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1、PART VIIIApplied MicrobiologyCHAPTER 15Antimicrobial drugsChapter Overview Antimicrobial drugs include antibiotics derived from bacteria and fungi, and synthetic drugs produced by chemical reactions. Narrow-spectrum antimicrobial drugs affect a small range of microbes, and broad-spectrum drugs affec
2、t a wider range of microbes.Chapter Overview The best antimicrobial drugs have low toxicity to humans and lack other side effects such as drug resistance, allergy, and disruption of natural flora.The primary action of antimicrobial drugs is to interfere with some specific component of the microbes s
3、tructure, its enzymes, or synthesis of proteins and other molecules. Drug resistance is a process by which microbes develop genetic changes that allow them to circumvent the effects of a drug. Hundreds of drugs have been developed for treating bacterial, fungal, protozoan, and viral infections. The
4、predominant antibacterial drug classes are the penicillins, cephalosporins, tetracyclines, sulfa drugs, and fluoroquinolones. Selecting a drug for therapy is based upon the microbes sensitivity to the drug, the drugs toxicity, and the health of the patient. Adverse side effects of drugs include dama
5、ge to skin, liver, kidney, circulatory system, nervous system, and gastrointestinal tract. Drugs may cause allergies and disrupt the hosts normal flora, leading to other infections. Antimicrobial drugs are often overprescribed, ineffective, taken in incorrect doses for too short a time, and broadcas
6、t into the environment in livestock feeds. People need to become aware of the correct guidelines for drug therapy as a way to protect drug diversity and prevent drug resistance.GLOSSARYAntimicrobial drugs: (also termed anti-infective drugs) are a special class of compounds capable even in high dilut
7、ions of destroying or inhibiting microorganisms.Antibiotics: are substances produced by the natural metabolic processes of some microorganisms that can inhibit or destroy other microorganisms.Synthetic antimicrobial drugs: are derived in the laboratory from dyes or other organic compounds, through c
8、hemical reactions.Although separation into these two categories has been traditional, they tend to overlap, because most antibiotics, termed semisynthetic, are now chemically altered in the laboratory. The current trend is to use the term antimicrobic for all antimicrobial drugs, regardless of origi
9、n.Narrow-spectrum agents: are effective against a limited array of different microbial types. Examples are bacitracin(杆菌肽), an antibiotic whose inhibitory effects extend mainly to certain gram-positive bacteria, or griseofulvin, which is used chiefly in fungal skin infections.Broad-spectrum or exten
10、ded-spectrum agents are active against a wider range of different microbes. The targets of antibiotics in the tetracycline group, for example, are a variety of gram-positive and gram-negative bacteria, rickettsias, mycoplasmas, and even protozoa. 15.1 THE ORIGINS OF ANTIMICROBIAL DRUGSNature is undo
11、ubtedly the most prolific producer of antimicrobial drugs.Spore-forming bacteria and fungi are the primary sources of most antibiotics. Thus, the greatest numbers of antibiotics are derived from bacteria in the genera Streptomyces and Bacillus and molds in the genera Penicillium and Cephalosporium.1
12、5.2 MECHANISMS OF DRUG ACTION Antimicrobial drugs function specifically in one of the following ways : (1) They inhibit cell wall synthesis; (2) they inhibit nucleic acid synthesis or function; (3) they inhibit protein synthesis; (4) they interfere with the function of the cell membrane. These categ
13、ories are not completely discrete, and some effects can overlap.1.Antimicrobial Drugs That Affect the Bacterial Cell WallThe cell walls of most bacteria contain a rigid girdle of peptidoglycan, which protects the cell against rupture from hypotonic environments. Active cells must constantly synthesi
14、ze new peptidoglycan and transport it to its proper place in the cell envelope. Drugs such as penicillins and cephalosporins react with one or more of the enzymes required to complete this process, causing the cell to develop weak points at growth sites and to become osmotically fragile.Antibiotics
15、that produce this effect are considered bactericidal, because the weakened cell is subject to lysis. It is essential to note that most of these antibiotics are active only in young, growing cells, because old, inactive, or dormant cells do not synthesize peptidoglycan.(e) Scanning electron micrograp
16、h of bacterial cells in their normal state (10,000). (f) Scanning electron micrograph of the same cells in the drug-affected state, showing surface bulges (10,000).A plate with several discrete colonies of soil bacteria was sprayed with a culture of Escherichia coli and incubated. Zones of inhibitio
17、n (clear areas with no growth) surrounding several colonies indicate species that produce antibiotics.Synthesizing penicillins. (a) The original penicillin G molecule is a fermentation product of Penicillium chrysogenum that appears somewhat like a house with a removable patio on the left. This hous
18、e without the patio is the basic nucleus called aminopenicillanic acid.(b) methicillin; (c) ampicillin; (d) penicillin V.The mode of action of beta-lactam antibiotics on the bacterial cell wall.(a) Intact peptidoglycan has chains of NAM (N-acetyl muramic acid) and NAG (N-acetyl glucosamine) glycans
19、cross-linked by peptide bridges.(b) The beta-lactam antibiotics block the peptidases that link the cross-bridges between NAMs, thereby greatly weakening the cell wall meshwork.Cycloserine inhibits the formation of the basic peptidoglycan subunits.Vancomycin hinders the elongation of the peptidoglyca
20、n. The beta-lactams (penicillins and cephalosporins) bind and block peptidases that cross-link the glycan molecules, thereby interrupting the completion of the cell wall.Penicillins that do not penetrate the outer membrane are less effective against gram-negative bacteria, but broad-spectrum penicil
21、lins and cephalosporins can cross the cell walls of gram-negative species.2. Antimicrobial Drugs That Affect Nucleic Acid SynthesisThe metabolic pathway that generates DNA and RNA is a long, enzyme-catalyzed series of reactions. Like any complicated process, it is subject to breakdown at many differ
22、ent points along the way, and inhibition at any given point in the sequence can block subsequent events. Antimicrobial drugs interfere with nucleic acid synthesis by blocking synthesis of nucleotides, inhibiting replication, or stopping transcription. Because functioning DNA and RNA are required for
23、 proper translation as well, the effects on protein metabolism can be far-reaching.One of the more extensively studied modes of action is that of the sulfonamides (sulfa drugs). Because these synthetic drugs interfere with an essential metabolic process in bacteria, they represent a model for compet
24、itive inhibition. They act as structural or metabolic analogs that mimic the natural substrate of an enzyme and vie for its active site.In practice, sulfa drugs are very similar to the natural metabolic compound PABA (para-aminobenzoic acid) required by bacteria to synthesize the coenzyme tetrahydro
25、folic acid, which participates in the synthesis of purines and certain amino acids. A sulfonamide molecule has high affinity for the PABA site on the enzyme and can successfully compete in a “chemical race with PABA to occupy those sites.Sulfonamides ultimately cause an inadequate supply of tetrahyd
26、rofolic acid for purine production, which invariably halts nucleic acid synthesis and prevents bacterial cells from multiplying. Sulfonamides are valuable in therapy because they inhibit bacteria and certain fungi, but not mammalian cells. This one-sided inhibition stems from a basic nutritional dif
27、ference between humans and microorganisms. Although humans require tetrahydrofolic acid for nucleic acid synthesis as much as bacteria do, humans cannot synthesize it because human cells lack this special enzymatic system. Thus, it is an essential nutrient (vitamin) that must come from the diet, and
28、 human metabolism cannot be inhibited by sulfa drugs.Other antimicrobics inhibit DNA synthesis. Chloroquine (an antimalarial drug) binds and cross-links the double helix. The newer broad-spectrum quinolones inhibit DNA unwinding enzymes or helicases, thereby stopping DNA transcription. Antiviral dru
29、gs that are analogs of purines and pyrimidines (including azidothymidine AZT and acyclovir) insert in the viral nucleic acid and block further replication.3. Drugs That Block TranslationMost inhibitors of translation, or protein synthesis, react with the ribosome-mRNA complex.Two possible targets of
30、 ribosomal inhibition are the 30S subunit and the 50S subunit .Aminoglycosides (streptomycin, gentamicin, for example) insert on sites on the 30S subunit and cause the misreading of the mRNA, leading to abnormal proteins.Tetracyclines block the attachment of tRNA on the A acceptor site and effective
31、ly stop further synthesis. Other antibiotics attach to sites on the 50S subunit in a way that prevents the formation of peptide bonds (chloramphenicol) or inhibits translocation of the subunit during translation (erythromycin).4. Drugs That Disrupt Cell Membrane FunctionThe antibiotic classes that d
32、amage cell membranes have specificity for a particular microbial group, based on differences in the types of lipids in their cell membranes.Polymyxins (多粘菌素) interact with membrane phospholipids, distort the cell surface, and cause leakage of proteins and nitrogen bases, particularly in gram-negativ
33、e bacteria .The detergent action of polymyxin：After passing through the cell wall of gram-negative bacteria, polymyxin binds to the cell membrane and forms abnormal openings that cause the membrane to become leaky.The polyene（多烯）antifungal antibiotics, such as amphotericin B and nystatin (制霉菌素) form
34、 complexes with the sterols（甾醇） on fungal membranes; These complexes cause abnormal openings and seepage of small ions. Unfortunately, this selectivity is not exact, and the universal presence of membranes in microbial and animal cells alike means that most of these antibiotics can be quite toxic to
35、 humans.15.3 THE ACQUISITION OF DRUG RESISTANCEThe wide-scale use of antimicrobics soon led to microbial drug resistance, an adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory.The development of mechanisms for circumventing or inactivati
36、ng antimicrobic drugs is due largely to genetic versatility and adaptability of microbial populations. The property of drug resistance can be intrinsic as well as acquired. Intrinsic drug resistance exists naturally and is not acquired through specific genetic changes. In our context, the term drug
37、resistance will mean resistance acquired by microbes that had formerly been sensitive to the drug.1. How Does Drug Resistance Develop?The genetic events most often responsible for drug resistance are chromosomal mutations or extrachromosomal DNA that are transferred from a resistant species to a sen
38、sitive one.Chromosomal drug resistance usually results from spontaneous random mutations in bacterial populations. The chance that such a mutation will be advantageous is minimal, and the chance that it will confer resistance to a specific drug is lower still.Nevertheless, given the huge numbers of
39、microorganisms in any population and the constant rate of mutation, such mutations do occur. The end result varies from slight changes in microbial sensitivity, which can be overcome by larger doses of the drug, to complete loss of sensitivity.Resistance associated with intermicrobial transfer origi
40、nates from plasmids called resistance (R) factors that are transferred through conjugation, transformation, or transduction. Studies have shown that plasmids encoded with drug resistance are naturally present in microorganisms before they have been exposed to the drug. Many bacteria also maintain tr
41、ansposable drug resistance sequences (transposons) that are duplicated and inserted from one plasmid to another or from a plasmid to the chromosome. Chromosomal genes and plasmids containing codes for drug resistance are faithfully replicated and inherited by all subsequent progeny. This sharing of
42、resistance genes accounts for the rapid proliferation of drug-resistant species. A growing body of evidence points to the ease and frequency of gene transfers in nature, from totally unrelated bacteria living in the bodys normal flora and the environment.Spread of resistance factors: This figure tra
43、ces documented evidence of known cases in which R factors have been transferred among pathogens. Such promiscuous exchange of drug resistance occurs primarily by conjugation and transduction. Most of the bacteria are gram-negative, but Bacillus and Staphylococcus are unrelated gram-positive genera.
44、This phenomenon is responsible for the rapid spread of drug-resistant microbes.2. Specific Mechanisms of Drug ResistanceIn general, a microorganism loses its sensitivity to a drug by expressing genes that stop the action of the drug. Gene expression takes the form of: (1) Synthesis of enzymes that i
45、nactivate the drug;(2) Decrease in cell permeability and uptake of the drug;(3) Change in the number or affinity of the drug receptor sites;(4) Modification of an essential metabolic pathway.Some bacteria can become resistant indirectly by lapsing into dormancy.Or, in the case of penicillin, by conv
46、erting to a cell-wall-deficient form (L form) that penicillin cannot affect.(1) Drug Inactivation MechanismsMicrobes inactivate drugs by producing enzymes that permanently alter drug structure. One example, bacterial exoenzymes called beta-lactamases, hydrolyze the beta-lactam ring structure of some
47、 penicillins and cephalosporins. Two beta-lactamasespenicillinase and cephalosporinase disrupt the structure of certain penicillin or cephalosporin molecules so their activity is lost.So many strains of Staphylococcus aureus produce penicillinase that regular penicillin is rarely a possible therapeu
48、tic choice. Now that some strains of Neisseria gonorrhoeae(淋病奈瑟球菌), called PPNG（Penicillinase-producing Neisseria gonorrhoeae）, have also acquired penicillinase, alternative drugs are required to treat gonorrhea.A large number of other gram-negative species are inherently resistant to some of the pe
49、nicillins and cephalosporins because of naturally occurring beta-lactamases.（2）Decreased Drug Permeability or Increased Drug TransportThe resistance of some bacteria can be due to a mechanism that prevents the drug from entering the cell and acting on its target. For example, the outer membrane of t
50、he cell wall of certain gram-negative bacteria is a natural blockade for some of the penicillin drugs. Resistance to the tetracyclines can arise from plasmid-encoded proteins that pump the drug out of the cell. Resistance to the aminoglycoside antibiotics is a special case in which microbial cells h
51、ave lost the capacity to transport the drug intracellularly.Many bacteria possess multidrug resistant (MDR) pumps that actively transport drugs and other chemicals out of cells.These pumps are proteins encoded by plasmids and chromosomes. They are stationed in the cell membrane and expel molecules b
52、y a proton-motive force similar to ATP synthesis. They confer drug resistance on many gram-positive pathogens (Staphylococcus, Streptococcus) and gram-negative pathogens (Pseudomonas, E. coli). Because they lack selectivity, one type of pump can expel a broad array of antimicrobial drugs, detergents
53、, and other toxic substances.(3) Change of Drug ReceptorsBecause most drugs act on a specific target such as protein, RNA, DNA, or membrane structure, microbes can circumvent drugs by altering the nature of this target. In bacteria resistant to rifampin and streptomycin, the structure of key protein
54、s has been altered so that these antibiotics can no longer bind.Erythromycin and clindamycin(氯洁霉素) resistance is associated with an alteration on the 50S ribosomal binding site. Penicillin resistance in Streptococcus pneumoniae and methicillin resistance in Staphylococcus aureus are related to an al
55、teration in the binding proteins in the cell wall. Fungi can become resistant by decreasing their synthesis of ergosterol（麦角固醇）, the principal receptor for certain antifungal drugs.（4） Changes in Metabolic PatternsThe action of antimetabolites can be circumvented if a microbe develops an alternative
56、 metabolic pathway or enzyme. Sulfonamide and trimethoprim resistance develops when microbes deviate from the usual patterns of folic acid synthesis. Fungi can acquire resistance to flucytosine by completely shutting off certain metabolic activities.3.Natural Selection and Drug Resistance Any large
57、population of microbes is likely to contain a few individual cells that are already drug-resistant because of prior mutations or transfer of plasmids (a). As long as the drug is not present in the habitat, the numbers of these resistant forms will remain low because they have no particular growth ad
58、vantage. But if the population is subsequently exposed to this drug (b), sensitive individuals are inhibited or destroyed, and resistant forms survive and proliferate. During subsequent population growth, all offspring of these resistant microbes will inherit this drug resistance. In time, the repla
59、cement population will have a preponderance of the drug-resistant forms and can eventually become completely resistant (c).In ecological terms, the environmental factor (in this case, the drug) has put selection pressure on the population, allowing the more “fit microbe (the drug-resistant one) to s
60、urvive, and the population has evolved to a condition of drug resistance. Natural selection for drug-resistant forms is apparently a common phenomenon. It takes place most frequently in various natural habitats, laboratories, and medical environments. 4. The Rise of Drug Resistance60% of hospital in
61、fections are caused by drug-resistant microbes.It is now a common event to discover microbes that have become resistant to relatively new drugs in a very short time. In fact, many strains of pathogens have multiple drug resistance, and a few are resistant to all drugs.(1) The Hospital FactorA classi
62、c example occurred with Staphylococcus aureus and penicillin. In the 1950s, hospital strains began to show resistance to this drug, and because of indiscriminate use, they became nearly 100% resistant in 30 years. In a short time, MRSA (multiply-resistant S. aureus) strains appeared, which can toler
63、ate nearly all antibiotics. Up until recently, MRSA has been sensitive to the drug of last resort, vancomycin, but due to transfer of resistant plasmids, it appears to be showing a level of resistance to this as well. To complicate this problem, strains of MRSA are now being spread into the communit
64、y.(2) Drugs in Animal FeedsAnother practice that has contributed significantly to growing drug resistance is the addition of antimicrobics to livestock feed, with the idea of decreasing infections and thereby improving animal health. This practice has had serious impact in both the United States and
65、 Europe. Enteric bacteria such as Salmonella, Escherichia coli, and enterococci that live as normal intestinal flora of these animals readily share resistance plasmids and are constantly selected and amplified by exposure to drugs.These pathogens subsequently “jump to humans and cause drug-resistant
66、 infections, often-times at epidemic proportions.In a deadly outbreak of Salmonella infection in Denmark, the pathogen was found to be resistant to seven different antimicrobics. In the United States, a strain of fluoroquinolone-resistant Campylobacter (弯曲菌属) from chickens caused over 5,000 cases of
67、 food infection in the late 1990s. The opportunistic pathogen called VRE (vancomycin-resistant enterococcus) has been traced to the use of a vancomycin-like drug in cattle feed. It is now one of the most tenacious of hospital-acquired infections for which there are few drug choices. To attempt to cu
68、rb this source of resistance, Europe and the United States have banned the use of human drugs in animal feeds.(3) Worldwide Drug ResistanceThe drug dilemma has become a widespread problem, affecting all countries and socioeconomic groups. In general, the majority of infectious diseases, whether bact
69、erial, fungal, protozoan, or viral, are showing increases in drug resistance.In parts of India, the main drugs used to treat cholera (furazolidone呋喃唑酮,痢特灵, ampicillin) have gone from being highly effective to essentially useless in 10 years. In Southeast Asia 98% of gonococcus infections are multi-d
70、rug resistant. Malaria, tuberculosis, and typhoid fever pathogens are gaining in resistance, with few alternate drugs to control them. To add to the problem, global travel and globalization of food products means that drug resistance can be rapidly exported.In the United States alone, the extra cost
71、 for treating the drug-resistant variety is around $10 billion per year. In many developing countries, drugs are mishandled by overuse and underuse, either of which can contribute to drug resistance. Many countries that do not regulate the sale of prescription drugs make them readily available to pu
72、rchase over the counter.For example, the antituberculosis drug INH (isoniazid异烟肼) is sometimes used as a “lung vitamin to improve health, and antibiotics are taken in the wrong dose and wrong time for undiagnosed conditions. This means that these countries serve as breeding grounds for drug resistan
73、ce that can eventually be carried to other countries.It is clear that we are in a race with microbes and we are falling behind. If the trend is not contained, the world may indeed return to a time when there are few effective drugs left. We simply cannot develop them as rapidly as microbes can devel
74、op resistance. In this light, it is essential to fight the battle on more than one front. Table following summarizes the several critical strategies to give us an edge in controlling drug resistance.TABLE12.B Strategies to Limit Drug Resistance by Microorganisms (Continue)Drug Research Developing sh
75、orter-term, higher-dose antimicrobics that are more effective, less expensive, and have fewer side effects. Pharmaceutical companies continue to seek new antimicrobic drugs with structures that are not readily inactivated by microbial enzymes or drugs with modes of action that are not readily circum
76、vented.TABLE12.B Strategies to Limit Drug Resistance by Microorganisms (Continue)Long-Term Strategies : Proposals to reduce the abuses range from educational programs for health workers to requiring written justification from the physician on all antibiotics prescribed. Especially valuable antimicro
77、bics may be restricted in their use to only one or two types of infections. The addition of antimicrobics to animal feeds must be curtailed worldwide. Increase government programs which make effective therapy available to low-income populations. Use vaccines to provide alternative protection.15.4 Ma
78、jor Antimicrobial Drug GroupsAlthough the medical and pharmaceutical literature contains a wide array of names for antimicrobics, most of them are variants of a small number of drug families. About 260 different antimicrobial drugs currently classified in 20 drug families.1. ANTIBACTERIAL DRUGS(1) P
79、enicillin and Its RelativesThe penicillin group of antibiotics, named for the parent compound, is a large, diverse group of compounds, most of which end in the suffix -cillin.Although penicillins could be completely synthesized in the laboratory from simple raw materials, it is more practical and ec
80、onomical to obtain natural penicillin through microbial fermentation.The natural product can then be used either in unmodified form or to make semisynthetic derivatives. Penicillium chrysogenum is the major source of the drug. All penicillins consist of three parts: a thiazolidine(噻唑烷) ring, a beta-
81、lactam ring, and a variable side chain that dictates its microbicidal activity .Chemical structure of penicillins： All penicillins contain a thiazolidine ring (yellow) and a beta-lactam ring (red), but each differs in the nature of the side chain (R group), which is also responsible for differences
82、in biological activity.Subgroups and Uses of Penicillins： The characteristics of certain penicillin drugs are shown in table following. Penicillins G and V are the most important natural forms. Penicillin is considered the drug of choice for infections by known sensitive, gram-positive cocci (most s
83、treptococci) and some gram-negative bacteria (meningococci 脑膜炎球菌and the spirochete of syphilis). Certain semisynthetic penicillins such as ampicillin, carbenicillin（羧苄青霉素）, and amoxicillin have broader spectra and thus can be used to treat infections by gram-negative enteric rods. Penicillinase-resi
84、stant penicillins such as methicillin（甲氧西林）, nafcillin（乙氧萘胺青霉素，萘夫西林）, and cloxacillin（氯洒西林） are useful in treating infections caused by some penicillinase-producing bacteria. Mezlocillin and azlocillin have such an extended spectrum that they can be substituted for combinations of antibiotics. All o
85、f the cillin drugs are relatively mild and well tolerated because of their specific mode of action on cell walls (which humans lack). The primary problems in therapy include allergy and resistant strains of pathogens.（2）The Cephalosporin Group of DrugsThe first compounds in this group were isolated
86、in the late 1940s from the mold Cephalosporium acremonium. Cephalosporins are similar to penicillins in their beta-lactam structure that can be synthetically altered and in their mode of action. The generic names of these compounds are often recognized by the presence of the root cef, ceph, or kef i
87、n their names.Subgroups and Uses of Cephalosporins： The cephalosporins are versatile. They are relatively broad-spectrum, resistant to penicillinases, and cause fewer allergic reactions than penicillins. Although some cephalosporins are given orally, many are poorly absorbed from the intestine and m
88、ust be administered parenterally（A route of drug administration other than the gastrointestinal tract） , by injection into a muscle or a vein. Three generations of cephalosporins exist, based upon their antibacterial activity. First-generation cephalosporins such as cephalothin（先锋霉素I） and cefazolin(
89、塞发查令) are most effective against gram-positive cocci and a few gram-negative bacteria. Second-generation forms include cefaclor and cefonacid, which are more effective than the first-generation forms in treating infections by gram-negative bacteria such as Enterobacter, Proteus, and Haemophilus. Thi
90、rd-generation cephalosporins, such as cephalexin (Keflex) and cefotaxime（头孢噻肟）, are broad-spectrum with especially well-developed activity against enteric bacteria that produce beta-lactamases. Ceftriaxone (rocephin) is a new semisynthetic broad-spectrum drug for treating a wide variety of respirato
91、ry, skin, urinary, and nervous system infections.（3）Other Beta-Lactam Antibiotics：Related antibiotics include imipenem（亚胺青霉烯）, a broad-spectrum drug for infections with aerobic and anaerobic pathogens. It is active in very small concentrations and can be taken by mouth with few side effects. Aztreon
92、am, isolated from the bacterium Chromobacterium violaceum（紫色色杆菌）, is a newer narrow-spectrum drug for treating pneumonia, septicemia（败血症）, and urinary tract infections by gram-negative aerobic bacilli.（4）The Aminoglycoside DrugsAntibiotics composed of two or more amino sugars and an aminocyclitol (6
93、-carbon) ring are referred to as aminoglycosides. These complex compounds are exclusively the products of various species of soil actinomycetes in the genera Streptomyces and Micromonospora.Subgroups and Uses of Aminoglycosides： The aminoglycosides have a relatively broad antimicrobial spectrum beca
94、use they inhibit protein synthesis. They are especially useful in treating infections caused by aerobic gram-negative rods and certain gram-positive bacteria. Streptomycin is among the oldest of the drugs and has gradually been replaced by newer forms with less mammalian toxicity. It is still the an
95、tibiotic of choice for treating bubonic（腹股沟） plague and tularemia（兔热病） and is considered a good antituberculosis agent. Gentamicin is less toxic and is widely administered for infections caused by gram-negative rods (Escherichia, Pseudomonas, Salmonella, and Shigella). Two relatively new aminoglycos
96、ides, tobramycin（妥布拉霉素） and amikacin（丁胺卡那霉素）, are also used for gram-negative bacillary infections and have largely replaced kanamycin.（5）Tetracycline AntibioticsIn 1948, a colony of Streptomyces isolated from a soil sample gave off a substance, aureomycin（金霉素）, with strong antimicrobic properties.
97、This antibiotic was used to synthesize its relatives terramycin（土霉素，氧四环素） and tetracycline.These natural parent compounds and semisynthetic derivatives are known as the tetracyclines . Their action of binding to ribosomes and blocking protein synthesis accounts for the broad-spectrum effects in the
98、group.(a) Tetracyclines：These are named for their regular group of four rings. The several types vary in structure and activity by substitution at the four R groups. Subgroups and Uses of Tetracyclines： The scope of microorganisms inhibited by tetracyclines includes gram-positive and gram-negative r
99、ods and cocci, aerobic and anaerobic bacteria, mycoplasmas, rickettsias, and spirochetes. Tetracycline compounds such as doxycycline（强力霉素，脱氧土霉素） and minocycline（米诺四环素） are administered orally to treat several sexually transmitted diseases, Rocky Mountain spotted fever, typhus, Mycoplasma pneumonia,
100、cholera, leptospirosis（钩端螺旋体病）, acne（痤疮，粉刺）, and even some protozoan infections. Although generic tetracycline is low in cost and easy to administer, its side effectsnamely, gastrointestinal disruption and deposition in hard tissuescan limit its use .（6）ChloramphenicolOriginally isolated in the late
101、 1940s from Streptomyces venezuelae, chloramphenicol is a potent broad-spectrum antibiotic with a unique nitrobenzene（硝基苯） structure. Its primary effect on cells is to block peptide bond formation and protein synthesis. It is one type of antibiotic that is no longer derived from the natural source b
102、ut is entirely synthesized through chemical processes. Although this drug is fully as broad-spectrum as the tetracyclines, it is so toxic to human cells that its uses are restricted. A small number of people undergoing long-term therapy with this drug incur irreversible damage to the bone marrow tha
103、t usually results in a fatal form of aplastic anemia（A failure of the blood-producing tissue that results in very low levels of blood cells）.Its administration is now limited to typhoid fever, brain abscesses, and rickettsial and chlamydial infections for which an alternative therapy is not availabl
104、e. Chloramphenicol should never be given in large doses repeatedly over a long time period, and the patients blood must be monitored during therapy .（7）Erythromycin, Clindamycin, Vancomycin, RifamycinErythromycin is a macrolide（大环内酯物） antibiotic first isolated in 1952 from a strain of Streptomyces.
105、Its structure consists of a large lactone（内酯） ring with sugars attached. This drug is relatively broad-spectrum and of fairly low toxicity. (c) Erythromycin, an example of a macrolide drug. Its central feature is a large lactone ring to which two hexose sugars are attached. Its mode of action is to
106、block protein synthesis by attaching to the ribosome. It is administered orally as the drug of choice for Mycoplasma pneumonia, legionellosis, Chlamydia infections, pertussis（百日咳）, and diphtheria（白喉） and as a prophylactic（预防剂） drug prior to intestinal surgery. It also offers a useful substitute for
107、dealing with penicillin-resistant streptococci and gonococci and for treating syphilis and acne. Newer semisynthetic macrolides include clarithromycin and azithromycin. Both drugs are useful for middle ear, respiratory, and skin infections and have also been approved for Mycobacterium (MAC) infectio
108、ns in AIDS patients. Clarithromycin has additional applications in controlling infectious stomach ulcers.Clindamycin（氯洁霉素，氯林可霉（氯洁霉素，氯林可霉素）素） is a broad-spectrum antibiotic related to lincomycin. The tendency of clindamycin to cause adverse reactions in the gastrointestinal tract limits its applicati
109、ons to ： i. Serious infections in the large intestine and abdomen due to anaerobic bacteria that are unresponsive to other antibiotics. ii. Infections with penicillin-resistant staphylococci. iii. Acne medications applied to the skin.Vancomycin is a narrow-spectrum antibiotic most effective in treat
110、ing staphylococcal infections in cases of penicillin and methicillin resistance or in patients with an allergy to penicillins. It has also been chosen to treat Clostridium infections in children and endocarditis (infection of the lining of the heart) caused by Enterococcus faecalis. Because it is ve
111、ry toxic and hard to administer, vancomycin is usually restricted to the most serious, life-threatening conditions.Another product of the genus Streptomyces is rifamycin, which is altered chemically into rifampin. It is somewhat limited in spectrum because the molecule cannot pass through the cell e
112、nvelope of many gram-negative bacilli. It is mainly used to treat infections by several gram-positive rods and cocci and a few gram-negative bacteria. Rifampin figures most prominently in treating mycobacterial infections, especially tuberculosis and leprosy(麻风病), but it is usually given in combinat
113、ion with other drugs to prevent development of resistance. Rifampin is also recommended for prophylaxis in Neisseria meningitidis（脑膜炎奈瑟菌） carriers and their contacts, and it is occasionally used to treat Legionella, Brucella, and Staphylococcus infections.（8）The Bacillus Antibiotics: Bacitracin and
114、PolymyxinBacitracin（杆菌肽）（杆菌肽） is a narrow-spectrum peptide antibiotic produced by a strain of the bacterium Bacillus subtilis. Since it was first isolated, its greatest claim to fame has been as a major ingredient in a common drugstore antibiotic ointment (Neosporin) for combating superficial skin i
115、nfections by streptococci and staphylococci. For this purpose, it is usually combined with neomycin (an aminoglycoside) and polymyxin（多粘菌素）.Bacillus polymyxa is the source of the polymyxins, narrow-spectrum peptide antibiotics with a unique fatty acid component that contributes to their detergent ac
116、tivity. Only two polymyxinsB and E (also known as colistin)have any routine applications, and even these are limited by their toxicity to the kidney. Either drug can be indicated to treat drug-resistant Pseudomonas aeruginosa and severe urinary tract infections caused by other gram-negative rods. (9
117、) SYNTHETIC ANTIBACTERIAL DRUGSThe synthetic antimicrobics as a group do not originate from bacterial or fungal fermentations. Some were developed from aniline(苯胺) dyes, and others were originally isolated from plants. Although they have been largely supplanted by antibiotics, several types are stil
118、l useful.The Sulfonamides,Trimethoprim, and Sulfones The very first modern antimicrobic drugs were the sulfonamides（磺胺）（磺胺）, or sulfa drugs, named for sulfanilamide（磺胺，对氨基苯磺酰胺）, an early form of the drug. Although thousands of sulfonamides have been formulated, only a few have gained any importance
119、in chemotherapy. The structures of some sulfonamides. (a) Sulfacetamide（磺乙酰胺）（磺乙酰胺）; (b) sulfadiazine(磺胺嘧啶)；and (c) sulfisoxazole（磺胺二甲基异恶唑）（磺胺二甲基异恶唑）. Because of its solubility, sulfisoxazole is the best agent for treating shigellosis, acute urinary tract infections, and certain protozoan infections
120、. Silver sulfadiazine ointment and solution are prescribed for treatment of burns and eye infections. In many cases, sulfamethoxazole（磺胺甲噻二唑） is given in combination with trimethoprim（三甲氧苄氨嘧啶）（三甲氧苄氨嘧啶）to take advantage of the synergistic effect of the two drugs. This combination is one of the primar
121、y treatments for Pneumocystis carinii pneumonia (PCP) in AIDS patients. Sulfones（砜） are compounds chemically related to the sulfonamides but lacking their broad-spectrum effects. This lack does not diminish their importance as key drugs in treating leprosy. The most active form is dapsone（氨苯砜）, usua
122、lly given in combination with rifampin and clofazamine (氯苯吩秦，an antibacterial dye) over long periods.2. AGENTS TO TREAT FUNGAL INFECTIONSBecause the cells of fungi are eucaryotic, they present special problems in chemotherapy. For one, the great majority of chemotherapeutic drugs are designed to act
123、 on bacteria and are generally ineffective in combating fungal infections.For another, the similarities between fungal and human cells often mean that drugs toxic to fungal cells are also capable of harming human tissues.Four main drug groups currently in use are the macrolide polyene antibiotics, g
124、riseofulvin, synthetic azoles（吡咯）, and flucytosine（5-氟胞嘧啶）.（1）Macrolide polyeneMacrolide polyenes, represented by amphotericin B (named for its acidic and basicamphotericproperties) and nystatin (制霉菌素，for New York State, where it was discovered), have a structure that mimics the lipids in some cell
125、membranes. Amphotericin B (fungizone) is by far the most versatile and effective of all antifungals. Not only does it work on most fungal infections, including skin and mucous membrane lesions caused by Candida albicans, but it is one of the few drugs that can be injected to treat systemic fungal in
126、fections such as histoplasmosis（组织胞浆菌病） and cryptococcus meningitis（脑膜炎隐球菌）. Nystatin is used only topically or orally to treat candidiasis of the skin and mucous membranes, but it is not useful for subcutaneous（皮下的） or systemic fungal infections or for ringworm（癣）.（2） GriseofulvinGriseofulvin is an
127、 antifungal product especially active in certain dermatophyte（皮肤真菌） infections such as athletes foot. The drug is deposited in the epidermis, nails, and hair, where it inhibits fungal growth. Because complete eradication requires several months and griseofulvin is relatively nephrotoxic（肾毒性）, this t
128、herapy is given only for the most stubborn cases.（3）Synthetic azolesThe azoles are broad-spectrum antifungal agents with a complex ringed structure. The most effective drugs are ketoconazole, fluconazole, clotrimazole（克霉唑）, and miconazole（霉抗唑）. Ketoconazole is used orally and topically for cutaneous
129、（皮肤的） mycoses, vaginal and oral candidiasis, and some systemic mycoses. Fluconazole can be used in selected patients for AIDS-related mycoses such as aspergillosis and cryptococcus meningitis. Clotrimazole and miconazole are used mainly as topical ointments for infections in the skin, mouth, and vag
130、ina.（4）FlucytosineFlucytosine is an analog of cytosine that has antifungal properties.It is rapidly absorbed after oral therapy, and it is readily dissolved in the blood and cerebrospinal fluid. Alone, it can be used to treat certain cutaneous mycoses. Now that many fungi are resistant to flucytosin
131、e, it must be combined with amphotericin B to effectively treat systemic mycoses.15.5 How to Selectan Antimicrobic DrugBefore actual antimicrobic therapy can begin, it is important that at least three factors be known: (1) the nature of the microorganism causing the infection; (2) the degree of the
132、microorganisms susceptibility (also called sensitivity) to various drugs; (3) the overall medical condition of the patient.1. IDENTIFYING THE AGENTIdentification of infectious agents from body specimens should be attempted as soon as possible. It is especially important that such specimens be taken
133、before the antimicrobic drug is given, just in case the drug eliminates the infectious agent. Direct examination of body fluids, sputum, or stool is a rapid initial method for detecting and perhaps even identifying bacteria or fungi. A doctor often begins the therapy on the basis of such immediate f
134、indings. The choice of drug will be based on experience with drugs that are known to be effective against the microbe; this is called the “informed best guess.”For instance, if a sore throat appears to be caused by Streptococcus pyogenes(酿脓链球菌), the physician might prescribe penicillin, because this
135、 species seems to be universally sensitive to it so far. If the infectious agent is not or cannot be isolated, epidemiologic statistics may be required to predict the most likely agent in a given infection. For example, Streptococcus pneumoniae accounts for the majority of cases of meningitis in chi
136、ldren, followed by Neisseria meningitidis and Haemophilus influenzae.2. TESTING FOR THE DRUG SUSCEPTIBILITYOF MICROORGANISMSTesting is essential in those groups of bacteria commonly showing resistance, primarily Staphylococcus species, Neisseria gonorrhoeae, Streptococcus pneumoniae, and Enterococcu
137、s faecalis, and the aerobic gram-negative enteric bacilli.However, not all infectious agents require antimicrobial sensitivity testing. Drug testing in fungal or protozoan infections is difficult and is often unnecessary. When certain groups, such as group A streptococci and all anaerobes (except Ba
138、cteroides), are known to be uniformly susceptible to penicillin G, testing may not be necessary unless the patient is allergic to penicillin.Selection of a proper antimicrobial agent begins by demonstrating the in vitro activity of several drugs against the infectious agent by means of standardized
139、methods. In general, these tests involve exposing a pure culture of the bacterium to several different drugs and observing the effects of the drugs on growth.Kirby-Bauer technique*The Kirby-Bauer technique（滤纸片琼脂扩（滤纸片琼脂扩散技术）散技术） is an agar diffusion test that provides useful data on antimicrobic susc
140、eptibility. In this test, the surface of a plate of special medium is seeded with the test bacterium, and small discs containing a premeasured amount of antimicrobic are dispensed onto the bacterial lawn.During incubation, antimicrobics become increasingly diluted as they diffuse out of the disc int
141、o the medium. If the test bacterium is sensitive to a drug, a zone of inhibition develops around its disc. The larger the size of this zone, the greater is the bacteriums sensitivity to the drug. The diameter of each zone is measured in millimeters and evaluated for susceptibility or resistance by m
142、eans of a comparative standard . Drug resistance can be detected by a small or nonexistent zone, or by tiny colonies within the zone of inhibition.The profile of antimicrobic sensitivity, or antibiogram（抗菌谱）, provides data for drug selection. The Kirby-Bauer procedure is less effective for bacteria
143、that are anaerobic, highly fastidious, or slow-growing (Mycobacterium). A different diffusion system that provides additional information on drug effectiveness is the E-test .E-test*Alternate to the Kirby-Bauer procedure： Another diffusion test is the E-test, which uses a strip to produce the zone o
144、f inhibition. The advantage of the E-test is that the strip contains a gradient of drug calibrated in g. This way, the MIC can be measured by observing the mark on the strip that corresponds to the edge of the zone of inhibition. This test can also be used to detect and quantify developing resistanc
145、e.These E-tests have been carried out on an isolate ofPseudomonas aeruginosa.THE MIC*More sensitive and quantitative results can be obtained with tube dilution tests. First the antimicrobic is diluted serially in tubes of broth, and then each tube is inoculated with a small uniform sample of pure cu
146、lture, incubated, and examined for growth (turbidity). The smallest concentration (highest dilution) of drug that visibly inhibits growth is called the minimum inhibitory concentration, or MIC.The MIC is useful in determining the smallest effective dosage of a drug and in providing a comparative ind
147、ex against other antimicrobics. In many clinical laboratories, these antimicrobic testing procedures are performed in automated machines that can test dozens of drugs simultaneously.Tube dilution test for determining the minimum inhibitory concentration (MIC)：The antibiotic is diluted serially throu
148、gh tubes of liquid nutrient from right to left. All tubes are inoculated with an identical sample of a test bacterium and then incubated. The first tube on the left is a control that lacks the drug and shows maximum growth. The dilution of the first tube in the series that shows no growth (no turbid
149、ity) is the MIC.THERAPEUTIC INDEX*Because drug toxicity is of concern, it is best to choose the one with high selective toxicity for the infectious agent and low human toxicity. The therapeutic index (TI) is defined as the ratio of the dose of the drug that is toxic to humans as compared to its mini
150、mum effective (therapeutic) dose. The closer these two figures are (the smaller the ratio), the greater is the potential for toxic drug reactions. For example, a drug that has a therapeutic index of:SUMMARY1.Antimicrobial drugs are classified by their range of effectiveness. Broad-spectrum antimicro
151、bics are effective against many types of microbes. Narrow-spectrum antimicrobics are effective against a limited group of microbes.2.Spore-forming bacteria and fungi are the primary sources of most antibiotics. The molecular structures of these compounds can be chemically altered to form additional
152、semisynthetic antimicrobics.3.Drug resistance is genetic; microbes develop or acquire genes that code for methods of inactivating or escaping the antimicrobic. Resistance is selected for in environments where antimicrobics are present in high concentrations, such as in hospitals.4.Microbial drug res
153、istance develops through the selection of preexisting random mutations and through acquisition of resistance genes from other microorganisms.5. Varieties of microbial drug resistance include drug inactivation, decreased drug uptake, decreased drug receptor sites, and modification of metabolic pathwa
154、ys formerly attacked by the drug.6. Antimicrobics are classified into 20 major drug families, based on their chemical composition, source of origin, and their site of action.7. The majority of antimicrobics are effective against bacteria, but a limited number are effective against protozoa, fungi, a
155、nd viruses.8. Penicillins, cephalosporins, bacitracin, vancomycin, and cycloserines block cell wall synthesis, primarily in gram-positive bacteria.9. Aminoglycosides and tetracyclines block protein synthesis in procaryotes.10. Sulfonamides, trimethoprim, isoniazid, nitrofurantoin, and the fluoroquin
156、olones are synthetic antimicrobics effective against a broad range of microorganisms. They block steps in the synthesis of nucleic acids.11. Fungal antimicrobials, such as macrolide polyenes, griseofulvin, azoles, and flucytosine, must be monitored carefully because of the potential toxicity to the
157、infected host. They promote lysis of cell membranes.12. The three major considerations necessary to choose an effective antimicrobic are the nature of the infecting microbe, the microbes sensitivity to available drugs, and the overall medical status of the infected host.13. The Kirby-Bauer test iden
158、tifies antimicrobics that are effective against a specific infectious bacterial isolate.14. The MIC (minimum inhibitory concentration) identifies the smallest effective dose of an antimicrobic toxic to the infecting microbe.15. The therapeutic index is a ratio of the amount of drug toxic to the infe
159、cted host and the MIC. The smaller the ratio, the greater the potential for toxic host-drug reactions.HOMEWORKI. MULTIPLE-CHOICE QUESTIONS1. A compound synthesized by bacteria or fungi that destroys or inhibits the growth of other microbes is a/an ( ).a. synthetic drugb. antimicrobic drugc. competit
160、ive inhibitord. all of these2. Drugs that prevent the formation of the bacterial cell wall area. quinolones b. beta-lactamsc. tetracyclines d. aminoglycosides3. Sulfonamide drugs initially disrupt which process?a. folic acid synthesisb. transcriptionc. PABA synthesisd. protein synthesis4. Microbial
161、resistance to drugs is acquired througha. conjugation b. transformationc. transduction d. all of these5. R factors are ( )that contain a code for ( ).a. genes, replicationb. plasmids, drug resistancec. transposons, interferond. plasmids, conjugation6. When a patients immune system becomes reactive t
162、o a drug, this is an example ofa. superinfection b. drug resistancec. allergy d. toxicity7. The MIC is the ( ) of a drug that is required to inhibit growth of a microbe.a. largest concentrationb. standard dosec. smallest concentrationd. lowest dilutionII. CONCEPT QUESTIONS1. Differentiate between an
163、tibiotics and synthetic drugs.2. Differentiate between narrow-spectrum and broad-spectrum antibiotics.3. Can you determine why some drugs have narrower spectra than others? (Hint: Look at their mode of action.) How might one determine whether a particular antimicrobic is broad- or narrow-spectrum?4.
164、 a. Explain four general ways that microbes evade the effects of drugs. b. What is the effect of beta-lactamase?5. What causes mutated or plasmid-altered strains of drug-resistant microbes to persist in a population?III. CRITICAL-THINKING QUESTIONS1. Your pregnant neighbor has been prescribed a dail
165、y dose of oral tetracycline for acne. Do you think this therapy is advisable for her? Why or why not?2. A woman has been prescribed a broad-spectrum oral cephalosporin for a strep throat. What are some possible consequences in addition to cure of the infected throat?3. A man has a severe case of gastroenteritis that is negative for bacterial pathogens. A physician prescribes an oral antibacterial drug in treatment. What are your opinions of this therapy?
