Chemotherapy of infections

Chemotherapy of infections

Chemotherapy is the term originally used to describe the use of drugs that are selectively toxic to invading micro-organisms (viruses, bacteria, protozoa, fungi, worms) while having minimal effects on the host. By convention, the term is also used to include therapy of cancer.

Antibiotics: substances produced by some micro-organisms (or by pharmaceutical chemists) that kill or inhibit the growth of other micro-organisms

Principles of Anti-microbial (Antibiotic) Therapy

Selection of Antimicrobial Agents

Selection of the most appropriate antimicrobial agent requires knowledge of:

1) The organism s identity,

2) The organism s susceptibility to a particular agent,

3) The site of the infection,

4) Patient factors,

5) The safety of the agent, and

6) The cost of therapy.

I. Identification of the infecting organism

1. Gram stain

2. Culture and sensitivity: (it is essential to obtain a sample for culture of the organism prior to initiating treatment).

it is essential to obtain a sample for culture of the organism prior to initiating treatment).

3. Definitive identification: detection of microbial antigens, microbial DNA or RNA, or detection of an inflammatory or host immune response to the microorganism. BUT…..

detection of microbial antigens, microbial DNA or RNA, or detection of an inflammatory or host immune response to the microorganism. BUT….. it is essential to obtain a sample for culture of the organism prior to initiating treatment). detection of microbial antigens, microbial DNA or RNA, or detection of an inflammatory or host immune response to the microorganism. BUT….. it is essential to obtain a sample for culture of the organism prior to initiating treatment). detection of microbial antigens, microbial DNA or RNA, or detection of an inflammatory or host immune response to the microorganism. BUT…..

Empiric therapy prior to identification of the organism

Used for critically ill patients, in whom such a delay could prove fatal, and immediate therapy is indicated.

1. Timing: Therapy is initiated after specimens for laboratory analysis have been obtained but before the results of the culture are available.

Therapy is initiated after specimens for laboratory analysis have been obtained but before the results of the culture are available.

2. Selecting a drug: The choice of drug in the absence of susceptibility data is influenced by the site of infection and the patient s history.

: The choice of drug in the absence of susceptibility data is influenced by the site of infection and the patient s history.

Broad-spectrum therapy may be needed initially for serious infections when the identity of the organism is unknown or the site makes a polymicrobial infection likely.

ز The choice of agents may also be guided by known association of particular organisms with infection in a given clinical setting. For example, a gram-positive coccus in the spinal fluid of a newborn infant is most likely to be Streptococcus agalactiae (Group B), which is sensitive to penicillin G.By contrast, a gram-positive coccus in the spinal fluid of a 40-year-old patient is most likely to be S. pneumoniae. This organism is frequently resistant to penicillin G and often requires treatment with a third-generation cephalosporin (such as cefotaxime or ceftriaxone) or vancomycin.

II. Determination of 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 to various antibiotics and require susceptibility testing to determine appropriate antimicrobial therapy.

, 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.

The minimum inhibitory and bactericidal concentrations (MIC, MBC) of a drug can be experimentally determined.

ز Minimum inhibitory concentration: the lowest concentration of antibiotic that inhibits bacterial growth. To provide effective antimicrobial therapy, the clinically obtainable antibiotic concentration in body fluids should be greater than the MIC. the lowest concentration of antibiotic that inhibits bacterial growth. To provide effective antimicrobial therapy, the clinically obtainable antibiotic concentration in body fluids should be greater than the MIC.

the lowest concentration of antibiotic that inhibits bacterial growth. To provide effective antimicrobial therapy, the clinically obtainable antibiotic concentration in body fluids should be greater than the MIC.

ز Minimum bactericidal concentration: the lowest concentration of antimicrobial agent that results in a 99.9 percent decline in colony count after overnight broth dilution incubations. the lowest concentration of antimicrobial agent that results in a 99.9 percent decline in colony count after overnight broth dilution incubations.

the lowest concentration of antimicrobial agent that results in a 99.9 percent decline in colony count after overnight broth dilution incubations.

Bacteriostatic versus bactericidal drugs

Bacteriostatic drugs arrest the growth and replication of bacteria at serum levels achievable in the patient, thus limiting the spread of infection while the body s immune system attacks, immobilizes, and eliminates the pathogens.

Bactericidal drugs kill bacteria at drug serum levels achievable in the patient. Because of their more aggressive antimicrobial action, these agents are often the drugs of choice in seriously ill patients. Note: chloramphenicol : chloramphenicol is bacteriostatic against gram-negative rods and is bactericidal against other organisms, such as S. pneumoniae.

III. Effect of the site of infection on therapy: The blood-brain barrier (BBB)

Factors which influence the penetration of a drug into the CSF:

a. Lipid solubility of the drug: e.g., the quinolones and metronidazole are lipid-soluble drugs have significant penetration into the CNS while , ?-lactams, such as penicillins, are ionized at physiologic pH and have low solubility in lipids. (limited penetration)

Some drugs e.g., ?-lactams can then enter the CSF in therapeutic amount in meningitis (barrier’s permeability is increased)

b. Molecular weight of the drug: low M.Wt. drugs have enhanced ability to cross BBB (e.g., vancomycin has a high M.Wt. so it penetrates poorly, even in the presence of meningeal inflammation.)

low M.Wt. drugs have enhanced ability to cross BBB (e.g., a high M.Wt. so it penetrates poorly, even in the presence of meningeal inflammation.)

c. Protein binding of the drug: free (unbound) drug rather than the total amount of drug present in serum, is important for CSF penetration.

free (unbound) drug rather than the total amount of drug present in serum, is important for CSF penetration.e.g., the quinolones and arelipid-soluble drugshave significant penetration into the CNS while

IV. Patient factors

In selecting an antibiotic, attention must be paid to the condition of the patient e.g., the status of the patient s immune system, kidneys, liver, circulation, and age must be considered. In women, pregnancy or breastfeeding also affects selection of the antimicrobial agent.

Pregnancy: All antibiotics cross the placenta. Adverse effects to the fetus are rare, except 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. See (Figure 30.6 in textbook). (United States Food and Drug Administration categories of antimicrobials and fetal risk).

Lactation: Although the concentration of an antibiotic in breast milk is usually low, the total dose to the infant may be enough to cause problems.

Although the concentration of an antibiotic in breast milk is usually low, the total dose to the infant may be enough to cause problems.

V. 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.

All antibiotics cross the placenta. Adverse effects to the fetus are rare, except 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. See ( drugs kill bacteria at drug serum levels achievable in the patient. Because of their more aggressive antimicrobial action, these agents are often the drugs of choice in seriously ill patientse.g., the quinolones and arelipid-soluble drugshave significant penetration into the CNS while

VI. Cost of therapy: (see Figure 30.7 in textbook)

Determinants of Rational Dosing

Rational Dosing of drugs is based on their pharmacodynamics as well as their pharmacokinetic properties. Three important properties that have a significant influence on the frequency of dosing are concentration-dependent killing, time-dependent killing, and postantibiotic effect. (See Figure 30.8 textbook)

Utilizing these properties to optimize antibiotic dosing regimens will improve clinical outcomes and possibly decrease the development of resistance.

A. Concentration-dependent killing: Certain antimicrobial agents, including aminoglycosides, fluoroquinolones, and carbapenems 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 (Figure 30.8A). Giving such drugs by a once-a-day bolus infusion achieves high peak levels, favoring rapid killing of the infecting pathogen.

: Certain antimicrobial agents, including aminoglycosides, fluoroquinolones, and carbapenems 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 (Figure 30.8A). Giving such drugs 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, B-lactams, glycopeptides, macrolides, clindamycin, and linezolid do not exhibit this property; that is, increasing the concentration of antibiotic to higher multiples of the MIC does not significantly increase the rate of killing (Figure 30.8B).

: By contrast, B-lactams, glycopeptides, macrolides, and do not exhibit this property; that is, increasing the concentration of antibiotic to higher multiples of the MIC does not significantly increase the rate of killing (Figure 30.8B).

· For example, for the penicillins and cephalosporins, dosing schedules that ensure blood levels greater than the MIC 60 to 70 percent of the time have been demonstrated to be clinically effective. Some experts therefore suggest that some severe infections are best treated by continuous infusion of these agents rather than by intermittent dosing.

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.

: The postantibiotic effect (PAE) is a persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC.

· 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.

Combinations of Antimicrobial Drugs

It is therapeutically advisable to use single agent that is most specific for the infecting organism. This strategy reduces the possibility of superinfection, decreases the emergence of resistant organisms (see below), and minimizes toxicity.

However, situations in which combinations of drugs are employed do exist. For example, the treatment of tuberculosis benefits from drug combinations.

ز A. Advantages of drug combinations

Certain combinations of antibiotics, such as B-lactams + aminoglycosides = synergism ( 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.

ز B. Disadvantages of drug combinations

A number of antibiotics act only when organisms are multiplying (bactericidal).

Bacteriostatic + bactericidal = first drug interfering with the action of the second e.g.,tetracyclines + penicillins or cephalosporins.

Drug Resistance

ز 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.

Resistance may be:

1. Inherited: e.g., gram-negative organisms are resistant to vancomycin.

2. Acquired: spontaneous mutation or resistance and selection. (may be 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 (Figure 30.11).

DNA transfer of drug resistance: Of particular clinical concern is resistance acquired due to DNA transfer from one bacterium to another. Resistance properties are usually encoded in extrachromosomal R factors (resistance plasmids).

Of particular clinical concern is resistance acquired due to DNA transfer from one bacterium to another. Resistance properties are usually encoded in extrachromosomal ( ).

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 (see Figure 30.11).

1. Modification of target sites: For example, S. pneumoniae resistance to ?-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 or increased efflux 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.

Decreased uptake or increased efflux 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 ?-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. Enzymic inactivation: The ability to destroy or inactivate the antimicrobial agent can also confer resistance on microorganisms.

The ability to destroy or inactivate the antimicrobial agent can also confer resistance on microorganisms.

Examples of antibiotic-inactivating enzymes include:

a. B-lactamases (penicillinase) that hydrolytically inactivate the B-lactam ring of penicillins, cephalosporins, and related drugs;

(penicillinase) that hydrolytically inactivate the B-lactam ring of penicillins, cephalosporins, and related drugs;

b. acetyltransferases that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or aminoglycosides; and

that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or aminoglycosides; and

c. esterases that hydrolyze the lactone ring of macrolides.

Prophylactic Antibiotics

ز Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections.

ز 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 is dictated by the duration of the risk of infection.

Indications of Prophylactic Antibiotics:

1. Prevention of streptococcal infections in patients with a history of rheumatic heart disease. Patients may require years of treatment.

2. Pretreatment of patients undergoing dental extractions who have implanted prosthetic device, such as artificial heart valves, to prevent seeding of the prosthesis.

3. Prevention of tuberculosis or meningitis among individuals who are in close contact with infected patients.

4. Treatment prior to certain surgical procedures (such as bowel surgery, joint replacement and some gynecologic intervention) to prevent infection.

5. Treatment of the mother with zidovudine to protect the fetus in the case of an HIV-infected pregnant woman.

Complications of Antibiotic Therapy

A. Hypersensitivity: frequently occur. E.g., penicillins.

frequently occur. E.g., penicillins.

B. Direct toxicity: E.g., aminoglycosides can cause ototoxicity.

E.g., aminoglycosides can cause ototoxicity.

C. Superinfections: 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.

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.frequently occur. E.g., penicillins. E.g., aminoglycosides can cause ototoxicity.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.For example, S. pneumoniae resistance to prior to identification of the organism the lowest concentration of antibiotic that inhibits bacterial growth. To provide effective antimicrobial therapy, the clinically obtainable antibiotic concentration in body fluids should be greater than the MIC. the lowest concentration of antimicrobial agent that results in a 99.9 percent decline in colony count after overnight broth dilution incubations. drugs arrest the growth and replication of bacteria at serum levels achievable in the patient, thus limiting the spread of infection while the body s immune system attacks, immobilizes, and eliminates the pathogens. drugs kill bacteria at drug serum levels achievable in the patient. Because of their more aggressive antimicrobial action, these agents are often the drugs of choice in seriously ill patientse.g., the quinolones and arelipid-soluble drugshave significant penetration into the CNS while frequently occur. E.g., penicillins. E.g., aminoglycosides can cause ototoxicity.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.