Principles of Antimicrobial - PowerPoint Presentation

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Principles of Antimicrobial

Therapy

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The development of antimicrobial drugs represents one of the most important advances in therapeutics, both in the control or cure of serious infections and in the prevention and treatment of infectious complications of other therapeutic modalities such as cancer chemotherapy, immunosuppression, and surgery.

Antimicrobial drugs have the ability to injure or kill an invading microorganism without harming the cells of the host taking the advantage of the biochemical differences that exist between microorganisms and human beings. In most instances, this

selective toxicity

is relative rather than absolute, requiring that the concentration of the drug be carefully controlled to attack the microorganism, while still being tolerated by the host.

The antimicrobial drugs can be

subclassified

as antibacterial, antifungal, antiviral agents, and

antiparasitic

drugs. These agents include natural compounds, called

antibiotics

, as well as synthetic compounds. An antibiotic is a substance produced by one microbe that can inhibit the growth or viability of another microbe.

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Classification of Antimicrobial Drugs

Antimicrobial drugs are usually classified on the basis of their site and mechanism of action and are

subclassified

on the basis of their chemical structure. The antimicrobial drugs include

cell wall synthesis inhibitors

,

protein synthesis inhibitors

,

metabolic and nucleic acid inhibitors

,

and

cell membrane inhibitors.

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Antimicrobial Activity

The antimicrobial activity of a drug can be characterized in terms of its bactericidal or

bacteriostatic

effect, its spectrum of activity against important groups of pathogens, and its concentration- and time-dependent effects on sensitive organisms.

 

Bactericidal or Bacteriostatic Effect

A

bactericidal drug

kills sensitive organisms at serum levels achievable in the patient so that the number of viable organisms falls rapidly after exposure to the drug. In contrast, a

bacteriostatic

drug

arrest the growth and replication of bacteria at serum levels achievable in the patient but does not kill them. For this reason, the number of bacteria remains relatively constant in the presence of a

bacteriostatic

drug, and immunologic mechanisms are required to eliminate organisms during treatment of an infection with this type of drug. (The same principle applies to a drug that kills or inhibits the growth of fungi and is referred to as a

fungicidal drug

or a

fungistatic

drug,

respectively.)

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A bactericidal drug is usually preferable to a

bacteriostatic

drug for the treatment of most bacterial infections. This is because bactericidal drugs typically produce a more rapid microbiologic response and more clinical improvement and are less likely to elicit microbial resistance.

Bactericidal drugs have actions that induce lethal changes in microbial metabolism or block activities that are essential for microbial viability. For example, drugs that inhibit the synthesis of the bacterial cell wall (e.g.,

penicillins

) prevent the formation of a structure that is required for the survival of bacteria. In contrast,

bacteriostatic

drugs usually

inhibit a metabolic reaction

that is needed for bacterial growth but is not necessary for survival. For example,

sulfonamides

block the synthesis of folic acid, which is a cofactor for enzymes that synthesize DNA components and amino acids.

Most

bacteriostatic agents are able to effectively kill organisms; however, they are unable to meet the arbitrary cutoff value in the bactericidal definition

.

Some drugs can be either bactericidal or bacteriostatic, depending on their concentration and the bacterial species against which they are used. For example,

linezolid

is bacteriostatic against

Staphylococcus

aureus

and enterococci but is bactericidal against most strains of

S.

pneumoniae

.

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Antimicrobial Spectrum

The spectrum of antimicrobial activity of a drug is the primary determinant of its clinical use. Antimicrobial agents that are active against a single species or a limited group of pathogens are called

narrow- spectrum drugs

e.g.,

isoniazid

is active only against Mycobacterium tuberculosis

Whereas agents that are active against a wide range of pathogens are called

broad-spectrum drugs

e.g.,

tetracycline

,

fluoroquinolones

and

carbapenems

. Agents that have an intermediate range of activity are sometimes called

extended-spectrum drugs

e.g.,

ampicillin

.

Narrow-spectrum drugs are sometimes preferred because they target a specific pathogen without disturbing the normal flora of the gut or respiratory tract. Broad-spectrum drugs are sometimes preferred for the initial treatment of an infection when the causative pathogen is not yet identified.

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Concentration- and Time-Dependent Effects

Antimicrobial drugs exhibit various concentration- and time-dependent effects that influence their clinical efficacy, dosage, and frequency of administration. Examples of these effects are the

minimal inhibitory concentration

(MIC)

 

, the

concentration-dependent killing rate

(CDKR),

Time-dependent (concentration-independent) killing

and the

postantibiotic

effect

(PAE).

The MIC is the lowest concentration of a drug that inhibits bacterial growth after 24 hours of incubation. Based on the MIC, a particular strain of bacteria can be classified as susceptible or resistant or with intermediate sensitivity to a particular drug and is commonly used in practice to streamline therapy.

The minimum bactericidal concentration (MBC) is the lowest concentration of antimicrobial agent that results in

a 99.9

% decline in colony count after overnight broth dilution

incubations.It

is

rarely determined

in clinical practice due to the time and labor requirements.]

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An example of a CDKR: some

aminoglycosides

(e.g., tobramycin) and some

fluoroquinolones

(e.g., ciprofloxacin) 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 these drugs by a one dose per day achieves high peak levels, favoring rapid killing of the infecting pathogen.

In contrast,

β-lactams

,

glycopeptides

,

macrolides

,

clindamycin

, and

linezolid

effects are best predicted by the percentage of time that blood concentrations of a drug remain above the

MIC.

This effect is sometimes called

time-dependent

(

or concentration-independent

) killing. For example, dosing schedules for the

penicillins

and

cephalosporins

that

ensure blood

levels greater than the MIC for 50% and 60% of the time, respectively, provide the most clinical

efficacy. Therefore

,

frequent dosing

is important to achieve prolonged time above the MIC and kill more bacteria.

After

an antibacterial drug is removed from a bacterial culture, evidence of a persistent effect on bacterial growth may exist. This effect is the

PAE

. Antimicrobial drugs that exhibit a long PAE are aminoglycosides and

fluoroquinolones

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Selection of Antimicrobial Agents

Selection of the most appropriate antimicrobial agent requires knowing: 1) The organism’s identity,

2) The organism’s susceptibility to a particular agent, 3) Pharmacokinetic Properties, 4) Host factors, 5) Adverse Effect Profile, and 6) The cost of therapy.

However, some patients require

empiric therapy

(immediate administration of drug(s) prior to bacterial identification and susceptibility testing).

 

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A. Identification of the infecting organism

Characterizing the organism is central to selection of the proper drug. A rapid assessment of the nature of the pathogen can sometimes be made on the basis of the

Gram stain

, which is particularly useful in identifying the presence and morphologic features of microorganisms in body fluids that are normally sterile (blood, serum, cerebrospinal fluid [CSF], pleural fluid, synovial fluid, peritoneal fluid, and urine). However, it is generally necessary to culture the infective organism to arrive at a conclusive diagnosis and determine the susceptibility to antimicrobial agents. Thus, it is essential to obtain a sample culture of the organism prior to initiating treatment. Otherwise, it is impossible to differentiate whether a negative culture is due to the absence of organisms or is a result of antimicrobial effects of administered antibiotic.

Definitive identification of the infecting organism may require other laboratory techniques, such as detection of microbial antigens, DNA, or RNA, or an inflammatory or host immune response to the microorganism.

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Empiric therapy prior to identification of the organism

The antimicrobial agent used to treat an infection is selected after the organism has been identified and its drug susceptibility established. However, in the critically ill patient, such a delay could prove fatal, and immediate empiric therapy is indicated.

1. Timing:

Acutely ill patients with infections of unknown origin for example, a

neutropenic

patient or a patient with meningitis require immediate treatment. If possible, therapy should be initiated after specimens for laboratory analysis have been obtained but before the results of the culture and sensitivity are available.

2. Selecting a drug:

Drug choice in the absence of susceptibility data is influenced by the site of infection and the patient’s history (for example, previous infections, age, recent travel history, recent antimicrobial therapy, immune status, and whether the infection was hospital- or community-acquired).

Broad-spectrum therapy

may be indicated initially when the organism is unknown or poly-microbial infections are likely. The choice of agent(s) may also be guided by known association of particular organisms in a given clinical setting. For example, gram-positive

cocci

in the spinal fluid of a newborn infant is unlikely to be

Streptococcus

pneumoniae

and most likely to be

Streptococcus

agalactiae

(a group B streptococci), which is sensitive to penicillin G. By contrast, gram- positive

cocci

in the spinal fluid of a 40-year-old patient are most likely to be

S.

pneumoniae

. This organism is frequently resistant to penicillin G

and often requires treatment with a high-dose third- generation cephalosporin (such as

ceftriaxone

) or

vancomycin

.

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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

meningitidis

, usually have predictable susceptibility patterns to certain antibiotics. In contrast, most gram-negative bacilli,

enterococci

, and staphylococcal species often show unpredictable susceptibility patterns and require susceptibility testing to determine appropriate antimicrobial therapy. The minimum inhibitory and bactericidal concentrations of a drug can be experimentally determined.

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Pharmacokinetic Properties

The pharmacokinetic properties that influence antibiotic selection include oral bioavailability, peak serum concentration, distribution to particular sites of infection, routes of elimination, and elimination half-life. An ideal antimicrobial drug for patients would have

good oral bioavailability and a long plasma half-life

so that it would need to be taken only once a day.

Azithromycin

is an example of an antibiotic that meets these criteria.

The oral route of administration is appropriate for mild infections that can be treated on an outpatient basis. Parenteral administration is used for drugs that are poorly absorbed from the GI tract (such as

vancomycin

, and the aminoglycosides) and for treatment of patients with serious infections such as bacterial meningitis or endocarditis, for whom it is necessary to maintain higher serum concentrations of antimicrobial agents,

for critically ill

patients and for

patients with nausea, vomiting,

gastrectomy

,

ileus, or diseases that may impair oral

absorption.

The peak serum concentration of an antimicrobial drug should be several times greater than the MIC of the pathogenic organism for the drug to eliminate the organism. This is partly because the tissue concentrations of a drug are sometimes lower than the plasma concentration.

The urine concentration of an antimicrobial drug can be 10 to 50 times the peak serum concentration. For this reason, infections of the urinary tract can be easier to treat than are infections at other sites.

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Sites of infection that are not readily penetrated by many antimicrobial drugs include the

central nervous system, bone, prostate gland, and ocular tissues.

The treatment of meningitis requires that drugs achieve adequate concentrations in the cerebrospinal fluid. The penetration and concentration of an antibacterial agent in the CSF are particularly influenced by lipid solubility of the drug (lipid soluble drugs as chloramphenicol and metronidazole penetrate significantly whereas β-lactam antibiotics, such as penicillin, are ionized and penetrate the blood-cerebrospinal fluid barrier only when the meninges are inflamed), molecular weight and protein binding of the drug.

Because antimicrobial drug concentrations are low in bone, patients with

osteomyelitis

must usually be treated with antibiotics for several weeks to produce a cure. The prostate gland restricts the entry of some antimicrobial drugs because the drugs have difficulty crossing the prostatic epithelium and because prostatic fluid has a low

pH.

These characteristics favor the entry and accumulation of weak bases (e.g.,

trimethoprim

) and tend to exclude the entry of weak acids (e.g., penicillin).

The route of elimination affects both the selection and the use of antimicrobial drugs. Drugs that are eliminated by renal excretion (e.g.,

fluoroquinolones

) are more effective for urinary tract infections than are drugs that are largely metabolized or undergo

biliary

excretion (e.g., erythromycin). Antibiotics that are eliminated by the kidneys (e.g., the

aminoglycosides

) can accumulate in patients whose renal function is compromised, so their dosage must be reduced in these patients.

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Host Factors

Host factors that influence the choice of a drug include pregnancy, drug allergies, age and immune status, and the presence of renal impairment, hepatic insufficiency, circulation status, abscesses, or indwelling catheters and similar devices.

Most antimicrobial drugs cross the placenta and can thereby affect the fetus. For example, administering

tetracyclines

to a woman during

pregnancy

can cause permanent staining of her offspring’s teeth.

Penicillins

and

cephalosporins

, however, cause very little fetal toxicity and can be safely administered to pregnant women who are not allergic to these drugs.

Many individuals are allergic to one or more antimicrobial drugs.

Penicillins

are the most common cause of drug allergy.

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 and joints, respectively.

Decreased circulation to an anatomic area, such as the lower limbs of a diabetic patient, reduces the amount

of antibiotic

that reaches that site of infection, making it more difficult to treat.

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The patient’s

immune status

is an important factor determining the success of antimicrobial therapy.

Advanced age, diabetes, cancer chemotherapy,

and

human immunodeficiency virus (HIV) infection

are among the more common causes of impaired immunity.

Immunocompromised

individuals should be treated with larger doses of bactericidal drugs and may require a longer duration of therapy than do

immunocompetent

individuals.

Many antibiotics are excreted unchanged by the kidneys, and lower doses must be used if the patient has significant

renal impairment.

Less commonly,

hepatic insufficiency

may require dosage adjustment for antimicrobial drugs that are extensively metabolized in the liver.

Antibiotic access to an

abscess

is poor, and the concentration of an antibiotic in an abscess is usually lower than in the surrounding tissue. Moreover, immune function is often impaired in an abscess. For these reasons, it is often necessary to surgically drain an abscess before the infection can be cured.

Foreign bodies,

such as

indwelling catheters,

provide sites where microbes can become covered with a

glycocalyx

coating (biofilm) that protects them from antibiotics and immunologic destruction.

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Adverse Effect Profile

Even though antibiotics are selectively toxic to an invading organism, any antimicrobial drug can cause mild to severe adverse effects.

Hypersensitivity or immune reactions to antimicrobial drugs or their metabolic products frequently occur. For example penicillin allergy.

High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. For example,

aminoglycosides

can cause

ototoxicity

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, oral, intestinal, and genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. These infections usually require secondary treatments using specific anti-infective agents.

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Microbial Sensitivity and Resistance

Laboratory Tests for Microbial Sensitivity

Microbial sensitivity to drugs can be determined by various means, including the

broth dilution test,

the

disk diffusion method (Kirby-Bauer test),

and the

E-test method.

Either the broth dilution test or the E-test method can be used to determine the MIC or MBC of a drug. On the basis of the MIC, the organism is classified as having

susceptibility, intermediate sensitivity,

or

resistance

to the drug tested. These categories are based on the relationship between the MIC and the peak serum concentration of the drug after administration of typical doses. In general, the peak serum concentration of a drug should be 4 to 10 times greater than the MIC in order for a pathogen to be susceptible to a drug. Pathogens with intermediate sensitivity may respond to treatment with maximal doses of an antimicrobial agent.

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Microbial Resistance to Drugs

Nowadays, the

antimicrobial

agents are

vastly overprescribed in outpatient

settings. The

availability of antimicrobial agents without prescription

in many

developing countries has—by facilitating the

development of

resistance—already severely limited therapeutic options in

the treatment

of life-threatening infections. Therefore, the

clinician should

first determine whether antimicrobial therapy is

necessary for

a given patient.

Origin of Resistance

Resistance can be innate or acquired. Acquired drug resistance arises from mutation and selection or from the transfer of plasmids that confer drug resistance.

Mutation and Selection

:

Microbes can spontaneously mutate to a form that is resistant to a particular antimicrobial drug. These mutations occur at a relatively constant rate, such as in 1 in 10

12

organisms per unit of time. If the organisms are exposed to an antimicrobial drug during this time period, the sensitive organisms may be eradicated, enabling the resistant mutant to multiply and become the dominant strain.

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The probability that mutation and selection of a resistant mutant will occur is increased during the exposure of an organism to

suboptimal

concentrations of an antibiotic, and it is also increased during

prolonged

exposure to an antibiotic. This observation has obvious implications for antimicrobial therapy. Laboratory tests should be used to guide the selection of an antimicrobial drug, and the dosage and duration of therapy should be adequate for the type of infection being treated. Whenever possible, the bacteriologic response to drug therapy should be verified by culturing samples of appropriate body fluids.

Transferable Resistance:

Transferable resistance usually results from bacterial conjugation and the transfer of

plasmids

(

extrachromosomal

DNA) that confer drug resistance. Transferable resistance, however, can also be mediated by

transformation

(uptake of naked DNA) or

transduction

(transfer of bacterial DNA by a bacteriophage). Bacterial conjugation enables a bacterium to donate a plasmid containing genes that encode proteins responsible for resistance to an antibiotic. These genes are called

resistance factors.

The resistance factors can be transferred both within a particular species and between different species, so they often confer

multidrug resistance.

Studies have shown that resident

microflora

of the human body can serve as reservoirs for resistance genes, allowing the transfer of these genes to organisms that later invade and colonize the host.

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Mechanisms of Resistance

The three primary mechanisms of microbial resistance to an antibiotic are (1) inactivation of the drug by microbial enzymes, (2) decreased accumulation of the drug by the microbe, and (3) reduced affinity of the target macromolecule for the drug.

Inactivation

of the drug by enzymes is an important mechanism of resistance to β-

lactam

antibiotics, including the

penicillins

. This form of resistance results from bacterial elaboration of β-

lactamase

enzymes that destroy the β-

lactam

ring. Resistance to

aminoglycosides

(e.g.,

gentamicin

) is partly caused by the elaboration of drug-inactivating enzymes that

acetylate

,

adenylate

, or

phosphorylate

these antibiotics.

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Decreased accumulation

of an antibiotic can result from

increased efflux

or

decreased uptake

of the drug. Both of these mechanisms contribute to the resistance of microbes to

tetracyclines

and

fluoroquinolones

. Increased drug efflux is often mediated by membrane proteins that transport antimicrobial drugs out of bacterial cells. Decreased uptake of antimicrobial drugs can result from altered bacterial

porins

.

Porins

are membrane proteins containing channels through which drugs and other compounds enter bacteria. Resistance to

penicillins

by gram-negative bacilli is partly caused by altered

porin

channels that do not permit penicillin entry.

Reduced affinity

of target molecules for antimicrobial drugs is a common mechanism of microbial resistance to most classes of antibiotics. This type of drug resistance often results from bacterial mutation followed by the selection of resistant mutants during exposure to an antimicrobial drug

. 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.

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Combination Drug Therapy

It is therapeutically advisable to treat patients with a single agent that is most specific to the infecting organism. This strategy reduces the possibility

superinfections

, decreases the emergence of resistant organisms, and minimizes toxicity. However, some situations require combinations of antimicrobial drugs. For example, the treatment of mixed infections e.g. intra-abdominal abscess , life-threatening infections (to provide broad spectrum empiric therapy) and to decrease the emergence of resistant strains as in tuberculosis.

When antimicrobial drugs are given in combination, they can exhibit antagonistic, additive, synergistic, or indifferent effects against a particular microbe. The relationship between two drugs and their combined effect is as follows:

antagonistic

if the combined effect is less than the effect of either drug alone;

additive

if the combined effect is equal to the sum of the independent effects;

synergistic

if the combined effect is greater than the sum of the independent effects; and

indifferent

if the combined effect is similar to the greatest effect produced by either drug alone. Some

bacteriostatic

drugs (e.g.,

chloramphenicol

or tetracycline) are antagonistic to bactericidal drugs. Bactericidal drugs are usually more effective against rapidly dividing bacteria, and their effect may be reduced if bacterial growth is slowed by a

bacteriostatic

drug.

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If two bactericidal drugs that target different microbial functions are given in combination, they often exhibit

additive or synergistic effects

against susceptible bacteria. For example,

penicillins

, which are cell wall synthesis inhibitors, often show additive or synergistic effects with aminoglycosides, which inhibit protein synthesis, against gram-negative bacilli such as

P.

aeruginosa

and against gram-positive enterococci and staphylococci. Likewise,

sulfamethoxazole

and

trimethoprim

inhibit sequential steps in bacterial folate synthesis and have synergistic activity against organisms that may be resistant to either drug alone.

Combination therapy may also serve to reduce the emergence of resistant organisms, such as in the treatment of tuberculosis. This is because about 1 in 10

6

Mycobacterium tuberculosis

organisms will mutate to a resistant form during treatment with any single drug. The rate of mutation to a form resistant to two drugs is the product of the individual drug resistance rates, or about 1 in 10

12

organisms. Because fewer than 10

12

organisms are usually present

in a patient with tuberculosis, it is unlikely that

a resistant

mutant will emerge during combination therapy.

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