Basic principles of antimicrobial therapy

CHAPTER 83


Basic principles of antimicrobial therapy


With this chapter we begin our study of drugs used to treat infectious diseases. These drugs are given to about 30% of all hospitalized patients, and constitute one of our most widely used groups of medicines.


Modern antimicrobial agents had their debut in the 1930s and 1940s, and have greatly reduced morbidity and mortality from infection. As newer drugs are introduced, our ability to fight infections increases even more. However, despite impressive advances, continued progress is needed. Why? Because there are organisms that respond poorly to available drugs; there are effective drugs whose use is limited by toxicity; and there is, because of evolving microbial resistance, the constant threat that currently effective antibiotics will be rendered useless.


In this introductory chapter, we focus on two principal themes. The first is microbial susceptibility to drugs, with special emphasis on resistance. The second is clinical usage of antimicrobials. Topics addressed include criteria for drug selection, host factors that modify drug use, use of antimicrobial combinations, and use of antimicrobial agents for prophylaxis.


Before going further, we need to consider three terms: chemotherapy, antibiotic, and antimicrobial agent. Although we often think of chemotherapy as the use of drugs to kill or suppress cancer cells, this term was first defined as the use of chemicals against invading organisms (eg, bacteria, viruses, fungi). Today, the word is applied to the treatment of both cancer and infection. Hence, not only do we speak of cancer chemotherapy, we also speak of chemotherapy of infectious diseases.


In common practice, the terms antibiotic and antimicrobial drug are used interchangeably, as they are in this book. However, be aware that the formal definitions of these words are not identical. Strictly speaking, an antibiotic is a chemical that is produced by one microbe and has the ability to harm other microbes. Under this definition, only those compounds that are actually made by microorganisms qualify as antibiotics. Drugs such as the sulfonamides, which are produced in the laboratory, would not be considered antibiotics under the strict definition. In contrast, an antimicrobial drug is defined as any agent, natural or synthetic, that has the ability to kill or suppress microorganisms. Under this definition, no distinction is made between compounds produced by microbes and those made by chemists. From the perspective of therapeutics, there is no benefit to distinguishing between drugs made by microorganisms and drugs made by chemists. Hence, the current practice is to use the terms antibiotic and antimicrobial drug interchangeably.




Selective toxicity





How is selective toxicity achieved?

How can a drug be highly toxic to microbes but harmless to the host? The answer lies with differences in the cellular chemistry of mammals and microbes. There are biochemical processes critical to microbial well-being that do not take place in mammalian cells. Hence, drugs that selectively interfere with these unique microbial processes can cause serious injury to microorganisms while leaving mammalian cells intact. Three examples of how we achieve selective toxicity are discussed below.




Inhibition of an enzyme unique to bacteria.

The sulfonamides represent antibiotics that are selectively toxic because they inhibit an enzyme critical to bacterial survival but not to our survival. Specifically, sulfonamides inhibit an enzyme needed to make folic acid, a compound required by all cells, both mammalian and bacterial. If we need folic acid, why don’t sulfonamides hurt us? Because we can use folic acid from dietary sources. In contrast, bacteria must synthesize folic acid themselves (because, unlike us, they can’t take up folic acid from the environment). Hence, to meet their needs, bacteria first take up para-aminobenzoic acid (PABA), a precursor of folic acid, and then convert the PABA into folic acid. Sulfonamides block this conversion. Since mammalian cells do not make their own folic acid, sulfonamide toxicity is limited to microbes.




Classification of antimicrobial drugs


Various schemes are employed to classify antimicrobial drugs. The two schemes most suited to our objectives are considered below.




Classification by susceptible organism

Antibiotics differ widely in their antimicrobial activity. Some agents, called narrow-spectrum antibiotics, are active against only a few species of microorganisms. In contrast, broad-spectrum antibiotics are active against a wide variety of microbes. As discussed below, narrow-spectrum drugs are generally preferred to broad-spectrum drugs.


Table 83–1 classifies the major antimicrobial drugs according to susceptible organisms. The table shows three major groups: antibacterial drugs, antifungal drugs, and antiviral drugs. In addition, the table subdivides the antibacterial drugs into narrow-spectrum and broad-spectrum agents, and indicates the principal classes of bacteria against which they are active.




Classification by mechanism of action

The antimicrobial drugs fall into seven major groups based on mechanism of action. This classification is summarized in Table 83–2. Properties of the seven major classes are discussed briefly below.




• Drugs that inhibit bacterial cell wall synthesis or activate enzymes that disrupt the cell wall—These drugs (eg, penicillins, cephalosporins) weaken the cell wall and thereby promote bacterial lysis and death.


• Drugs that increase cell membrane permeability—Drugs in this group (eg, amphotericin B) increase the permeability of cell membranes, causing leakage of intracellular material.


• Drugs that cause lethal inhibition of bacterial protein synthesis—The aminoglycosides (eg, gentamicin) are the only drugs in this group. We do not know why inhibition of protein synthesis by these agents results in cell death.


• Drugs that cause nonlethal inhibition of protein synthesis—Like the aminoglycosides, these drugs (eg, tetracyclines) inhibit bacterial protein synthesis. However, in contrast to the aminoglycosides, these agents only slow microbial growth; they do not kill bacteria at clinically achievable concentrations.


• Drugs that inhibit bacterial synthesis of DNA and RNA or disrupt DNA function—These drugs inhibit synthesis of DNA or RNA by binding directly to nucleic acids or by interacting with enzymes required for nucleic acid synthesis. They may also bind with DNA and disrupt its function. Members of this group include rifampin, metronidazole, and the fluoroquinolones (eg, ciprofloxacin).


• Antimetabolites—These drugs disrupt specific biochemical reactions. The result is either a decrease in the synthesis of essential cell constituents or synthesis of nonfunctional analogs of normal metabolites. Examples of antimetabolites include trimethoprim and the sulfonamides.


• Drugs that suppress viral replication—Most of these drugs inhibit specific enzymes—DNA polymerase, reverse transcriptase, protease, integrase, or neuraminidase—required for viral replication and infectivity.


When considering the antibacterial drugs, it is useful to distinguish between agents that are bactericidal and agents that are bacteriostatic. Bactericidal drugs are directly lethal to bacteria at clinically achievable concentrations. In contrast, bacteriostatic drugs can slow bacterial growth but do not cause cell death. When a bacteriostatic drug is used, elimination of bacteria must ultimately be accomplished by host defenses (ie, the immune system working in concert with phagocytic cells).



Acquired resistance to antimicrobial drugs


In this section, we discuss bacterial resistance to antibiotics, which may be innate (natural, inborn), or acquired over time. Discussion here is limited to acquired resistance, which is a much greater clinical concern than innate resistance.


Over time, an organism that had once been highly sensitive to an antibiotic may become less susceptible, or it may lose drug sensitivity entirely. In some cases, resistance develops to several drugs. Acquired resistance is of great concern in that it can render currently effective drugs useless, thereby creating a clinical crisis and a constant need for new antimicrobial agents. As a rule, antibiotic resistance is associated with extended hospitalization, significant morbidity, and excess mortality. Organisms for which drug resistance is now a serious problem include Enterococcus faecium, Staphylococcus aureus, Enterobacter species, Pseudomonas aeruginosa, Acinetobacter baumanii, Klebsiella species, and Clostridium difficile (Table 83–3). Two of these resistant bacteria—methicillin-resistant Staph. aureus and C. difficile—are discussed at length in Chapter 84 (Box 84–1) and Chapter 85 (Box 85–1), respectively.



TABLE 83–3 


Drugs for Some Highly Resistant Bacteria





















































































Bacterium Resistance Resistance Mechanism Alternative Treatments
Enterococcus faecium Ampicillin Mutation and overexpression of PBP5 Quinupristin/dalfopristin, daptomycin, tigecycline, linezolid
  Linezolid Production of altered 23S ribosomes Quinupristin/dalfopristin, daptomycin, tigecycline
  Daptomycin Unknown Quinupristin/dalfopristin
  Quinupristin/dalfopristin Production of enzymes that inactivate quinupristin/dalfopristin, altered drug target Daptomycin, tigecycline, linezolid
  Aminoglycosides Production of aminoglycoside-modifying enzymes, ribosomal mutations No reliable alternative available
Staphylococcus aureus* Vancomycin Thickening of cell wall and altered structure of cell wall precursor molecules Quinupristin/dalfopristin, daptomycin, tigecycline, linezolid, telavancin, ceftobiprole
  Daptomycin Altered structure of cell wall and cell membrane Quinupristin/dalfopristin, tigecycline, linezolid, telavancin, ceftobiprole
  Linezolid Production of altered 23S ribosomes Quinupristin/dalfopristin, daptomycin, tigecycline, telavancin, ceftobiprole, ceftaroline
Enterobacter species Ceftriaxone, cefotaxime, ceftazidime, cefepime Production of extended-spectrum beta-lactamases Carbapenems, tigecycline
  Carbapenems Production of carbapenemases, decreased permeability Polymyxins, tigecycline
Klebsiella species Ceftriaxone, cefotaxime, ceftazidime, cefepime Production of extended-spectrum beta-lactamases Carbapenems, tigecycline
  Carbapenems Production of carbapenemases, decreased permeability Polymyxins, tigecycline
Pseudomonas aeruginosa Carbapenems Decreased permeability, increased drug efflux, production of carbapenemases Polymyxins
Acinetobacter baumannii Carbapenems Decreased permeability, increased drug efflux, production of carbapenemases Polymyxins
Clostridium difficile† Metronidazole Reduced drug activation, increased drug efflux, increased repair of drug-induced DNA damage Vancomycin, rifaximin


image


PBP5 = penicillin-binding protein 5.


*Methicillin-resistant Staphylococcus aureus is discussed at length in Chapter 84 (see Box 84–1).


†Clostridium difficile infection is discussed at length in Chapter 85 (see Box 85–1).


In the discussion that follows, we examine the mechanisms by which microbial drug resistance is acquired and the measures by which emergence of resistance can be delayed. As you read this section, keep in mind that it is the microbe that becomes drug resistant, not the patient.



Microbial mechanisms of drug resistance


Microbes have four basic mechanisms for resisting drugs. They can (1) decrease the concentration of a drug at its site of action, (2) alter the structure of drug target molecules, (3) produce a drug antagonist, and (4) cause drug inactivation.







Drug inactivation.

Microbes can resist harm by producing drug-metabolizing enzymes. For example, many bacteria are resistant to penicillin G because of increased production of penicillinase, an enzyme that inactivates penicillin. In addition to penicillins, bacterial enzymes can inactivate other antibiotics, including cephalosporins, carbapenems, and fluoroquinolones.



New delhi metallo-beta-lactamase 1 (ndm-1) gene.


Extensive drug resistance is conferred by the NDM-1 gene, which codes for a powerful form of beta-lactamase. As discussed in Chapters 84 and 85, beta-lactamases are enzymes that can inactivate drugs that have a beta-lactam ring. The form of beta-lactamase encoded by NDM-1 is both unusual and troubling in that it can inactivate essentially all beta-lactam antibiotics, a group that includes penicillins, cephalosporins, and carbapenems. Worse yet, the DNA segment that contains the NDM-1 gene also contains genes that code for additional resistance determinants, including drug efflux pumps, and enzymes that can inactivate other important antibiotics, including erythromycin, rifampicin, chloramphenicol, and fluoroquinolones. Furthermore, all of these genes are present on a plasmid, a piece of DNA that can be easily transferred from one bacterium to another (see below). Of note, bacteria that have the NDM-1 gene are resistant to nearly all antibiotics, except for tigecycline and colistin. Since its discovery in Klebsiella pneumoniae in 2008, NDM-1 has been found in other common enteric bacteria, including Escherichia coli, Enterobacter, Salmonella, Citrobacter freundii, Providencia rettgeri, and Morganella morganii. To date, only a few cases of NDM-1 infection have been reported in the United States and Canada.



Mechanisms by which resistance is acquired


How do microbes acquire mechanisms of resistance? Ultimately, all of the alterations in structure and function discussed above result from changes in the microbial genome. These genetic changes may result either from spontaneous mutation or from acquisition of DNA from an external source. One important mechanism of DNA acquisition is conjugation with other bacteria.





Conjugation.

Conjugation is a process by which extrachromosomal DNA is transferred from one bacterium to another. In order to transfer resistance by conjugation, 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. Together, these two DNA segments constitute an R factor (resistance factor).


Conjugation takes place primarily among gram-negative bacteria. Genetic material may be transferred between members of the same species or between members of different species. 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. Because R factors are becoming common in normal flora, the possibility of transferring resistance from normal flora to pathogens is a significant clinical concern.


In contrast to spontaneous mutation, conjugation frequently confers multiple drug resistance. This can be achieved, for example, by transferring DNA that codes for several different drug-metabolizing enzymes. Hence, in a single event, a drug-sensitive bacterium can become highly drug resistant.



Relationships between antibiotic use and emergence of drug-resistant microbes


Use of antibiotics promotes the emergence of drug-resistant microbes. Please note, however, that although antibiotics promote drug resistance, they are not mutagenic and do not directly cause the genetic changes that underlie reduced drug sensitivity. Spontaneous mutation and conjugation are random events whose incidence is independent of drug use. Drugs simply make conditions favorable for overgrowth of microbes that have acquired mechanisms for resistance.




How do antibiotics promote resistance?

To answer this question, we need to recall two aspects of microbial ecology: (1) microbes secrete compounds that are toxic to other microbes, and (2) microbes within a given ecologic niche (eg, large intestine, urogenital tract, skin) compete with each other for available nutrients. Under drug-free conditions, the various microbes in a given niche keep each other in check. Furthermore, if none of these organisms is drug resistant, introduction of antibiotics will be equally detrimental to all members of the population, and therefore will not promote the growth of any individual. However, if a drug-resistant organism is present, antibiotics will create selection pressure favoring its growth. How? By killing off sensitive organisms, the drug will eliminate the toxins they produce, and will thereby facilitate survival of the microbe that is drug resistant. Also, elimination of sensitive organisms will remove competition for available nutrients, thereby making conditions even more favorable for the resistant microbe to flourish. Hence, although drug resistance is of no benefit to an organism when there are no antibiotics present, when antibiotics are introduced, they create selection pressure favoring overgrowth of microbes that are resistant.




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Jul 24, 2016 | Posted by in NURSING | Comments Off on Basic principles of antimicrobial therapy

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