Anti-microbials therapy and complications.pptx

ANTI-
MICROBIAL
S
Best regards,
Ms. Sushma kaphle
Lecturer, Department of
Pharmacology
KAHS, Jumla

ANTIMICROBIAL DRUGS
Anti-Microbials agents (AMA) are the synthetic as well as naturally
obtained drugs that attenuate microorganism.
Antimicrobial therapy takes advantages of the biochemical
differences that exist between microorganisms and human beings.
Antimicrobials drugs are effective in treatment of infections because
of their selective toxicity; that is, they have ability to injure or kill an
invading micro-organism without harming the cells of the host.

SELECTION OF MICROBIAL
AGENTS
Selection of most appropriate antimicrobial agents requires:
1. Identification of Infecting organism
2. Empiric therapy prior to identification of infecting organism
3. Determination of antimicrobial susceptibility of infective organism
4. Effect of site on infection on therapy: The Blood Brain Barrier
5. Patient factors
6. Safety of the agent
7. Cost of therapy

1. IDENTIFICATION OF
INFECTING ORGANISM
A rapid assessment of the nature of the pathogen can sometime be
made on the basis of nature of the gram strain, which is particularly
useful in identifying the presence and morphologic features of
microorganism in body fluids.
However it is generally necessary to culture the infective organism to
arrive at a conclusive diagnosis and determine the susceptibility of
the bacteria to antimicrobial agents.
Thus, it is essential to obtain a sample culture of the organism prior
to the initiating treatment otherwise it is impossible to differentiate
whether a negative culture is due to the absence of organism or is a
result of antimicrobial effects of administered antibiotics.
Definitive identification of the infecting organism may require other
laboratory techniques such as detection of antigens, DNA or RNA, or
host immune response.

2. EMPIRIC THERAPY PRIOR
TO IDENTIFICATION OF THE
ORGANISM
Ideally, the antimicrobial agent used to treat an infection is selected
after the organism has been identified and its drug susceptibility
established. However in critically ill patient, such a delay could prove
fatal, and immediate empiric therapy is indicated.
 Timing:
Acutely ill patients with infections of unknown origin, for example , a neutropenic
patient or patient with meningitis, require immediate treatment.
Therapy should be initiated after the specimen for laboratory analysis have been
obtained but before the results of the culture are available.
 Selecting a drug:
Drug choice in the absence of susceptibility data is influenced by the site of
infection and patient’s history. For example: previous infection, recent travel
history, age, immune status and whether the infection was hospital acquired or
community acquired.
Broad spectrum therapy must be indicated initially when the identity of the
organism is unknown or polymicrobial infection is likely.

3. DETERMINING
ANTIMICROBIAL
SUSCEPTIBILITY OF
INFECTIVE ORGANISMS
After a pathogen is cultured, its susceptibility to specific antibiotics
serves as a guide in choosing antimicrobial therapy. Some pathogens,
such as Streptococcus pyogenes and Neisseria meningitis, usually
have predictable susceptibility patterns to certain antibiotics.
In contrast, most gram negative bacilli, enterococci, and
staphylococcal species often show unpredictable susceptibility
patterns to various antibiotics and require susceptibility testing to
determine appropriate antimicrobial therapy.
A. Bacteriostatic vs Bacteriocidal drugs
Antimicrobial drugs are classified as either bacteriostatic or bacteriocidal.
Bacteriostatic drugs arrest the growth and replication of bacteria in host, thus
limiting the spread of infection until the body’s immune system attacks,
immobilizes and eliminates the pathogen.

Bacteriocidal drugs directly kill bacteria because of their more
aggressive antimicrobial action, bacteriocidal agents are often drug of
choice in seriously ill patient.
It is possible for an antibiotic to be bacteriostatic for one organism
and bactericidal for another.
For example: Chloramphenicol is bacteriostatic against gram negative
rods and bactericidal against other organisms, such as S.
pneumoniae.

B. Minimum Inhibitory Concentration
To determine the minimum inhibitory concentration (MIC), tubes
containing serial dilutions of an antibiotic are inoculated with the
organism whose susceptibility is to be tested.
The tubes are incubated and later observed to determine the MIC—
that is, the lowest concentration of antibiotic that inhibits bacterial
growth.
To provide effective antimicrobial therapy, the clinically obtainable
antibiotic concentration in body tissues and fluids should be greater
than the MIC.

C. Minimum bactericidal concentration: This quantitative assay
determines the minimum concentration of antibiotic that kills the
bacteria under investigation.
The tubes that show no growth in the MIC assay are subcultured into
antibiotic-free media.
The minimum bactericidal concentration (MBC) is the lowest
concentration of antimicrobial agent that results in a 99.9 percent
decline in colony count after overnight broth dilution incubations.

D. EFFECT OF THE SITE OF
INFECTION ON THERAPY:
THE BLOOD-BRAIN BARRIER
Adequate levels of an antibiotic must reach the site of infection for
the invading microorganisms to be effectively eradicated. Capillaries
with varying degrees of permeability carry drugs to the body tissues.
For example, the endothelial cells comprising the walls of capillaries
of many tissues have fenestrations (slit junctions) that allow most
drugs not bound by plasma proteins to penetrate.
However, natural barriers to drug delivery are created by the
structures of the capillaries of some tissues, such as the prostate, the
vitreous body of the eye, and the central nervous system (CNS).
1. Lipid solubility of the drug: All compounds without a specific
transporter must pass intracellularly from the blood to the CSF
(through two endothelial cell membranes . The lipid solubility of a
drug is therefore a major determinant of its ability to penetrate into
the brain. For example, lipid-soluble drugs, such as chloramphenicol
and metronidazole, have significant penetration into the CNS.

In contrast, β-lactam antibiotics, such as penicillin, are ionized at
physiologic pH and have low solubility in lipids.
They therefore have limited penetration through the intact blood-
brain barrier under normal circumstances.
In infections such as meningitis in which the brain becomes inflamed,
the barrier does not function as effectively, and local permeability is
increased. Some β-lactam antibiotics can then enter the CSF in
therapeutic amounts.
2. Molecular weight of the drug:
A compound with a low molecular weight has an enhanced ability to
cross the blood-brain barrier, whereas compounds with a high
molecular weight (for example, vancomycin) penetrate poorly, even in
the presence of meningeal inflammation.

3. Protein binding of the drug:
A high degree of protein binding of a drug in the serum restricts its
entry into the CSF.
Therefore, the amount of free (unbound) drug in serum, rather than
the total amount of drug present, is important for CSF penetration.

E. PATIENT FACTORS
In selecting an antibiotic, attention must be paid to the condition of
the patient. For example, the status of the patient’s immune system,
kidneys, liver, circulation, and age must be considered. In women,
pregnancy or breast-feeding also affects selection of the
antimicrobial agent.
1. Immune system: Elimination of infecting organisms from the body
depends on an intact immune system. Antibacterial drugs decrease
the microbial population (bactericidal) or inhibit further bacterial
growth (bacteriostatic), but the host defense system must ultimately
eliminate the invading organisms. Alcoholism, diabetes, infection
with the human immunodeficiency virus, malnutrition, autoimmune
diseases, pregnancy or advanced age can affect a patient’s
immunocompetence, as can therapy with immunosuppressive drugs.
Higher-than-usual doses of bactericidal agents or longer courses of
treatment are generally required to eliminate infective organisms in

2. Renal dysfunction:
Poor kidney function (10 percent or less of normal) causes
accumulation of antibiotics that would be otherwise be eliminated.
Dosage adjustment prevents drug accumulation and therefore
adverse effects.
Serum creatinine levels are frequently used as an index of renal
function for adjustment of drug regimens.
However, direct monitoring of serum levels of some antibiotics (for
example, aminoglycosides) is preferred to identify maximum and
minimum values. Rising minimum values alert the physician to
potential toxicity.
[Note: The number of functioning nephrons decreases with age. Thus,
elderly patients are particularly vulnerable to accumulation of drugs
eliminated by the kidneys. Antibiotics that undergo extensive
metabolism or are excreted via the biliary route may be favored in
such patients.]

3. Hepatic dysfunction: Antibiotics that are concentrated or
eliminated by the liver (for example, erythromycin and tetracycline)
are must be used with caution when treating patients with liver
dysfunction.
4. Poor perfusion: Decreased circulation to an anatomic area, such as
the lower limbs of a diabetic, reduces the amount of antibiotic that
reaches that area, making these infections notoriously difficult to
treat.
5. Age: Renal or hepatic elimination processes are often poorly
developed in newborns, making neonates particularly vulnerable to
the toxic effects of chloramphenicol and sulfonamides.
Young children should not be treated with tetracyclines or
quinolones, which affect bone growth.

6. Pregnancy:
Many antibiotics cross the placenta.
Adverse effects to the fetus are rare, except the for tooth dysplasia
and inhibition of bone growth encountered with the tetracyclines.
However, some anthelmintics are embryotoxic and teratogenic.
Aminoglycosides should be avoided in pregnancy because of their
ototoxic effect on the fetus.
Any drug used during pregnancy should be taken only under the
supervision of the patient’s physician.
Moreover, clinicians should reference the most current literature
before prescribing medications for pregnant patients, to stay up-to-
date on risk assessment.

7. Lactation:
Drugs administered to a lactating mother may enter the nursing
infant via the breast milk.
Although the concentration of an antibiotic in breast milk is usually
low, the total dose to the infant may be sufficient to produce
detrimental effects.

F. SAFETY OF THE AGENT
Many of the antibiotics, such as the penicillins, are among the least
toxic of all drugs because they interfere with a site unique to the
growth of microorganisms.
Other antimicrobial agents (for example, chloramphenicol) are less
microorganism specific and are reserved for life-threatening
infections because of the drug’s potential for serious toxicity to the
patient. )
[Note: As discussed above, safety is related not only to the inherent
nature of the drug, but also to patient factors that can predispose
one to toxicity.]

G. COST OF THERAPY
Often several drugs may show similar efficacy in treating an infection,
but vary widely in cost. Standard treatment of Helicobacter pylori
includes various combinations of two or three antimicrobial agents
along with a proton pump inhibitor. Below chart illustrates relative
cost of some drugs used for the treatment of peptic ulcers caused by
H. pylori. It also demonstrates that a triple therapy regimen including
clarithromycin is significantly more expensive than the bismuth
subsalicylate based quadruple therapy.
Relative cost of some drugs
used for the treatment of
peptic ulcers caused by
Helicobacter pylori.

ROUTE OF ADMINISTRATION
The oral route of administration is chosen for infections that are mild
and is favorable for treatment on an outpatient basis. In addition,
economic pressures have prompted the use of oral antibiotic therapy
in all but the most serious infectious diseases.
In patients requiring a course of intravenous therapy initially, the
switch to oral agents should occur as soon as possible. However,
some antibiotics, such as vancomycin, the aminoglycosides, and
amphotericin B, are so poorly absorbed from the gastrointestinal tract
that adequate serum levels cannot be obtained by oral
administration.
Parenteral administration is used for drugs that are poorly absorbed
from the gastrointestinal tract and for treatment of patients with
serious infections, for whom it is necessary to maintain higher serum
concentrations of antimicrobial agents than can be reliably obtained
by the oral route.

DETERMINANTS OF
RATIONAL DOSING
Rational dosing of antimicrobial agents is based on their
pharmacodynamics (the relationship of drug concentrations to
antimicrobial effects) and pharmacokinetic properties (the absorption,
distribution, metabolism and elimination of the drug by the body).
Three important properties that have a significant influence on the
frequency of dosing are concentration-dependent killing, time-
dependent killing, and post antibiotic effect.
Utilizing these properties to optimize antibiotic dosing regimens can
improve clinical outcomes and possibly decrease the development of
resistance.

A. Concentration-dependent killing
Certain antimicrobial agents, including aminoglycosides, show a
significant increase in the rate of bacterial killing as the concentration
of antibiotic increases from 4- to 64-fold the MIC of the drug for the
infecting organism.
Giving drugs that exhibit this concentration dependent killing by a
once-a-day bolus infusion achieves high peak levels, favoring rapid
killing of the infecting pathogen.
B. Time-dependent (concentration-independent) killing
By contrast, β-lactams, glycopeptides, macrolides, clindamycin, and
linezolid do not exhibit this concentration-dependent property; that
is, increasing the concentration of antibiotic to higher multiples of
the MIC does not significantly increase the rate of kill.
The clinical efficacy of antimicrobials that have a nonsignificant,
dose-dependent killing effect is best predicted by the percentage of
time that blood concentrations of a drug remain above the MIC.

C. Postantibiotic effect
The postantibiotic effect (PAE) is a persistent suppression of microbial
growth that occurs after levels of antibiotic have fallen below the MIC.
To measure the PAE of an antibiotic, a test culture is first incubated in
antibiotic-containing medium and then transferred to antibiotic-free
medium.
The PAE is defined as the length of time it takes (after the transfer)
for the culture to achieve log-phase growth.
Antimicrobial drugs exhibiting a long PAE (several hours) often
require only one dose per day.
For example, antimicrobials, such as aminoglycosides and
fluoroquinolones, exhibit a long PAE, particularly against gram-
negative bacteria.

CHEMOTHERAPEUTIC
SPECTRA
A. Narrow-spectrum antibiotics Chemotherapeutic agents acting only
on a single or a limited group of microorganisms are said to have a
narrow spectrum.
For example, isoniazid is active only against mycobacteria.
B. Extended-spectrum antibiotics Extended spectrum is the term
applied to antibiotics that are effective against gram-positive
organisms and also against a significant number of gram-negative
bacteria.
For example, ampicillin is considered to have an extended spectrum
because it acts against gram-positive and some gram-negative
bacteria.

C. Broad-spectrum antibiotics
Drugs such as tetracycline and chloramphenicol affect a wide variety
of microbial species and are referred to as broad-spectrum
antibiotics.
Administration of broad-spectrum antibiotics can drastically alter the
nature of the normal bacterial flora and precipitate a superinfection
of an organism such as Clostridium difficile, the growth of which is
normally kept in check by the presence of other microorganisms.

COMBINATIONS OF
ANTIMICROBIAL DRUGS
It is therapeutically advisable to treat patients with a single agent that
is most specific to the infecting organism. This strategy reduces the
possibility of superinfection, decreases the emergence of resistant
organisms, and minimizes toxicity. However, situations in which
combinations of drugs are employed do exist. For example, the
treatment of tuberculosis benefits from drug combinations.
A. Advantages of drug combinations
Certain combinations of antibiotics, such as β-lactams and
aminoglycosides, show synergism; that is, the combination is more
effective than either of the drugs used separately. Because such
synergism among antimicrobial agents is rare, multiple drugs used in
combination are only indicated in special situations for example,
when an infection is of unknown origin.

B. Disadvantages of drug combinations
A number of antibiotics act only when organisms are multiplying.
Thus, co-administration of an agent that causes bacteriostasis plus a
second agent that is bactericidal may result in the first drug
interfering with the action of the second.
For example, bacteriostatic tetracycline drugs may interfere with the
bactericidal effect of penicillins and cephalosporins.

DRUG RESISTANCE
Bacteria are said to be resistant to an antibiotic if the maximal level of
that antibiotic that can be tolerated by the host does not halt their
growth.
Some organisms are inherently resistant to an antibiotic.
For example, gram-negative organisms are inherently resistant to
vancomycin.
However, microbial species that are normally responsive to a
particular drug may develop more virulent or resistant strains
through spontaneous mutation or acquired resistance and selection.
Some of these strains may even become resistant to more than one
antibiotic.

A. Genetic alterations leading to drug resistance
Acquired antibiotic resistance requires the temporary or permanent
gain or alteration of bacterial genetic information. Resistance
develops due to the ability of DNA to undergo spontaneous mutation
or to move from one organism to another.
1. Spontaneous mutations of DNA:
Chromosomal alteration may occur by insertion, deletion, or
substitution of one or more nucleotides within the genome. The
resulting mutation may persist, be corrected by the organism, or be
lethal to the cell.
If the cell survives, it can replicate and transmit its mutated
properties to progeny cells.
Some spontaneous mutations have little or no effect on the
susceptibility of the organism to antimicrobial agents.
However, mutations that produce antibiotic-resistant strains can
result in organisms that may proliferate under certain selective
pressures.
An example is the emergence of Rifampin-resistant Mycobacterium
tuberculosis when rifampin is used as a single antibiotic.

2. DNA transfer of drug resistance:
Resistance acquired due to DNA transfer from one bacterium to
another. Resistance properties are usually encoded in
extrachromosomal R factors, known as resistance plasmids.
In fact, most resistance genes are plasmid mediated, although
plasmid-mediated traits can become incorporated into host bacterial
DNA.
Plasmids may enter cells by processes such as transduction (phage
mediated), transformation, or bacterial conjugation.

B. Altered expression of proteins in drug-resistant organisms
Drug resistance may be mediated by a variety of mechanisms, such as
a lack of or an alteration in an antibiotic target site, lowered
penetrability of the drug due to decreased permeability, increased
efflux of the drug, or presence of antibiotic-inactivating enzymes .
1. Modification of target sites:
Alteration of an antibiotic’s target site through mutation can confer
organism resistance to one or more related antibiotics.
For example, S. pneumoniae resistance to β-lactam antibiotics
involves alterations in one or more of the major bacterial penicillin-
binding proteins, resulting in decreased binding of the antibiotic to
its target.

2. Decreased accumulation:
Decreased uptake of an antibiotic can confer resistance because the
drug is unable to attain access to the site of its action in sufficient
concentrations to injure or kill the organism.
For example, gram-negative organisms can limit the penetration of
certain agents, including β-lactam antibiotics, tetracyclines, and
chloramphenicol, as a result of an alteration in the number and
structure of porins (channels) in the outer membrane. Also, the
presence of an efflux pump can limit levels of a drug in an organism.

3. Enzymatic inactivation:
The ability to destroy or inactivate the antimicrobial agent can also
confer resistance on microorganisms. Examples of antibiotic-
inactivating enzymes include
1) β-lactamases (“penicillinases”) that hydrolytically inactivate the β-
lactam ring of penicillins, cephalosporins, and related drugs;
2) Acetyltransferases that transfer an acetyl group to the antibiotic,
inactivating chloramphenicol or aminoglycosides; and
3) Asterases that hydrolyze the lactone ring of macrolides

PROPHYLACTIC ANTIBIOTICS
Certain clinical situations require the use of antibiotics for the
prevention rather than the treatment of infections.
Because the indiscriminate use of antimicrobial agents can result in
bacterial resistance and superinfection, prophylactic use is restricted
to clinical situations in which the benefits outweigh the potential
risks.
The duration of prophylaxis should be closely observed to prevent
unnecessary antibiotic exposure.

COMPLICATIONS OF
ANTIBIOTIC THERAPY
Because the mechanism of action of a particular antibiotic is
selectively toxic to an invading organism, it does not protect the host
against adverse effects. For example, the drug may produce an
allergic response or be toxic in ways unrelated to the drug’s
antimicrobial activity.
A. Hypersensitivity
Hypersensitivity reactions to antimicrobial drugs or their metabolic
products frequently occur.
For example, the penicillins, despite their almost absolute selective
microbial toxicity, can cause serious hypersensitivity problems,
ranging from urticaria (hives) to anaphylactic shock.

B. Direct toxicity
High serum levels of certain antibiotics may cause toxicity by directly
affecting cellular processes in the host.
For example, aminoglycosides can cause ototoxicity by interfering
with membrane function in the hair cells of the organ of Corti.
C. Superinfections
Drug therapy, particularly with broad-spectrum antimicrobials or
combinations of agents, can lead to alterations of the normal
microbial flora of the upper respiratory, intestinal, and genitourinary
tracts, permitting the overgrowth of opportunistic organisms,
especially fungi or resistant bacteria.
These infections are often difficult to treat.

CHOOSE THE ONE BEST
ANSWER.
1.Which one of the following patients is least likely to require
antimicrobial treatment tailored to the individual’s condition?
A. Patient undergoing cancer chemotherapy.
B. Patient with kidney disease.
C. Elderly patient.
D. Patient with hypertension.
E. Patient with liver disease.

2. In which one of the following clinical situations is the
prophylactic use of antibiotics not warranted?
A. Prevention of meningitis among individuals in close contact
with infected patients.
B. Patient with a hip prosthesis who is having a tooth removed.
C. Presurgical treatment for implantation of a hip prosthesis.
D. Patient who complains of frequent respiratory illness.
E. Presurgical treatment in gastrointestinal procedures

3. Which one of the following is the best route of administration
and dosing schedule for treatment with aminoglycosides based
on the drug’s concentration dependent killing property?
A. Oral every 8 hours.
B. Oral every 24 hours.
C. Parenterally by continuous intravenous infusion.
D. Parenterally every 8 hours.
E. Parenterally every 24 hours.

4. A 57-year-old man complains of fever, headache, confusion,
aversion to light, and neck rigidity. A presumptive diagnosis of
bacterial meningitis is made. Antimicrobial therapy should be
initiated after which one of the following occurrences?
A. Fever is reduced with antipyretic drugs.
B. Sample of blood and cerebrospinal fluid have been taken.
C. A Gram stain has been performed.
D. The results of antibacterial drug susceptibility tests are
available.
E. Infecting organism(s) have been identified by the
microbiology laboratory.

Anti-microbials therapy and complications.pptx

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