Chapter 79 - Basic Principles Of Antimicrobial Therapy

CHAPTER 79

BASIC PRINCIPLES

OF

ANTIMICROBIAL

THERAPY

Drugs used to treat infectious diseases constitute one of our most widely used families of medicines. - despite impressive advances, continued progress is needed = there are organisms that respond poorly to available drugs; there are effective drugs whose use is limited by toxicity; there is the constant threat that currently effective antibiotics will be rendered useless Drug Clarification: chemotherapy – use of drugs to kill or suppress cancer cells; use of chemicals against invading organisms antibiotic – chemical that is produced by one microorganism and has the ability to harm other microbes - only those compounds that are actually made by microorganisms qualify as antibiotics antimicrobial drug – any agent, natural or synthetic, with the ability to kill or suppress microorganisms What is selective toxicity?

I.

SELECTIVE TOXICITY

II.

CLASSIFICATION

selective toxicity – ability of a drug to injure a target cell or target organism without injuring other cells or organisms that are in intimate contact with the target - as applied to antimicrobial drugs, indicates the ability of an antibiotic to kill or suppress infecting microbes without causing injury to the host - property that make antibiotics valuable

OF

ANTIMICROBIAL DRUGS

A.

CLASSIFICATION BY SUSCEPTIBLE ORGANISM What is the difference between narrow and broad spectrum antibiotics? Which is better? narrow-spectrum antibiotics – active against only a few species of microorganisms - generally preferred broad-spectrum antibiotics – active against a wide variety of microbes - for successful therapy, one must choose an antibiotic that is active against specific organism responsible for the infection to be treated What is the difference between bactericidal and bacteriostatic drugs?

1.

Groups: a. antibacterial drugs bactericidal drugs – directly lethal to bacteria at clinically achievable concentrations - ex. Penicillin bacteriostatic drugs – slow microbial growth but do not cause cell death - elimination of bacteria must ultimately be accomplished by host defenses (immune system working in concert with phagocytic cells) - ex. Tetracycline

2.

III.

b. antifungal drugs c. antiviral drugs Classification of Mechanism of Action • Inhibition of cell wall synthesis or activate enzymes that disrupt the cell wall (penicillin, cephalosporin) • Drugs that increase cell membrane permeability • Drugs that cause lethal inhibition of bacterial protein synthesis (aminoglycosides) • drugs that cause non-lethal inhibition of protein synthesis (tetracyclines) • drugs that inhibit bacterial synthesis of nucleic acids (fluroquinolones) • Antimetabolites (sulpha) • Inhibitors of viral enzymes (antivirals)

ACQUIRED RESISTANCE

TO

ANTIMICROBIAL DRUGS

- keep in mind, it is the microbe that becomes drug resistant, not the

patient 1.

Mechanisms by which Resistance is Acquired - alterations in structure and function are brought about by changes in the microbial genome a.

Spontaneous Mutation – produce random changes in a microbe’s

DNA - result is a gradual increase in resistance - confer resistance to only one drug b. Conjunction – process by which extra chromosomal DNA is transferred from one bacterium to another - to transfer resistance, the donor organism must possess two unique DNA segments, one that codes for the mechanisms of drug resistance and one that codes for

the “sexual” apparatus required for DNA transfer - constitute an R factor (resistance factor) - because transfer of R factors is not species specific, it is possible for pathogenic bacteria to acquire R factors from the normal flora of the body - serious clinical concern - frequently results in multiple drug resistance 2. Relationships between Antibiotic Use and Emergence of DrugResistant Microbes - use of antibiotics promotes the emergence of drug-resistant microbes - antibiotics are not mutagenic and do not directly cause the genetic changes that underlie reduced drug sensitivity - drugs simply serve to make conditions favorable for overgrowth of those microbes that have already acquired mechanisms for drug resistance - spontaneous mutation and conjugation incidence are independent of drug use a.

How Antibiotics Promote Resistance - if a drug-resistant organism is present, antibiotics will create selection pressure favoring the growth of that microbe - by killing off the sensitive organisms, the drug will eliminate toxins produced by those microbes, facilitating survival of the microbe that is drug resistant - elimination of sensitive organisms will remove competition for available nutrients, making conditions even more favorable for the drugresistant microbe to flourish b.

Which Antibiotics Promote Resistance? - all antimicrobial drugs promote the emergence of drugresistant organisms c. Does the Amount of Antibiotic Use Influence the Emergence of Resistance? - YES, the more that antibiotics are used, the faster drugresistant organisms emerge - every effort should be made to avoid use of antibiotics by individuals who don’t actually need them Why does drug resistance occur? What is a nosocomial infection? Give an example of one. nosocomial infections – infections acquired in hospitals, typically caused by invasive devices

(foley catheters, subclavian catheters, endotracheal tubes, etc.) - most difficult to treat - ex. UTI from catheters is the most common ventilator associated pneumonia Can you provide an example of a suprainfection? A. SUPRAINFECTION – special example of the emergence of drug resistance - new infection that appears during the course of treatment for a primary infection - more likely in patients receiving broad-spectrum agents - caused by drug-resistant microbes and are often difficult to treat - referred to as superinfections - ex. when a patient is being treated with antibiotics for several weeks and develops oral thrush Please list the 12 steps to prevent antimicrobial resistance among hospitalized adults 1. 12 Steps to Prevent Antimicrobial Resistance Prevent Infection a. Vaccinate – reduces the use of antimicrobial drugs, helping to prevent emergence of resistance - recommendation that predischarge vaccination of all at-risk patients, especially against two repiratory infections; influenza and pneumococcal pneumonia; all health care personnel who have patient care duties should receive a flu shot annually b. Get the Catheters Out – catheters and other invasive devises are the leading exogenous cause of nosocomial infections - can occur in association with IV catheters, arterial catheters, urinary tract catheters, endotracheal tubes, and other devices - catheters should be used only when essential for patient care, and should be removed as soon as they are no longer needed What does Culture and Sensitivity mean? Diagnose and Treat Infection Effectively c. Target the Pathogen – choose drugs that are active against the causative organism - determine both the identity and drug sensitivity of the pathogen - culture and sensitivity

d. Access the Experts – input from infectious disease expert can improve patient outcomes, decrease treatment costs, and shorten the time to discharge - especially helpful in: patients with serious infections patients receiving complex antimicrobial regimens patients who fail to respond as expected patients with complicated underlying illnesses Use Antimicrobials Wisely e. Practice Antimicrobial Control – most effective option is to implement a computerized support system designed to help clinicians select antimicrobial regimens - measures include use of standardized antimicrobial order forms, providing interactive education for prescribers, giving individual prescribers critical feedback on their choices, and establishing a multidisciplinary system to evaluate drug utilization f. Use Local Data – drug susceptibility of microbes varies over time and according to locale, patient population, and hospital unit - compile data on drug susceptibility into an “antibiogram”, providing an overview of common local pathogens and their current pattern of drug sensitivity g. Treat Infection, Not Contamination – contamination of culture samples can lead to false-positive results on bacteriologic tests, leading to unneeded treatment with antimicrobial drugs - major cause of unnecessary antimicrobial use h. Treat Infection, Not Colonization – a small, localized colony of bacteria does not constitute an infection - colonization is a concern because: in patients who do not have an active infection, treatment because of colonization would be an unnecessary use of antibiotics in patients who do have an active infection, wrongly attributing the infection to colonizing bacteria could lead to treatment with drugs that are inactive against the real cause

i. Know when to say “No” to Vanco – vanco is a drug of last resort against several important pathogens, including methicillin-resistant Staphylococcus Aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae - use the drug only when clearly necessary j. Stop Treatment when Infection is Cured or Unlikely – administer antibiotics only when they are actually needed Prevent Transmission k. Isolate the Pathogen – proper containment and disposal of contagious body fluids - reduces the risk of transferring resistant organisms from one patient to another l. Break the Chain of Contagion – WASH YOUR HANDS!!! before and after touching any patient Your patient is being prescribed Bactrim for an urinary tract infection – What education would you provide regarding this antibiotic prescription? 2. Bactrim – Patient Education Are you allergic to Sulfa? Please take all medication as prescribed Drink plenty of fluids with the medication Report sore throat, fever, jaundice (early sign of serious reactions)

IV.

SELECTION

OF

ANTIBIOTICS

- therapeutic objective = produce maximal antimicrobial effects while causing minimal harm to the host Principal Factors: identity of the infecting organism, drug sensitivity of the infecting organism host factors, such as the site of infection and the status of host defenses - usually one drug of first choice may be preferred for several reasons, such as greater efficacy, lower toxicity, or more narrow spectrum - conditions might rule out a first-choice agent, such as allergy to the drug of choice, inability of the drug of choice to penetrate to the site of infection, and unusual susceptibility of the patient to toxicity of the firstchoice drug A.

EMPIRIC THERAPY PRIOR

TO

COMPLETION

OF

LABORATORY TESTS

- drug selection must be based on clinical evaluation and knowledge of which microbes are most likely to cause infection at a particular site - broad-spectrum agent can be used for initial treatment; however, once the identity and drug sensitivity of the infecting organism have been determined, switch to a more selective antibiotic - essential that samples of exudates and body fluids be obtained for culture prior to initiation of treatment - if antibiotics are present, these agents can suppress microbial growth in culture and confound identification B.

IDENTIFYING THE INFECTING ORGANISM - match the drug with the bug - infecting organism should be identified prior to initiation of therapy - quickest, simplest and most versatile technique for identification is microscopic exam of a gramstained preparation - samples can be obtained from pus, sputum, urine, blood, and other body fluids - most useful are direct aspirates from the site of infection - should be taken in a fashion that minimizes contamination with normal body flora - should not be exposed to low temperature, antiseptics, or oxygen C.

DETERMINING DRUG SUSCEPTIBILITY - testing is common, indicated only when the infecting organism is one in which resistance is likely 1.

Disk-Diffusion Test – most widely used method - also known as the Kirby-Bauer test - performed by inoculating an agar plate with the infecting organism and then placing on that plate several small disks, each of which is impregnated with a different antibiotic - growth will be inhibited around the disks that contain an antibiotic to which the bacteria are sensitive What is the Broth Dilution Procedure? 2. Broth Dilution Procedure – bacteria are grown in a series of tubes containing different concentrations of an antibiotic - provides a more precise measure of drug sensitivity - useful for guiding therapy of infections that are unusually difficult to treat - can establish close estimates of:

minimum inhibitory concentration (MIC) – lowest concentration of drug that produces a complete inhibition of bacterial growth (but does not kill bacteria) minimum bacterial concentration (MBC) – lowest concentration of a drug that produces a 99.9% decline in the number of bacterial colonies (indicating bacterial kill)

V. HOST FACTORS DOSAGE

THAT

MODIFY DRUG CHOICE, ROUTE

OF

ADMINISTRATION,

OR

- host defenses and site of infection are unique to the selection of antibiotics - other factors such as age, pregnancy and previous drug reactions are the same factors that must be considered when choosing any other drug A.

HOST DEFENSES - consist primarily of the immune system and phagocytic cells - drugs used to treat infections do not produce cure on their own - they work in concert with host defense system to subdue infection - objective of antibiotic treatment is not outright kill of infecting organisms, rather to suppress microbial growth to the point at which the balance is tipped in favor of the host - people whose defenses are impaired, such as those with AIDS and those undergoing cancer chemotherapy, frequently die from infections that drugs alone are unable to control B.

INFECTION - an antibiotic must be present at the site of infection in a concentration greater than the MIC - drug penetration may be hampered, making it difficult to achieve the MIC - when pus and other fluids hinder drug access, surgical drainage is indicated - foreign materials (cardiac pacemakers, prosthetic joints) present a special local problem - when attempts are made to treat these infections, relapse and failure are common C.

SITE

OF

OTHER HOST FACTORS 1. Age – multiple factors contribute to infants being highly vulnerable to drug toxicity - poorly developed kidney and liver function - drug sensitivity is heightened in the elderly due in large to reduced rates of drug metabolism and drug secretion, which can result in accumulation of antibiotics to toxic levels

2. Pregnancy and Lactation – antimicrobial drugs can cross the placenta and enter breast milk - antibiotic use may pose a risk to the expectant mother also 3. Previous Allergic Reaction – severe allergic reactions are more common with the penicillins than any other family of drugs - patients with a history of allergy to penicillins should not receive them again, except with a lifethreatening infection for which no suitable alternative is available 4. Genetic Factors – genetic factors can influence responses to antibiotics and also affect the rate of metabolism

VI.

DOSAGE SIZE

AND

DURATION

OF

TREATMENT

- successful therapy requires that the antibiotic be present at the site of infection in an effective concentration for a sufficient time - dosages should be adjusted to produce drug concentrations that are equal to or greater than MIC for the infection being treated - drug levels 4 – 8 times the MIC are often desirable - duration of therapy depends on a number of variables, including the status of host defenses, the site of the infection and the identity of the infecting organism - it is imperative that antibiotics not be discontinued prematurely - patients should be instructed to take their medication for the entire prescribed course, even though symptoms may subside before the full course has been completed - early withdrawal is a common cause of recurrent infection, and the organisms responsible for relapse are likely to be more drug resistant

VII. THERAPY

WITH

ANTIBIOTIC COMBINATIONS

- combination of antimicrobial agents is indicated only in specific situations - although antibiotic combinations do have a valuable therapeutic role, routine use of two or more antibiotics should be discouraged A.

ANTIMICROBIAL EFFECTS OF ANTIBIOTIC COMBINATIONS additive response - one in which the antimicrobial effect of the combination is equal to the sum of the effects of the two drugs alone

potentiative interaction – one in which the effect of the combination is greater than the sum of the effects of the individual agents - also called a synergistic interaction - in certain cases, combination of two antibiotics may be less effective than one of the agents by itself - indicate antagonism between the drugs - most likely when bacteriostatic agent (tetracycline) is combined with a bactericidal drug (penicillin) - occurs because bactericidal drugs are usually effective only against organisms that are actively growing - if host defenses are compromised, consequences of antagonism can be dire B.

INDICATIONS FOR ANTIBIOTIC COMBINATIONS 1. Initial Therapy of Severe Infection – until the infecting organism has been identified, wide antimicrobial coverage is indicated - just how broad depends on the clinician’s skill in narrowing the field of potential causative organisms - once the infecting microbe is identified, drug selection can be adjusted accordingly 2. Mixed Infections – multiple infecting organisms are common in brain abscesses, pelvic infections, and infections resulting from perforation of abdominal organs - when the infecting microbes differ from one another in drug susceptibility, treatment with more than one antibiotic is required 3. Prevention of Resistance – one disease – tuberculosis – drug combinations are employed for specific purpose of suppressing the emergence of resistant bacteria 4.

Decreased Toxicity

5.

Enhanced Antibacterial Action

6.

Disadvantages of Antibiotic Combinations • increased risk of toxic and allergic reactions • possible antagonism of antimicrobial effects • increased risk of suprainfeciton • selection of drug-resistant bacteria

•

VIII.

increased cost

PROPHYLACTIC USE

OF

ANTIMICROBIAL DRUGS

- agents are given to prevent infection rather than to treat an established

infection - much of the prophylactic use of antibiotics is uncalled for - when prophylaxis is attempted, benefits must be weighed against the risks of toxicity, allergic reactions, suprainfection, and selection of drug-resistant organisms A.

SURGERY - antibiotics can decrease the incident of infection in certain kinds of surgery, such as cardiac surgery, peripheral vascular surgery, orthopedic surgery, and surgery on the GI tract - beneficial for women undergoing a hysterectomy or an emergency cesarean section - in “dirty” surgery (operations performed on perforated abdominal organs, compound fractures, or lacerations from animal bites), use of antibiotics is considered treatment - when given for prophylaxis, antibiotics should be administered before surgery has begun and may need to be readministered if the procedure is unusually long B.

BACTERIAL ENDOCARDITIS - individuals with congenital or valvular heart disease and those with prosthetic heart valves are unusually susceptible to bacterial endocarditis - endocarditis can develop following surgery, dental procedures, and other procedures that may dislodge bacteria into the bloodstream C.

OTHER INDICATIONS FOR ANTIMICROBIAL PROPHYLAXIS - young women with recurrent urinary tract infection - against type A influenza - severe rheumatic endocarditis - following exposure to organisms responsible for sexually transmitted diseases

IX.

MISUSES

OF

ANTIMICROBIAL DRUGS

A.

ATTEMPTED TREATMENT OF UNTREATABLE INFECTION - majority of viral infections – including mumps, chickenpox, and the common cold do not respond to currently available drugs B.

TREATMENT

OF

FEVER

OF

UNKNOWN ORIGIN

- although fever can be a sign of infection, it can also signify other diseases, including hepatitis, arthritis, and cancer - unless the cause of a fever is a proven infection, antibiotics should not be employed because: • if the fever is not due to an infection, antibiotics would not only be inappropriate, they would expose the patient to unnecessary toxicity and delay correct diagnosis of the fever’s cause • if the fever is caused by infection, antibiotics could hamper later attempts to identify the infecting organism - the only situation in which fever, by itself, constitutes a legitimate indication for antibiotic use is when fever occurs in the severely immunocompromised host C.

IMPROPER DOSAGE - if dosage is too low, the patient will be exposed to a risk of adverse effects without benefit of antibacterial effects - if dosage is too high, the risks of suprainfection and adverse effects become unnecessarily high - lack of identification of the organism is the most common reason for misdosing D.

OMISSION OF SURGICAL DRAINAGE - antibiotics may have limited efficacy in the presence of foreign material, necrotic tissue or pus - when appropriate, surgical drainage and cleansing should be performed to promote antimicrobial effects

X.

MONITORING ANTIMICROBIAL THERAPY - therapy is assessed by monitoring clinical responses and laboratory

results - frequency of monitoring is directly proportional to the severity of infection - indicators of success are reduction of fever and resolution of signs and symptoms related to the affected organ system - serum levels may be monitored: • to ensure that levels are sufficient for antimicrobial effects • to avoid toxicity from excessive levels - success of therapy is indicated by the disappearance of infectious organisms from post-treatment cultures

XI.

ADVERSE EFFECTS •

OF

THERAPY

GI symptoms (nausea, vomiting, diarrhea)

• • •

Suprainfection Organ toxicities o liver o kidney Other o photosensitivity o skin rash