《传染病学 Infectious Disease》课程教学资源（MBBS）课程参考书籍教材《Infectious Diseases》

INFECTIOUS DISEASES

Contents 1 ANTH-NFECTIVE THERAPY 2 SEPSIS SYNDROME 3 THE FEBRILE PATIENT 4 PULMONARY INFECTIONS 5 MEASLES (RUBEOLA 6 CENTRAL NERVOUS SYSTOM INFECTIONS MUMPS 8 GASTROINTESTINAL AND HEPATOBILIARY INFECTIONS 9 SCARLET FEVER 10 STREPTOCOCCUS PYOGENES(GROUP A STREPTOCOCCUS) 11 DIPHTHERIA (CORYNEBACTERIUM DIPHTHERIAE) 12 PARASITIC INFECTIONS 13 ZOONOTIC INFECTIONS 14 BIOTERRORISM 15 SERIOUS VIRAL ILLNESS IN THE ADULT PATIENT 16 PERTUSSIS (BORDETELLA PERTUSSIS AND BORDETELLA 17 H INFECTION 18 VARICELLA (CHICKENPOX) 19 TYPHOID FEVER

Contents 1 ANTI-INFECTIVE THERAPY 2 SEPSIS SYNDROME 3 THE FEBRILE PATIENT 4 PULMONARY INFECTIONS 5 MEASLES (RUBEOLA) 6 CENTRAL NERVOUS SYSTOM INFECTIONS 7 MUMPS 8 GASTROINTESTINAL AND HEPATOBILIARY INFECTIONS 9 SCARLET FEVER 10 STREPTOCOCCUS PYOGENES (GROUP A STREPTOCOCCUS) 11 DIPHTHERIA (CORYNEBACTERIUM DIPHTHERIAE) 12 PARASITIC INFECTIONS 13 ZOONOTIC INFECTIONS 14 BIOTERRORISM 15 SERIOUS VIRAL ILLNESS IN THE ADULT PATIENT 16 PERTUSSIS (BORDETELLA PERTUSSIS AND BORDETELLA 17 HIV INFECTION 18 VARICELLA (CHICKENPOX) 19 TYPHOID FEVER

Anti-Infective Therapy Time Recommended to complete: 3 days Frederick Southwick. M.D GUIDING QUESTIONS Are we at the end of the antibiotic era? 6. Does one antibiotic cure all infections? 2. Why are"superbugs"suddenly appearing in ou 7. What are the strategies that underlie optimal 3. How do bacteria become resistant to antibiotics? 8. How is colonization distinguished from infection 4. How can the continued selection of highly resis and why is this distinction important? tant organisms be prevented? 5. Is antibiotic treatment always the wisest course of action? Despite dire warnings that we are approaching the end of They use one or two broad-spectrum antibiotics to treat antibiotic era, the incidence of antibiotic-resistant all p acteria continues to rise. The proportions of penicillin Many excellent broad-spectrum antibiotics can resistant Streptococcus pneumoniae, hospital-acquired effectively treat most bacterial infections without requir rancomycin-resistant Enterococcus(VRE)strains continue empiric broad-spectrum antibiotics has resulted in the to increase. Community-acquired MRSA(cMRSA)is selection of highly resistant pathogens. A simplistic now common throughout the world. Multiresistant approach to anti-infective therapy and establishment of Acinetobacter and Pseudomonas are everyday realities in a fixed series of simple rules concerning the use of these Public of the existence of "diry ha w warning the lay agents is unwise and has proved harmful to patients fore, it is critical that health care providers understand bacteria, fungi, and viruses. It is no coincidence that the principles of proper anti-infective therapy and use these more primitive life forms have survived for nti-infective agents judiciously. These agents need to be millions of years, far longer than the human race. reserved for treatable infections-not used to calm the The rules for the use of anti-infective the atient or the patient's family. Too often, patients with dynamic and must take into account the ability of these viralieche physician's office expecting to be treated with the overuse of antibiotic, antifungal, and antiviral agents antibiotics to fulfill those expectation ust end, or more and more patients will become Physicians unschooled in the principles of microbiol- infected with multiresistant orga at cannot ogy utilize anti-infective agents just as they would more treated. Only through the judicious use of anti-infective conventional medications, such as anti-infammatory therapy can we hope to slow the arrival of the end of the agents, anti-hypertensive medications, and cardiac drugs. antibiotic era. Copyright 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use

Despite dire warnings that we are approaching the end of the antibiotic era, the incidence of antibiotic-resistant bacteria continues to rise. The proportions of penicillin￾resistant Streptococcus pneumoniae, hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) strains continue to increase. Community-acquired MRSA (cMRSA) is now common throughout the world. Multiresistant Acinetobacter and Pseudomonas are everyday realities in many of our hospitals. The press is now warning the lay public of the existence of “dirty hospitals.” As never before, it is critical that health care providers understand the principles of proper anti-infective therapy and use anti-infective agents judiciously. These agents need to be reserved for treatable infections—not used to calm the patient or the patient’s family. Too often, patients with viral infections that do not warrant anti-infective therapy arrive at the physician’s office expecting to be treated with an antibiotic. And health care workers too often prescribe antibiotics to fulfill those expectations. Physicians unschooled in the principles of microbiol￾ogy utilize anti-infective agents just as they would more conventional medications, such as anti-inflammatory agents, anti-hypertensive medications, and cardiac drugs. They use one or two broad-spectrum antibiotics to treat all patients with suspected infections. Many excellent broad-spectrum antibiotics can effectively treat most bacterial infections without requir￾ing a specific causative diagnosis. However, overuse of empiric broad-spectrum antibiotics has resulted in the selection of highly resistant pathogens. A simplistic approach to anti-infective therapy and establishment of a fixed series of simple rules concerning the use of these agents is unwise and has proved harmful to patients. Such an approach ignores the remarkable adaptability of bacteria, fungi, and viruses. It is no coincidence that these more primitive life forms have survived for millions of years, far longer than the human race. The rules for the use of anti-infective therapy are dynamic and must take into account the ability of these pathogens to adapt to the selective pressures exerted by the overuse of antibiotic, antifungal, and antiviral agents. The days of the “shotgun” approach to infectious diseases must end, or more and more patients will become infected with multiresistant organisms that cannot be treated. Only through the judicious use of anti-infective therapy can we hope to slow the arrival of the end of the antibiotic era. 1 Time Recommended to complete: 3 days Frederick Southwick, M.D. GUIDING QUESTIONS Anti-Infective Therapy 1 1. Are we at the end of the antibiotic era? 2. Why are “superbugs” suddenly appearing in our hospitals? 3. How do bacteria become resistant to antibiotics? 4. How can the continued selection of highly resis￾tant organisms be prevented? 5. Is antibiotic treatment always the wisest course of action? 6. Does one antibiotic cure all infections? 7. What are the strategies that underlie optimal antibiotic usage? 8. How is colonization distinguished from infection, and why is this distinction important? Copyright © 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use

2/ CHAPTER 1 KEY POINTS About Anti-Infective Therapy 1. Too often, antibiotics are prescribed to fulfill the atients expectations, rather than to treat a true acterial infection 2. A single antibiotic cannot meet all infectious disease needs Transduction 3. Physicians ignore the remarkable adaptability of bacteria, fungi, ses at thei 4. Anti-infective therapy is dynamic and requires a basic understanding of microbiology. 5. The"shotgun"approach to infectious diseases Donor Recipient must end, or we may truly experience the end of Bacteria the antibiotic era Transformation ANTIBIOTIC RESISTANCE GENETIC MODIFICATIONS LEADING TO Figure 1-1 Mechanisms by which bacteria transfer ANTIMICROBIAL RESISTANCE antibiotic resistance genes. To understand why antibiotics must be used judi ciously, the physician needs to understand how bacte- ria are able to adapt to their environment. point second bacterium and serves as bridge for the mutations can develop in the dna of bacteria as they transfer of the plasmid DNA from the donor to replicate. These mutations occur in the natural envi- the recipient bacterium. Using this mechanism,a ronment, but are of no survival advantage unless the single resistant bacterium can transfer resistance bacteria are placed under selective pressures. In the to other bacteria case of a mutation that renders a bacterium resistant to 2. Transduction. Bacteriophages are protein-coated a specific antibiotic, exposure to the specific antibiotic allows the bacterial clone that possesses the antibiotic DNA segments that attach to the bacterial wall and resistance mutation to grow, while bacteria without the ject DNA in a process called"transduction. These infective particles can readily transfer resis- mutation die and no longer compete for nutrients. tance genes to multiple bacteria. Thus the resistant strain becomes the dominant bacte- 3. Transformation. Donor bacteria can also release rial flora. In addition to point mutations bacteria can also use three major mechanisms to transfer genetic linear segments of chromosomal DNA, which material among themselves hen taken up by recipient bacteria and incor ated into the recipient's genome. This process 1.Conjugation. Bacteria often contain circular called "transformation, "and the naked DNA double-stranded DNA structures called plasmids capable of incorporating into the genome of recip These circular dna structures lie outside the bac. nt bacteria is called a transposon(Figure 1.1) terial genome( Figure 1.1). Plasmids often carry Natural transformation most commonly occurs in resistance(“R”) genes. Through a mechanism Streptococcus, Haemophilus, and Neisseria species called "conjugation, plasmids can be transferred Transposons can transfer multiple antibiotic resis- from one bacterium to another. The plasmid ance genes in a single event and have been shown encodes for the formation of a pilus on the donor to be responsible for high-level vanco n resIs- bacterias outer surface. The pilus attaches to tance in enterococci

■ ANTIBIOTIC RESISTANCE GENETIC MODIFICATIONS LEADING TO ANTIMICROBIAL RESISTANCE To understand why antibiotics must be used judi￾ciously, the physician needs to understand how bacte￾ria are able to adapt to their environment. Point mutations can develop in the DNA of bacteria as they replicate. These mutations occur in the natural envi￾ronment, but are of no survival advantage unless the bacteria are placed under selective pressures. In the case of a mutation that renders a bacterium resistant to a specific antibiotic, exposure to the specific antibiotic allows the bacterial clone that possesses the antibiotic resistance mutation to grow, while bacteria without the mutation die and no longer compete for nutrients. Thus the resistant strain becomes the dominant bacte￾rial flora. In addition to point mutations bacteria can also use three major mechanisms to transfer genetic material among themselves: 1. Conjugation. Bacteria often contain circular, double-stranded DNA structures called plasmids. These circular DNA structures lie outside the bac￾terial genome (Figure 1.1). Plasmids often carry resistance (“R”) genes. Through a mechanism called “conjugation,” plasmids can be transferred from one bacterium to another. The plasmid encodes for the formation of a pilus on the donor bacteria’s outer surface. The pilus attaches to a second bacterium and serves as bridge for the transfer of the plasmid DNA from the donor to the recipient bacterium. Using this mechanism, a single resistant bacterium can transfer resistance to other bacteria. 2. Transduction. Bacteriophages are protein-coated DNA segments that attach to the bacterial wall and inject DNA in a process called “transduction.” These infective particles can readily transfer resis￾tance genes to multiple bacteria. 3. Transformation. Donor bacteria can also release linear segments of chromosomal DNA, which is then taken up by recipient bacteria and incorpo￾rated into the recipient’s genome. This process is called “transformation,” and the naked DNA capable of incorporating into the genome of recip￾ient bacteria is called a transposon (Figure 1.1). Natural transformation most commonly occurs in Streptococcus, Haemophilus, and Neisseria species. Transposons can transfer multiple antibiotic resis￾tance genes in a single event and have been shown to be responsible for high-level vancomycin resis￾tance in enterococci. 2 / CHAPTER 1 1. Too often, antibiotics are prescribed to fulfill the patient’s expectations, rather than to treat a true bacterial infection. 2. A single antibiotic cannot meet all infectious disease needs. 3. Physicians ignore the remarkable adaptability of bacteria, fungi, and viruses at their patient’s peril. 4. Anti-infective therapy is dynamic and requires a basic understanding of microbiology. 5. The “shotgun” approach to infectious diseases must end, or we may truly experience the end of the antibiotic era. KEY POINTS About Anti-Infective Therapy Figure 1–1. Mechanisms by which bacteria transfer antibiotic resistance genes

ANTI-INFECTIVE THERAPY 3 KEY POINTS B-lactamase activity occurs primarily through plasmids and Multiple classes of B-lactamases exist. Some preferen- About antibiotic resistance tially break down penicillins; others preferentially destroy 1. Bacteria can quickly alter their genetic makeup by trum B-lactamases(ESBLS) readily destroy most cp a)point mutation losporins. Another class of B-lactamase is resistant to b) transfer of dna by plasmid conjugation. clavulanate, an agent added to numerous antibiotics to inhibit B-lactamase activity. Some bacteria are able to pro- c) transfer of dna by bacteriophage trans duce B-lactamases called carbapenemases that are capable inactivating imipenem and meropenem. d) transfer of naked DNA by transposon trans- Gram-negative bacilli produce a broader spectrum formation of B-lactamases than do gram-positive organisms, and pility of bacteria to share DNA therefore infections with gram-negative urvival advantage, allowing them to quickly more commonly arise in patients treated for pro apt to antibiotic ex longed periods with broad-spectrum antibiotics. Ir 3. Biochemical alterations leading to antibiotic some instances, B-lactamase activity is low before the resistance include bacterium is exposed to antibiotics; however, follow a) degradation or modification of the antibiotic. re,B-lactamase activity is induced b)reduction of the bacterial antibiotic concen- Enterobacter is a prime example. This gram-negative tration by inhibiting entry or by efflux bacterium may appear sensitive to cephalosporins on initial testing. Following cephalosporin treatment c) modification of the antibiotic target. B-lactamase activity increases, resistance develops and the patient's infection relapses. For this reason, uestion is not whether, but when resistant third-generation cephalosporins are not recom- bacteria will take over. mended for serious Enterobacter infections OTHER ENZYME MODIFICATIONS OF ANTIBIOTICS Erythromycin is readily inactivated by an esterase than hydrolyzes the lactone ring of the antibiotic. This Thus bacteria possess multiple ways to transfer their esterase has been identified in Escherichia coli. Other lasmid-mediated erythromycin inactivating enzymes DNA, and they promiscuously share genetic informa- have been discovered in Streptococcus species and tion. This promiscuity provides a survival advantage, S. aureus. Chloramphenicol is inactivated by chloram- allowing bacteria to quickly adapt to their environment. phenicol acetyltransferase, which has been isolated from BIOCHEMICAL MECHANISMS FOR and gram-negative bacteria. Simi- larly, aminoglycosides can be inactivated by acetyltrans- ANTIMICROBIAL RESISTANCE ferases. Bacteria also inactivate this class of antibiotics by What are some of the proteins that these resistant gene phosphorylation and adenylation encode for, and how do they work? These resistance enzymes are found in many gram The mechanisms by which bacteria resist antibiotics negative strains and are increasingly detected in entero- can be classified into three major groups cocci, S. aureus and S epidermidis. of the antib Reduction of the bacterial Reduction of the bacterial antibiotic concentration Antibiotic Concentration Modification of the antibiotic target INTERFERENCE WITH ANTIBIOTIC ENTRY For an antibiotic to work, it must be able to penetrate Degradation or Modification the bacterium and reach its biochemical target. gram- of the Antibiotic negative bacteria contain an outer lipid coat that β- LACTAMASES neration by hydrophobic reagents( most antibiotics). The passage of hydrophobic antibi Many bacteria synthesize one or more enzymes called otics is facilitated by the presence of porins-small B-lactamases that inactivate antibiotics by breaking the channels in the cell walls of gram-negative I bacteria that amide bond on the B-lactam ring. Transfer of allow the passage of charged molecules. Mutations

Thus bacteria possess multiple ways to transfer their DNA, and they promiscuously share genetic informa￾tion. This promiscuity provides a survival advantage, allowing bacteria to quickly adapt to their environment. BIOCHEMICAL MECHANISMS FOR ANTIMICROBIAL RESISTANCE What are some of the proteins that these resistant genes encode for, and how do they work? The mechanisms by which bacteria resist antibiotics can be classified into three major groups: • Degradation or modification of the antibiotic • Reduction of the bacterial antibiotic concentration • Modification of the antibiotic target Degradation or Modification of the Antibiotic
-LACTAMASES Many bacteria synthesize one or more enzymes called
-lactamases that inactivate antibiotics by breaking the amide bond on the
-lactam ring. Transfer of
-lactamase activity occurs primarily through plasmids and transposons. Multiple classes of
-lactamases exist. Some preferen￾tially break down penicillins; others preferentially destroy specific cephalosporins or carbenicillin. Extended-spec￾trum
-lactamases (ESBLs) readily destroy most cepha￾losporins. Another class of
-lactamase is resistant to clavulanate, an agent added to numerous antibiotics to inhibit
-lactamase activity. Some bacteria are able to pro￾duce
-lactamases called carbapenemases that are capable of inactivating imipenem and meropenem. Gram-negative bacilli produce a broader spectrum of
-lactamases than do gram-positive organisms, and therefore infections with gram-negative organisms more commonly arise in patients treated for pro￾longed periods with broad-spectrum antibiotics. In some instances,
-lactamase activity is low before the bacterium is exposed to antibiotics; however, follow￾ing exposure,
-lactamase activity is induced. Enterobacter is a prime example. This gram-negative bacterium may appear sensitive to cephalosporins on initial testing. Following cephalosporin treatment,
-lactamase activity increases, resistance develops, and the patient’s infection relapses. For this reason, third-generation cephalosporins are not recom￾mended for serious Enterobacter infections. OTHER ENZYME MODIFICATIONS OF ANTIBIOTICS Erythromycin is readily inactivated by an esterase that hydrolyzes the lactone ring of the antibiotic. This esterase has been identified in Escherichia coli. Other plasmid-mediated erythromycin inactivating enzymes have been discovered in Streptococcus species and S. aureus. Chloramphenicol is inactivated by chloram￾phenicol acetyltransferase, which has been isolated from both gram-positive and gram-negative bacteria. Simi￾larly, aminoglycosides can be inactivated by acetyltrans￾ferases. Bacteria also inactivate this class of antibiotics by phosphorylation and adenylation. These resistance enzymes are found in many gram￾negative strains and are increasingly detected in entero￾cocci, S. aureus and S. epidermidis. Reduction of the Bacterial Antibiotic Concentration INTERFERENCE WITH ANTIBIOTIC ENTRY For an antibiotic to work, it must be able to penetrate the bacterium and reach its biochemical target. Gram￾negative bacteria contain an outer lipid coat that impedes penetration by hydrophobic reagents (such as most antibiotics). The passage of hydrophobic antibi￾otics is facilitated by the presence of porins—small channels in the cell walls of gram-negative bacteria that allow the passage of charged molecules. Mutations ANTI-INFECTIVE THERAPY / 3 1. Bacteria can quickly alter their genetic makeup by a) point mutation. b) transfer of DNA by plasmid conjugation. c) transfer of DNA by bacteriophage trans￾duction. d) transfer of naked DNA by transposon trans￾formation. 2. The ability of bacteria to share DNA provides a survival advantage, allowing them to quickly adapt to antibiotic exposure. 3. Biochemical alterations leading to antibiotic resistance include a) degradation or modification of the antibiotic. b) reduction of the bacterial antibiotic concen￾tration by inhibiting entry or by efflux pumps. c) modification of the antibiotic target. 4. Under the selection pressure of antibiotics, the question is not whether, but when resistant bacteria will take over. KEY POINTS About Antibiotic Resistance