CHOICE OF THE PROPER ANTIMICROBIAL AGENT



CHOICE OF THE PROPER ANTIMICROBIAL AGENT

• In choosing the appropriate antimicrobial agent for therapy for a given infection, a number of factors must be considered.

o First: the identity of the infecting organism must be known.

o Second: the information about the antimicrobial susceptibility of the infecting organism must be as accurate as possible.

o Third: a series of so-called host factors must be taken into consideration.

Identification of the Infecting Organism

• Methods for the rapid identification of pathogenic bacteria in clinical specimens

• A Gram stain preparation is perhaps the simplest, least expensive, and most useful ( bacterial (and some fungal) pathogens.

|CSF |Pleural fluid |Synovial fluid |Peritoneal fluid |

|Urine |Stool specimen |Sputum | |

• Gram staining of a buffy coat preparation of blood reveals phagocytosed organisms in the polymorphonuclear leukocytes of patients with bacteremia or fungemia.

• The presence of PNLs in the stool also provides a helpful clue to the cause of certain cases of diarrhea (shigellosis, salmonellosis, or campylobacteriosis, or invasive Escherichia coli gastroenteritis).

• Cultural techniques: definitive identification of pathogenic organisms. Once anti-infective therapy has been started, cultures often are rendered sterile.

• Immunologic methods for antigen detection (ELISA or latex agglutination).

• PCR to identify RNA or DNA of viruses, bacteria, and other microorganisms in the blood of patients

• In cases where it is impossible to determine the exact nature of the infecting organisms before the institution of antimicrobial therapy ( use of bacteriologic statistics.

• The term bacteriologic statistics refers to the application of knowledge of the organisms most likely to cause infection in a given clinical setting.

• Example:

• Person with normal host defense mechanisms who develops cellulitis after a minor abrasion ( Staphylococcus aureus or group A streptococci.

• A young child with acute otitis media ( Haemophilus influenzae, Streptococcus pneumoniae, Moraxella (Branhamella) catarrhalis, or a group A streptococcus.

Determination of Antimicrobial Susceptibility of Infecting Organisms

• Important considerations in determination of antimicrobial susceptibility

1. The widespread clinical use of antibiotics since the 1930s has resulted in the emergence of many strains of bacteria that are resistant to one or more antimicrobial agents.

• Some organisms are naturally resistant to the antibiotic used.

o Staphylococci ( resistant to nalidixic acid, aztreonam, and polymyxins.

o Streptococci ( resistant to nalidixic acid, aztreonam, and polymyxins.

o Many gram-negative bacilli ( resistant to penicillin G, erythromycin.

• In other cases, the resistant bacterial strains ( acquired genes encoded on transposons or plasmids ( provide the organisms with the ability to synthesize enzymes ( modify or inactivate the antimicrobial agent ( resist antimicrobial inhibition.

o Most strains of S. aureus contain plasmids that enable them to produce an extracellular β-lactamase ( hydrolyzes and inactivates penicillin G ( resistance to penicillin

o Many gram-negative bacilli contain genes on plasmids that code for the production of periplasmic enzymes that catalyze a modification of the aminoglycosides by phosphorylation, acetylation, or adenylation ( resistance to aminoglycosides such as streptomycin, gentamicin, and amikacin.

o Efflux mechanisms (which may be plasmid or transposon mediated) in S. aureus, pneumococci, and gram-negative bacilli ( resistance to tetracycline, macrolides.

o E. coli contain R factors that enable it to synthesize a new dihydrofolate reductase (the enzyme specifically inhibited by trimethoprim) ( resistance to trimethoprim.

2. The discovery of new resistant organisms worldwide:

o Penicillin-resistant meningococci.

o Fluoroquinolone-resistant gonococci in Asia & Africa

o Rapid spread of ampicillin-resistant and chloramphenicol-resistant strains of H. influenzae in the US and Europe.

o Vancomycin-resistant enterococci and staphylococci

o Streptomycin-resistant Yersinia pestis in Madagascar.

3. Testing of antimicrobial susceptibility whenever there is reasonable doubt about the susceptibility of a given organism.

• Pathogens isolated from a culture ( direct susceptibility testing.

o E test ( quantitative measurements of antimicrobial susceptibility.

o Broth dilution tests (incubated 18-24 hrs).

o Other rapid methods based on a determination of changes in bacterial growth rates caused by antimicrobial agents ( 4 to 8 hours.

4. Susceptibility testing is particularly important for certain organisms such as:

o S. aureus.

o Aerobic gram-negative bacilli.

5. Susceptibility testing need not be carried out routinely for certain organisms such as:

o All group A and other β-hemolytic streptococci remain susceptible to the penicillins and cephalosporins.

o All anaerobes except Bacteroides species are susceptible to penicillin

6. Consider geographic differences in patterns of susceptibility of organisms

7. Consider variations in susceptibility patterns between hospitals and the community or among hospitals themselves.

o Most aminoglycoside-resistant organisms are found in hospitals, whereas most isolates from nonhospitalized patients remain susceptible to gentamicin.

o Cases of methicillin resistant S. aureus (MRSA) were confined to hospitals, but now community-acquired MRSA infections have been documented.

Host Factors

• Host factors may influence the efficacy and toxicity of antimicrobial agents.

1. History of Previous Adverse Reactions to Antimicrobial Agents

• May prevent the inadvertent administration of an antimicrobial agent to which the patient is allergic.

2. Age

• The age of the patient is a major factor in choosing an antimicrobial agent.

• The pH of gastric secretions is higher in young children and low in elderly.

• Absorption of a number of antimicrobials administered via the oral route depends on their acid stability and the pH of gastric secretions.

• Example

o The oral absorption of penicillin G is markedly reduced by gastric acid.

o In young children and in older achlorhydric patients, the absorption of the drug is markedly enhanced.

o Drugs that are weak acids, such as ketoconazole, may be better absorbed at a low pH.

• Renal function varies with age ( diminished in premature and newborn children and elderly (creatinine clearance may be significantly reduced) ( serum half-lives of drugs that are primarily excreted by the kidneys may be increased.

• Example

o Penicillin G, its semisynthetic derivatives & aminoglycosides, must be reduced in neonates.

o High doses of penicillins or cephalosporins or carbapenems such as imipenem must be given with caution to older adults to prevent neurotoxic reactions such as myoclonus, seizures, and coma.

o Impaired renal excretion of the aminoglycoside antibiotics may be associated with an increasing incidence of ototoxicity in older patients.

• Age related adverse effects

• Example

o Tetracyclines bind to developing teeth ( purplish to brownish discoloration of the teeth to actual enamel hypoplasia ( not administered during pregnancy or in young children up to 8 ys.

o The quinolone antimicrobials ( cartilage damage and arthropathy in young animals( not recommended for use in prepubertal children.

o Hypersensitivity reactions to antimicrobial agents also appear to be more common in older adults than in younger patients (previously exposed, and thus sensitized, to these agents).

o Prior exposure to drugs such as the aminoglycosides, which produce irreversible cochlear damage, can result in cumulative toxicity on repeat exposure.

o Liver damage from isoniazid almost never occurs in patients younger than 20 years.

• Hepatic function in neonates is underdeveloped ( caution with drugs that are normally excreted or inactivated by the liver.

• Example

o Chloramphenicol is inactivated by conjugation to the glucuronide form in the liver + neonate; hepatic levels of glucuronyl transferase are relatively insufficient ( when neonates are given large doses of chloramphenicol( high serum levels of unconjugated chloramphenicol ( shock, cardiovascular collapse, and death (gray syndrome).

o Sulfonamides compete with bilirubin for binding sites on serum albumin ( when given to neonates ( increased serum levels of unbound bilirubin ( kernicterus.

3. Genetic or Metabolic Abnormalities

• The rate at which isoniazid is conjugated and biologically inactivated by acetylation in the liver is determined genetically.

o Polyneuritis is seen more frequently as a complication of isoniazid therapy in slow than in rapid acetylators.

• Sulfonamides, nitrofurantoin and chloramphenicol ( hemolysis in patients with G6PD deficiency.

• Chloramphenicol inhibits microsomal enzyme activity in the liver ( impairs the metabolism of the sulfonylurea.

• Rifampin may increase the hepatic metabolism(↓ effect of oral anticoagulants, oral contraceptives.

4. Pregnancy

• All antimicrobial agents cross the placenta in varying degrees ( direct exposure of the fetus to adverse effects of the drug.

• Penicillins, cephalosporins, macrolides and antituberculous drugs such as isoniazid, rifampicin, and ethambutol are safe for pregnant women to use.

• Drugs with teratogenic potential:

• Metronidazole.

• Tetracyclines.

• Streptomycin.

• Antimicrobials contraindicated in lactation:

• Nalidixic acid ( hemolysis in infants with G6PD deficiency. Sulfonamides ( increased levels of unbound bilirubin ( kernicterus.

Renal and Hepatic Function

• These organs serve as the major routes of excretion and inactivation of antimicrobials.

• Certain agents require dosage modification in patients with impaired renal function.

• Penicillin G or imipenem ( myoclonus, seizures, or coma.

• Piperacillin ( hemostatic defects.

• Aminoglycosides ( eighth nerve damage.

• Certain antimicrobial agents, including erythromycin, azithromycin, chloramphenicol, and clindamycin, should be used with caution in patients with impaired hepatic function ( primarily excreted or detoxified in the liver.

• The serum half-lives of both rifampin and isoniazid are prolonged in patients with cirrhosis.

• Drugs, for which serum levels should be monitored in patients with severe liver disease, include metronidazole, ketoconazole, fluconazole, itraconazole, nitrofurantoin, and pyrazinamide.

Site of Infection

• For antimicrobial therapy to be effective, an adequate concentration of the drug must be delivered to the site of infection.

• The lipid-soluble agents such as chloramphenicol, rifampin, trimethoprim, and isoniazid rapidly cross the blood-brain barrier and produce better CSF levels.

• For the treatment of bacterial meningitis in adults, there are two choices:

o Agents such as chloramphenicol or the 3rd-generation cephalosporins (cefotaxime, ceftriaxone) or the 4th-generation agent cefepime, all of which cross the blood-brain barrier.

o High parenteral doses of drugs such as penicillin G, ampicillin, or nafcillin, which penetrate into the CSF with difficulty.

o Agents such as the aminoglycosides and1st-generation cephalosporins produce inadequate CSF levels even after high-dose parenteral therapy must be administered directly into the CSF or must be avoided entirely.

• The penetration of antimicrobial agents into the heart valve vegetations of bacterial endocarditis & bones may be inadequate ( high-dose and prolonged parenteral therapy is required for bacterial endocarditis and osteomyelitis.

• Agents that are excreted by the liver and are concentrated in the bile, such as ampicillin, fluoroquinolones and doxycycline are effective in treating cholangitis.

• Local decreases in oxygen tension, as in abscesses and intraperitoneal infections, may impair the activity of certain antimicrobial agents ( aminoglycosides.

• Local alterations in pH such as occur in urine may have an important effect on the activity of a number of antimicrobial agents.

o Nitrofurantoin & novobiocin are more active at an acid pH, whereas alkalinization enhances the activity of erythromycin, azithromycin, clarithromycin, and aminoglycosides.

ANTIMICROBIAL COMBINATIONS

• Combinations may provide broad spectrum coverage than single agents.

• When two antimicrobial agents are combined, they may have one of three types of activity against a given organism:

1. Additive effect

2. Synergism.

3. Antagonism.

• Indications for Clinical Use of Antimicrobial Combinations

1. Preventing emergence of resistant organisms ( tuberculosis.

2. Polymicrobial infections.

o Intraperitoneal & pelvic sepsis ( mixed aerobic & anaerobic organisms

3. Initial therapy.

o Neutropenic patients

o Nature of the infection is not clear

o Examples of combination therapy with broad-spectrum coverage

o Cephalosporin + aminoglycoside or fluoroquinolone.

4. Decreased Toxicity

• Reduce the amount of drug required for treatment and, thus, to reduce dose-related toxicity.

5. Synergism

o Penicillin enhances the uptake of aminoglycosides by enterococci ( synergistic killing of the organisms.

o Penicillin-streptomycin combinations are synergistic against viridans streptococci.

o Piperacillin + gentamicin exhibit synergism against many strains of P. aeruginosa.

o Sulfamethoxazole and trimethoprim ( chronic urinary tract infections, typhoid fever and shigellosis.

• Disadvantages of Inappropriate Use of Antimicrobial Combinations

1. Antagonism ( partial loss of activity of the most active.

o Chloramphenicol + gentamicin.

o Ampicillin + chloramphenicol in bacterial meningitis.

o Chloramphenicol + erythromycin ( precipitate when mixed & lose activity.

o Piperacillin + aminoglycoside ( inactivation of the aminoglycoside.

2. Cost

o The inappropriate use of antimicrobial combinations can add greatly to the cost of the patient’s illness.

3. Adverse Effects

o Hypersensitivity reactions and direct toxic effects.

DOSAGES AND EVALUATION OF EFFICACY

Route of Administration

• Once the most appropriate drug has been determined for a given infection, a route of administration must be chosen that will maximize the benefits of therapy.

• The choice is between oral and parenteral routes.

• Oral route ( infections that are mild and can be treated on an outpatient basis.

o Drugs such as vancomycin, polymyxins & aminoglycosides are poorly absorbed from the GIT ( cannot be administered orally to treat systemic infections.

o Absorption of certain agents such as penicillin G is markedly impaired if it is taken with meals.

o Antacids may interfere with the absorption of the fluoroquinolones.

• Parenteral route (IV or IM)

o Agents that are inefficiently absorbed from the gastrointestinal tract.

o Treatment of patients with serious infections that require higher serum concentrations of antimicrobial agents.

1. Presence of shock.

2. Diabetic patients

3. Meningitis, endocarditis, and osteomyelitis.

Monitoring the Response of the Patient to Antimicrobial Therapy

• Clinical assessment.

• Measurement of serum concentrations of antimicrobial agents to avoid toxicity (

o Aminoglycosides in patients with impaired renal or hepatic function.

o Vancomycin.

• Serum bactericidal titer (serum antimicrobial dilution titer).

o Has been used to monitor therapy in patients with infective endocarditis, osteomyelitis, septic arthritis, empyema, and bacteremia.

Basic principles of appropriate antimicrobial use

ESTABLISH DEFINITIVE DIAGNOSIS BEFORE INITIATING ANTIMICROBIALS

1. Perform comprehensive clinical evaluation

2. Determine known or suspected site of infection

3. Perform appropriate diagnostic tests

4. Obtain appropriate specimens for culture and susceptibility testing

5. Gram stain of appropriate specimens

6. Evaluate cultures and Gram stains for colonization versus infection

Evaluate patient for noninfectious sources of fever

1. Hemorrhage

2. Inflammatory conditions

3. Medications

4. Metabolic conditions

5. Neoplasms

6. Thromboembolism

INITIATE APPROPRIATE EMPIRIC ANTIMICROBIAL THERAPY

1. Consider known/probable site of infection and most likely pathogens

2. Consider results of any previous diagnostic tests

3. Consider colonization versus infection when evaluating culture results

4. Consider rates of antimicrobial resistance among potential pathogens

5. Consider resistance among community-acquired and nosocomial pathogens

6. Consider differences in resistance patterns in ICU and among various units

7. Consider prior antimicrobial exposure and potential for selection of resistant pathogens

8. Consider need for combination antimicrobial therapy versus monotherapy

9. Initial therapy should be broad-spectrum, parenteral, and at appropriately aggressive doses

10. Consider pharmacokinetic properties of potentially used agents and potential alterations

11. Consider pharmacodynamic properties of potentially used agents

12. Consider age, organ dysfunction, and site of infection when determining proper dose

13. Consider potential drug-related adverse effects and toxicities

14. Consider potentially relevant drug-drug or drug–disease state interactions

15. Consider use of less expensive agents when appropriate

CHANGE TO APPROPRIATE DEFINITIVE DRUG THERAPY WHEN POSSIBLE

1. Monitor culture and susceptibility test results

2. Spectrum of antimicrobial activity of selected agents should be as narrow as possible when pathogens is known

3. Consider need for combination antimicrobial therapy versus monotherapy

4. Therapy should be at appropriately aggressive doses

5. Consider pharmacokinetic properties of potentially used agents and potential alterations

6. Consider pharmacodynamic properties of potentially used agents

7. Consider age, organ dysfunction, and site of infection when determining proper dose

8. Consider potential drug-related adverse effects and toxicities

9. Consider potentially relevant drug-drug or drug–disease state interactions

10. Consider use of less expensive agents when appropriate

CONSIDER USE OF ORAL ANTIMICROBIALS WHEN APPROPRIATE

1. Patients clinically responding to parenteral therapy

2. Patients have functional gastrointestinal tracts

3. Suitable oral alternatives to parenteral therapy available

PERFORM CAREFUL PATIENT MONITORING FOR DURATION OF ANTIMICROBIAL THERAPY

1. Evaluate for clinical resolution of signs and symptoms and evidence of response to therapy

2. Evaluate for changes in organ function that may require change in drug dosing regimen

3. Monitor serum drug concentrations when appropriate

4. Evaluate for drug-related adverse effects and toxicities

5. Evaluate for potential adverse drug interactions

CAREFULLY REASSESS PATIENTS WHO SEEM TO BE FAILING ANTIMICROBIAL THERAPY

1. Evaluate patient for unidentified or new sources or sites of infection or superinfection

2. Obtain additional specimens for culture and susceptibility testing

3. Evaluate drug regimen for proper spectrum of activity against known or presumed pathogens

4. Consider emergence of antibiotic resistance among certain pathogens (e.g., P aeruginosa)

5. Evaluate drug regimen for proper dosing of individual antimicrobial agents

6. Consider pharmacokinetic and pharmacodynamic properties of agents and potential need for increased daily doses or alternative dosing methods

LIMIT DURATION OF THERAPY WHEN POSSIBLE

1. Short courses are desired over long courses in patients who have responded promptly to antimicrobial therapy

2. In patients with no documented infection or pathogens, discontinue antimicrobials after appropriate course of therapy and assess continued need for treatment

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