses…..

Procalcitonin,

A prohormone of calcitonin, is rapidly produced in response to bacterial infection.

Serum levels in conjunction with clinical findings are increasingly being utilized
to assess both the need to initiate antibiotic therapy as well as determine when
antibiotic therapy may be safely discontinued

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Microbiologic Studies

• Allow for direct examination of a specimen (eg, sputum, blood, or urine) may aid
in a presumptive diagnosis and give an indication of the characteristics of the
infecting organism.

• A Gram stain is performed to identify

whether bacteria are present and

morphologic characteristics of bacteria (eg, gram-positive or gram-negative

and shape—cocci, bacilli).

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Microbiologic Studies

Certain specimens do not stain well or at all and must be identified by alternative
staining techniques (Mycoplasma spp., Legionella spp., Mycobacterium spp.)

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Microbiologic Studies

Presence of WBCs on a Gram stain indicates

inflammation and suggests that the

identified bacteria are pathogenic.

The Gram stain may be useful in evaluating a sputum specimen’s adequacy (e.g,
the presence of epithelial cells on sputum Gram stain suggests that the specimen is
either poorly collected or contaminated)…….gives to misleading information
AND inappropriate antimicrobial use.

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Culture and susceptibility

Gives additional information to the clinician to select appropriate therapy

The minimum inhibitory concentration (MIC) is a standard susceptibility test.

The MIC is the lowest concentration of antimicrobial that inhibits visible bacterial
growth after approximately 24 hours.

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Culture and susceptibility………..

Breakpoint and MIC values determine whether the organism is

 susceptible (S),

 intermediate (I), or

 resistant (R) to an antimicrobial

• The breakpoint is the concentration of the antimicrobial that can be achieved in

the serum after a standard dose of that antimicrobial.

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Culture and susceptibility………..

If the MIC is below the breakpoint, the organism is considered to be susceptible to that
agent.

 If the MIC is above the breakpoint, the organism is said to be resistant.

In general, bacterial cultures should be obtained prior to initiating antimicrobial therapy
in patients with a
 systemic inflammatory response,

 risk factors for antimicrobial resistance, or

 infections where diagnosis or antimicrobial susceptibility is uncertain.

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Culture and susceptibility………..

Cultures and susceptibility testing are routine for

sterile-site specimens (eg, blood and spinal fluid), as well as for

 material presumed to be infected (eg, from joints and abscesses).

NB! Cultures need to be interpreted with caution.

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Treatment
Non-antimicrobial Treatment
Adequate hydration,
Ventilatory support, and
Supportive medications.
Source control

involve the removal of prosthetic materials such as catheters and infected

tissue or drainage of an abscess
fundamental component of any infectious diseases treatment.

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Tx…. Do not harm!

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Spectrum of activity and Effects on Non-targeted Flora

Empirical therapy should be based on patient- and antimicrobial-specific factors

such as the
 anatomic location of the infection,

 the likely pathogens associated with the presentation,

 the potential for adverse effects in a given patient, and

 the antimicrobial spectrum of activity.

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Spectrum of activity and Effects on Non-targeted Flora

Antimicrobials are vary in their spectrum of activity, the ability to inhibit or kill different species of bacteria
 Broad spectrum

 Narrow spectrum

In acute setting, patients who receive appropriate initial antimicrobial therapy survive at twice the rate of

patients who receive inadequate therapy

Empirical selection of antimicrobial spectrum of activity should be related to the severity of the illness
- Acutely ill patients require broader-spectrum antimicrobial coverage

- less ill patients may be managed initially with narrows spectrum therapy

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Spectrum of activity and Effects on Non-targeted Flora

Collateral damage is defined as the development of resistance occurring in a patient’s

non-targeted flora that can cause secondary infections.
e.g.Clostridium difficile infection (CDI) is an example of a disease that occurs secondary to
collateral damage.

Antibiotics can increase the risk of CDI by suppressing normal intestinal flora, resulting
in overgrowth of the non-susceptible C. difficile bacteria.

In addition, CDI is associated with the prior use of broad-spectrum antibiotics;
particularly fluoroquinolones,cephalosporins,clindamycins
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Single versus Combination Therapy

Two opponents
• Double coverage may be synergistic, prevent the emergence of resistance and
improve outcome.

• However, there are few clinical examples in the literature to support these assertions

• E.g, double coverage is considered superior are limited to infections associated with
large bacterial loads and in species that are known to readily develop resistance such
as active tuberculosis or enterococcal endocarditis.

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Single versus Combination Therapy

Combination therapy increased the likelihood of appropriate empirical coverage;

however, once organism susceptibilities were known, there was no difference in
outcome between double coverage and monotherapy

Double antimicrobial coverage with two agents of similar spectra of activity may
help in infections associated with high bacterial loads or for initial empirical
coverage of critically ill patients in whom antimicrobial-resistant organisms are
suspected.

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Antimicrobial Dose

Dosage regimens may be different depending on the infectious process.

ciprofloxacin, a fluoroquinolone, has various dosage regimens based on site of

infection.

The dosing for uncomplicated UTIs is 250 mg twice daily for 3 days.

For complicated UTIs, the dose is 500 mg twice daily for 7 to 14 days.
Severe complicated pneumonia requires a dosage regimen of 750 mg twice daily
for 7 to 14 days. (proven efficacy and are most likely to minimize harm)

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Pharmacokinetics

PK-refers to a mathematical method of describing a patient’s drug exposure in

vivo in terms of ADME.

Bioavailability(F)- refers to the amount of antimicrobial that is absorbed orally

relative to an equivalent IV dose administered.
Drug related factors which affect F include:-
 formulation of the antimicrobial,
 dosage form, and
 stabilityof the drug in the gastrointestinal (GI) tract

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PK….

Patients with systemic signs of infection such as hypotension should receive IV

antimicrobials to ensure drug delivery as absorption is affected by GI blood flow.

 In cases where patients have a functioning GI tract and are not hypotensive,
antimicrobials with almost complete bioavailability (>80%) such as the
fluoroquinolones, fluconazole, and linezolid may be given orally.

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PK….

In sequestered infections, where higher systemic concentrations of antimicrobial

may be necessary to reach the infected source (eg, meningitis) or for
antimicrobials with poor bioavailability, IV formulations should be used.

Some antimicrobials may be bound to proteins in serum.

Only unbound drug is biologically active and distributes freely between tissues.

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PK……

Protein binding is clinically relevant in highly protein-bound antimicrobials

(greater than 50%) as the agents may not be able to penetrate sequestered

compartments, such as cerebral spinal fluid, resulting in insufficient

concentrations to inhibit bacteria.

some drugs may not achieve sufficient concentrations in specific compartments
based on distribution characteristics.

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PK…

E.g. Legionella pneumophila, an organism that causes severe pneumonia, is

known to survive and reside inside pulmonary macrophages.

Treatment with an antibiotic that inhibits bacterial cell wall synthesis, such as a
cephalosporin, will be ineffective because it only distributes into extracellular host
tissues.
 macrolide or fluoroquinolone antimicrobials, which concentrate in human pulmonary
macrophages, are highly effective against this organism

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Pharmacodynamic Properties

PD-describes the relationship between drug exposure and pharmacologic effect of

antibacterial activity or human toxicology.

Antimicrobials are categorized based on their concentration-related effects on

bacteria.

Concentration dependent pharmacodynamic activity occurs where higher drug

concentrations are associated with greater rates and extents of bacterial killing.

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PD…

• Concentration-dependent antimicrobial activity is maximized when peak antimicrobial

concentrations are high.

• In contrast, concentration-independent (or time-dependent) activity refers to a minimal

increase in the rate or extent of bacterial killing with an increase in antimicrobial dose.

• Concentration-independent antimicrobial activity is maximized when these

antimicrobials are dosed to maintain blood and/or tissue concentrations above the MIC
in a time-dependent manner.

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PD…

Examples of antimicrobials that exhibit concentration dependent activity,

Fluoroquinolones,

aminoglycosides, and

metronidazole

Antimicrobials that exhibit concentration-independent activity

β-lactam and

glycopeptide

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PD optimization

Pharmacodynamic properties have been optimized to develop new strategies for

older antimicrobials.
Examples include
single daily- dose aminoglycoside
β-lactam therapy administered by continuous or extended infusion

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Bactericidal VS bacteriostatic activity in vitro

…..cidal antibiotics generally kill at least 99.9% of a bacterial population,

…..static antibiotics possess antimicrobial activity but reduce bacterial load by

(99.9%).

 Clinically bactericidal antibiotics may be necessary to achieve success in

infections such as endocarditis or meningitis.

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AE and DI Properties

Antimicrobials with a low propensity to cause adverse events should be selected,

particularly for patients with risk factors for a particular complication.

Co-administration of the known nephrotoxic gentamicin with vancomycin increases the

risk for nephrotoxicity.

Other drug interactions may predispose the patient to dose-relate toxicity through
inhibition of drug metabolism.
 E.g. erythromycin has the potential to prolong cardiac QT intervals in a dose-dependent manner,
potentially increasing the risk for sudden cardiac death

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Patient Considerations in Antimicrobial Selection

Recent previous antimicrobial exposures,

Identification of the anatomic location of infection through physical examination and

diagnostic imaging,

History of drug allergies, pregnancy or breast-feeding status, organ dysfunction that

may affect drug clearance,

Immunosuppression, compliance, and

The severity of illness

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Host Factors

Age

Populations with diminished renal function include neonates and the elderly.

Hepatic function in the neonate is not fully developed, and drugs that are
metabolized or eliminated by this route may produce adverse effects.

E.g. sulfonamides and ceftriaxone may compete with bilirubin for binding sites
and may result in hyperbilirubinemia and kernicterus.

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 Age …

Gastric acidity also depends on age; the elderly and children < 3 years tend to be
achlorhydric.
 Drugs that need an acidic environment (eg, ketoconazole) are not well absorbed,
and those whose absorption is enhanced in an alkaline environment will have
increased concentrations (eg, penicillin G).
Site of infection & common pathogens
 E.g., CAP is caused most commonly by Streptococcus pneumoniae,
 E. coli is the primary cause of uncomplicated UTIs, and
 staphylococci and streptococci are implicated most frequently in skin and skin-structure
infections (e.g, cellulitis)

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Failure to Antimicrobial Therapy

Inadequate diagnosis Previous hospitalization or

 Poor source control
health care utilization
New infection with a resistant organism
eg, residing in a nursing home,
 Inappropriate dosing
hemodialysis, and
Patient compliance and

Drug interactions outpatient antimicrobial therapy

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Allergy

Penicillin - related allergy is common and can be problematic because there is an approximately 4%
cross-reactivity with cephalosporins as well as carbapenems.

Patients with mild or nonimmunologic reactions to penicillins may receive a β-lactam antimicrobial with
low cross-reactive potential (such as cephalosporins).

Patients with a history of findings consistent with IgE-mediated reactions such as

anaphylaxis,

urticaria, or

bronchospasm ……..should not be administered any type of β-lactam antimicrobial, including

cephalosporins.

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Allergy……..

Desensitization ( INH,Cotrimoxazole)???

Monobactams (ie, aztreonam) may be administered to patients with IgE-mediated

allergic reactions to penicillin.

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DDI

Drug interactions between antimicrobials and other medications may occur via the
 cytochrome P-450 system,
 protein-binding displacement, and
 alteration of vitamin K–producing bacteria.
Medications that commonly interact with antibiotics include, but are not limited to,
 warfarin,
 rifampin,
 phenytoin,
 digoxin,
 theophylline,
 multivalent cations (eg, calcium, magnesium, and zinc), and sucralfate.

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DDI…..Results

Increased concentrations of one or both agents,

Increasing the risk of adverse effects or additive toxicity.

A key consideration in selecting antimicrobial regimens starts with

obtaining a good patient medical and drug history,

recognizing drug-specific adverse-event characteristics, and

anticipating potential problems proactively.

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Pregnancy and Antimicrobials

Must be used with caution in pregnant and nursing women.

Some agents pose potential threats to the fetus or infant (eg, quinolones,
tetracyclines, and sulfonamides).

For some agents, avoidance during a specific trimester of pregnancy is warranted

(eg, the first trimester with trimethoprim/ sulfamethoxazole)
• PK variables alteration.. clearance and volume of distribution are increased during
pregnancy….increasing the dosage or frequent administration of certain drugs is
needed to achieve adequate concertation.

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Out come evaluation

After selection and initiation of an antimicrobial regimen, there are

additional patient care and monitoring considerations that should be
addressed to improve the likelihood of a successful outcome.
Patient education,

de-escalation of antimicrobial therapy based on culture results,

monitoring for clinical response and adverse effects, and

appropriate duration of therapy are important

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References

1. Marie A. Chisholm-Burns; Pharmacotherapy principles and practice ,5th ed.

McGraw-Hill Education,2016 pdf.

2.Caroline S. Zeind; Applied Therapeutics 11th ed. Wolters Kluwer,2017 pdf.

3. Dipro J. Pharmacotherapy A Phathophsyiologic Approach. 11th ed. New York,

NY: Mc GrawHill; 2016.

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 Thank
you !!!
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