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

Legions Ta N ganoeece Proteus ECo! kletsdeila Enterobacter Morg anella samoe styela Peet Citre freund Acinetobacter Aeromonas stenowapo Serratia Figure 1-5. Antibiogram of all major antibiotics

9 Figure 1–5. Antibiogram of all major antibiotics

0/ CHAPTER 1 and serum creatinine, and the potential for an culture). However, because the sputum culture was extended hospital stay because of nephrotoxicity are positive for a resistant E. coli, the physician switched factored into the cost equation, gentamicin is often to a broader-spectrum antibiotic. The correct decision should have been to continue cefazolin Obey the 3-day rule. Continuing broad-spectrum One of the most difficult and confusing issues for antibiotics beyond 3 days drastically alters the host's nor- many physicians is the interpretation of culture results mal fora and selects for resistant organi 3 days streamline the antibiotics Use narrower-spectrun terpreted. Once a patient has been started on an antibi antibiotics to treat the specific pathogens identified by otic, the bacterial fora on the skin and in the mouth ulture and Gram stain d sputum will change. Often these new organisms not invade the host, but simply represent new fora that COLONIZATION VERSUS INFECTION have colonized these anatomic sites. Too often, physi- cians try to eradicate the new flora by adding new more- powerful antibiotics. The result of this strategy is to select for organisms that are multiresistant. The eventual i CASE 1.1 outcome can be the selection of a bacterium that is resis- tant to all antibiotics Following a motor vehicle accident, a 40-year-old no definitive method exists for differentiating man was admitted to the intensive care unit with between colonization and true infection. However 4 fractured ribs and a severe lung contusion on the several clinical findings are helpful in guiding the right side. Chest X-ray( CXR) demonstrated an infil- physician. Evidence supporting the onset of a new trate in the right lower lobe. Because of depressed infection include a new fever or a change in fever pat- mental status, this man required respiratory tern, a rise in the peripheral WBC with a increase in the percentage of PMNs and band forms(left shift support. Gram stain demonstrating an increased number of Initially, Gram stain of the sputum demonstrated PMNs in association with predominance of bacteria few polymorphonuclear leukocytes(PMNs)and ne that are morphologically consistent with the culture organisms On the third hospital day, this patient results. In the absence of these findings, colonization developed a fever to 103F(39.5.C), and his periph- is more likely, and the current antibiotic regimen eral WBC increased to 17, 500 from 8000 (80% PMNs should be continued 6% band forms ) a new CXR demonstrated exten sion of the right lower lobe infiltrate. Gram stain of sputum revealed abundant PMNs and 20 to 30 ram-positive cocci in clusters per high-power field. KEY POINTS sputum culture Saureus. Intravenous cefazolin (1.5 g every 8 hours) About Differentiating Colonization initiated. He defervesced, and secretions fro. from Infection his endotracheal tube decreased over the next 3 days. On the fourth day, a repeat sputum sample was obtained. gram stain revealed a moderate resistant organisms is the rule in the number of PMNs and no organisms; however, ulture grew E coli resistant to cefazolin. The physi should be switched only on evi- cian changed the antibiotic to intravenous cefepime new infection (1 8 hours). 3. Evidence for a new superinfection includes a)new fever or a worsening fever pattern b)increased peripheral leukocyte count with left shift c)increased inflammatory exudate at the origi- Case 1. I represents a very typical example of how nal site of infection antibiotics are misused. The initial therapy for a prob d)increased polymorphonuclear leukocyt able early S. aureus pneumonia was appropriate, and Gram stain, and he patient responded(fever resolved, sputum pro- e)correlation between bacterial morphology duction decreased, gram-positive cocci disappeared and culture on gram stain from the gram stain, and S aureus no longer grew on

and serum creatinine, and the potential for an extended hospital stay because of nephrotoxicity are factored into the cost equation, gentamicin is often not cost-effective. Obey the 3-day rule. Continuing broad-spectrum antibiotics beyond 3 days drastically alters the host’s nor￾mal flora and selects for resistant organisms. After 3 days streamline the antibiotics. Use narrower-spectrum antibiotics to treat the specific pathogens identified by culture and Gram stain. COLONIZATION VERSUS INFECTION Case 1.1 represents a very typical example of how antibiotics are misused. The initial therapy for a prob￾able early S. aureus pneumonia was appropriate, and the patient responded (fever resolved, sputum pro￾duction decreased, gram-positive cocci disappeared from the Gram stain, and S. aureus no longer grew on 10 / CHAPTER 1 CASE 1.1 Following a motor vehicle accident, a 40-year-old man was admitted to the intensive care unit with 4 fractured ribs and a severe lung contusion on the right side. Chest X-ray (CXR) demonstrated an infil￾trate in the right lower lobe. Because of depressed mental status, this man required respiratory support. Initially, Gram stain of the sputum demonstrated few polymorphonuclear leukocytes (PMNs) and no organisms. On the third hospital day, this patient developed a fever to 103F (39.5C), and his periph￾eral WBC increased to 17,500 from 8000 (80% PMNs, 15% band forms). A new CXR demonstrated exten￾sion of the right lower lobe infiltrate. Gram stain of sputum revealed abundant PMNs and 20 to 30 gram-positive cocci in clusters per high-power field. His sputum culture grew methicillin-sensitive S. aureus. Intravenous cefazolin (1.5 g every 8 hours) was initiated. He defervesced, and secretions from his endotracheal tube decreased over the next 3 days. On the fourth day, a repeat sputum sample was obtained. Gram stain revealed a moderate number of PMNs and no organisms; however, culture grew E. coli resistant to cefazolin. The physi￾cian changed the antibiotic to intravenous cefepime (1 g every 8 hours). 1. Growth of resistant organisms is the rule in the patient on antibiotics. 2. Antibiotics should be switched only on evi￾dence of a new infection. 3. Evidence for a new superinfection includes a) new fever or a worsening fever pattern, b) increased peripheral leukocyte count with left shift, c) increased inflammatory exudate at the origi￾nal site of infection, d) increased polymorphonuclear leukocytes on Gram stain, and e) correlation between bacterial morphology and culture on Gram stain. KEY POINTS About Differentiating Colonization from Infection culture). However, because the sputum culture was positive for a resistant E. coli, the physician switched to a broader-spectrum antibiotic. The correct decision should have been to continue cefazolin. One of the most difficult and confusing issues for many physicians is the interpretation of culture results. Wound cultures and sputum cultures are often misin￾terpreted. Once a patient has been started on an antibi￾otic, the bacterial flora on the skin and in the mouth and sputum will change. Often these new organisms do not invade the host, but simply represent new flora that have colonized these anatomic sites. Too often, physi￾cians try to eradicate the new flora by adding new more￾powerful antibiotics. The result of this strategy is to select for organisms that are multiresistant. The eventual outcome can be the selection of a bacterium that is resis￾tant to all antibiotics. No definitive method exists for differentiating between colonization and true infection. However, several clinical findings are helpful in guiding the physician. Evidence supporting the onset of a new infection include a new fever or a change in fever pat￾tern, a rise in the peripheral WBC with a increase in the percentage of PMNs and band forms (left shift), Gram stain demonstrating an increased number of PMNs in association with predominance of bacteria that are morphologically consistent with the culture results. In the absence of these findings, colonization is more likely, and the current antibiotic regimen should be continued.

ANTI-INFECTIVE THERAPY new anti-infectives are frequently being introduced, pre- SPECIFIC ANTI-INFECTIVE scribing physicians should also take advantage of hand held de AGENTS antibiotic manuals so as to provide up-to-date treatment ANTIBIOTICS (see Further Reading at the end of the current chapter) When the proper therapeutic choice is unclear, on-the antibiotic, clinicians should job training can be obtained by requesting a consulta be able to answer these questions: tion with an infectious disease specialist. Anti-infective How does the antibiotic kill or inhibit bacterial growth? tiple potential toxicities outlined below, combined with What are the antibiotic's toxicities and how should the likelihood of selecting for resistant organisms, they be monitored? emphasize the dangers of over-prescribing antibiotics How is the drug metabolized, and what are the dosin recommendations? Does the dosing schedule need B-Lactam Antibiotics be modified in patients with renal dysfunction? What are the indications for using each specific CHEMISTRY AND MECHANISMS OF ACTION antibiotic? The B-Lactam antibiotics have a common central How broad is the antibiotic's antimicrobial spectrum? structure(Figure 1.6)consisting of a B-lactam ring and How much does the antibiotic cost? enemis Figure 1.6(A)] or a B-lactam ring and a dihydrothiazine Clinicians should be familiar with the general classes of ring [in the cephalosporins, Figure 1.6(B)). The side antibiotics, their mechanisms of action, and their major chain attached to the B-lactam ring(R)determines toxicities. The differences between the specific antibiotics many of the antibacterial characteristics of the specific in each class can be subtle, often requiring the expertise of antibiotic, and the structure of the side chain attached an infectious disease specialist to design the optimal to the dihydrothiazine ring(r2) determines the phar Eiati-infective regimen. The general internist or physician- macokinetics and metabolism in-training should not attempt to memorize all the facts The B-lactam antibiotics bind to various PBPs. outlined here, but rather should read the pages that follow The PBPs represent a family of enzymes important for as an overview of anti-infectives. The chemistry, mecha- bacterial cell wall synthesis, including the car- nisms of action, major toxicities, spectrum of activity, boxypeptidases, endopeptidases, transglycolases, and treatment indicatio ions, pharmacokinetics, dosing regimens, transpeptidases. Strong binding to PBP-1, a cell and cost are reviewed. The specific indications for ea anti-infective are briefly covered here. A more complete bacterial death. Inhibition of this transpeptidase discussion of specific regimens is included in the late prevents the cross-linking of the cell wall peptide- hapters that cover infections of specific anatomic sites. glycans, resulting in a loss of integrity of the bacterial Upon prescribing a specific antibiotic, physicians cell wall. Without its protective outer coat, the should reread the specific sections on toxicity, spectrur hyperosmolar ellular swell. and th of activity, pharmacokinetics, dosing, and cost. Because bacterial cell membrane lyses. Inhibition of PBP-3, a 2/ CH3 ⑧画 COOH Penicillin Cepha COOH A=阝- lactam ring b= Thiazolidine rin A= B-lactamase ring B= Dihydrothiazine ring Figure.6. Basic structure of the a penicillins and b the cephalosporins

■ SPECIFIC ANTI-INFECTIVE AGENTS ANTIBIOTICS Before prescribing a specific antibiotic, clinicians should be able to answer these questions: • How does the antibiotic kill or inhibit bacterial growth? • What are the antibiotic’s toxicities and how should they be monitored? • How is the drug metabolized, and what are the dosing recommendations? Does the dosing schedule need to be modified in patients with renal dysfunction? • What are the indications for using each specific antibiotic? • How broad is the antibiotic’s antimicrobial spectrum? • How much does the antibiotic cost? Clinicians should be familiar with the general classes of antibiotics, their mechanisms of action, and their major toxicities. The differences between the specific antibiotics in each class can be subtle, often requiring the expertise of an infectious disease specialist to design the optimal anti-infective regimen. The general internist or physician￾in-training should not attempt to memorize all the facts outlined here, but rather should read the pages that follow as an overview of anti-infectives. The chemistry, mecha￾nisms of action, major toxicities, spectrum of activity, treatment indications, pharmacokinetics, dosing regimens, and cost are reviewed. The specific indications for each anti-infective are briefly covered here. A more complete discussion of specific regimens is included in the later chapters that cover infections of specific anatomic sites. Upon prescribing a specific antibiotic, physicians should reread the specific sections on toxicity, spectrum of activity, pharmacokinetics, dosing, and cost. Because new anti-infectives are frequently being introduced, pre￾scribing physicians should also take advantage of hand￾held devices, online pharmacology databases, and antibiotic manuals so as to provide up-to-date treatment (see Further Reading at the end of the current chapter). When the proper therapeutic choice is unclear, on-the￾job training can be obtained by requesting a consulta￾tion with an infectious disease specialist. Anti-infective agents are often considered to be safe; however, the mul￾tiple potential toxicities outlined below, combined with the likelihood of selecting for resistant organisms, emphasize the dangers of over-prescribing antibiotics.
-Lactam Antibiotics CHEMISTRY AND MECHANISMS OF ACTION The
-Lactam antibiotics have a common central structure (Figure 1.6) consisting of a
-lactam ring and a thiazolidine ring [in the penicillins and carbapenems, Figure 1.6(A)] or a
-lactam ring and a dihydrothiazine ring [in the cephalosporins, Figure 1.6(B)]. The side chain attached to the
-lactam ring (R1) determines many of the antibacterial characteristics of the specific antibiotic, and the structure of the side chain attached to the dihydrothiazine ring (R2) determines the phar￾macokinetics and metabolism. The
-lactam antibiotics bind to various PBPs. The PBPs represent a family of enzymes important for bacterial cell wall synthesis, including the car￾boxypeptidases, endopeptidases, transglycolases, and transpeptidases. Strong binding to PBP-1, a cell wall transpeptidase and transglycolase causes rapid bacterial death. Inhibition of this transpeptidase prevents the cross-linking of the cell wall peptido￾glycans, resulting in a loss of integrity of the bacterial cell wall. Without its protective outer coat, the hyperosmolar intracellular contents swell, and the bacterial cell membrane lyses. Inhibition of PBP-3, a ANTI-INFECTIVE THERAPY / 11 Figure1.6. Basic structure of the A penicillins and B the cephalosporins

12/ CHAPTER 1 KEY POINTS cell wall synthesis in other ways, and activates bacre.( and bacterial death. Inhibition of other pbps block ial lysis About B-Lactam Antibiotics The activity of all B-lactam antibiotics bacterial growth and active cell wall synthesis. There- 1. Penicillins, cephalosporins, and carbapenems fore, bacteria in a dormant or static phase will not be are all b-lactam antibiotics: killed, but those in an active log phase of growth are a)All contain a B-lactam ring uickly lysed. Bacteriostatic agents slow bacterial e B-lactam antibiotics, and there b)All bind to and inhibit penicillin-binding pro- fore. in most cases. bacteriostatic antibiotics should not teins, enzymes important for cross-linking bacterial cell wall peptidoglycans be combined with B-lactam antibiotics. c) All require active bacterial growth for bacte- ToxICITY biocidal action Table 1. 2 summarizes the ities of the B-lactam d)All are antagonized by bacteriostatic anti- antibiotics biotics the most associated with the B-lactam antibiotics. Penicillins are the agents that most commonly cause allergic reactions, at rates ranging from 0.7% to 10% se and transglycolase that acts at the Allergic reactions to cephalosporins have been bacterium, causes the form reported in 1% to 3% of patients, and similar percent entous chains of non-dividing bacteria ages have been reported with carbapenems. However, Table 1.2. Toxicities of B-Lactam Antibiotics Clinical symptom Allergic skin rash Anaphylaxis Steven-Johnson Diarrhea(Clostridium difficile) Cholelithiasis Phlebitis aboratory tests: Eosinophilia AST/ALTI Encephalopathy associated with myoclonus has been elderly patients Black= principal side effect; dark gray less common light gray rare side effect; white= not reported or very rare: T=rise: AST/ALT= aspartate aminotransferase/ alanine transaminase

12 / CHAPTER 1 Table 1.2. Toxicities of
-Lactam Antibiotics Clinical symptom Antibiotic Allergic skin rash Anaphylaxis Steven–Johnson Seizures Encephalopathy a Diarrhea (Clostridium difficile) Cholelithiasis Phlebitis Laboratory tests: Coagulation Creatinine↑ Cytopenias Eosinophilia AST/ALT↑ a Encephalopathy associated with myoclonus has been reported in elderly patients. Black = principal side effect; dark gray = less common side effect; light gray = rare side effect; white = not reported or very rare; ↑ = rise; AST/ALT = aspartate aminotransferase/ alanine transaminase. Penicillins Cefazolin Cefotetan Ceftriaxone Cefepime Aztreonam Imipenem Meropenem and bacterial death. Inhibition of other PBPs blocks cell wall synthesis in other ways, and activates bacter￾ial lysis. The activity of all
-lactam antibiotics requires active bacterial growth and active cell wall synthesis. There￾fore, bacteria in a dormant or static phase will not be killed, but those in an active log phase of growth are quickly lysed. Bacteriostatic agents slow bacterial growth and antagonize
-lactam antibiotics, and there￾fore, in most cases, bacteriostatic antibiotics should not be combined with
-lactam antibiotics. TOXICITY Table 1.2 summarizes the toxicities of the
-lactam antibiotics. Hypersensitivity reactions are the most common side effects associated with the
-lactam antibiotics. Penicillins are the agents that most commonly cause allergic reactions, at rates ranging from 0.7% to 10%. Allergic reactions to cephalosporins have been reported in 1% to 3% of patients, and similar percent￾ages have been reported with carbapenems. However, 1. Penicillins, cephalosporins, and carbapenems are all b-lactam antibiotics: a) All contain a
-lactam ring. b) All bind to and inhibit penicillin-binding pro￾teins, enzymes important for cross-linking bacterial cell wall peptidoglycans. c) All require active bacterial growth for bacte￾riocidal action. d) All are antagonized by bacteriostatic anti￾biotics. KEY POINTS About
-Lactam Antibiotics transpeptidase and transglycolase that acts at the sep￾tum of the dividing bacterium, causes the formation of long filamentous chains of non-dividing bacteria

ANTI-INFECTIVE THERAPY/ 3 the incidence of serious, immediate immunoglobulin Other less common toxicities are associated with E (IgE)-mediated hypersensitivity reactions is much individual B-lactam antibiotics. Natural penicillins and lower with cephalosporins than with penicillins. imipenem lower the seizure threshold and can result in Approximately 1% to 7% of patients with penicillin grand mal seizures. Ceftriaxone is excreted in high con- sludging and cholecystitis. Antibiotics containing a spe Penicillins are the most allergenic of the B-lactam cific methylthiotetrazole ring(cefamandole, cefopera antibiotics because their breakdown products, partic- zone, cefotetan)can induce hypoprothrombinemia and ularly penicilloyl and penicillanic acid, are able to in combination with poor nutrition, may increase post form amide bonds with serum proteins. The resulting operative bleeding. Cefepime has been associated with antigens increase the probability of a host immune encephalopathy and myoclonus in elderly individuals response. Patients who have been sensitized by previ- All broad-spectrum antibiotics increase the risk of ous exposure to penicillin may develop an immediate pseudomembranous colitis(see Chapter 8). In combi IgE-mediated hypersensitivity reaction that can result nation with aminoglycosides, cephalosporins demon in anaphylaxis and urticaria. In the United States, strate increased nephrotoxicit penicillin-induced allergic reactions result in 400 to 800 fatalities annually. Because of the potential dan- Penicillins ger, patients with a history of an immediate hyperser itivity reaction to penicillin should never be given Tables 1.3 and 1.4, together with Figure 1.5, summarize any B-lactam antibiotic, including a cephalosporin or the characteristics of the various penicillins carbapenem. High levels of immunoglobulin G anti- Penicillins vary in their spectrum of activity. Natural penicillin antibodies can cause serum sickness, a syn- penicillins have a narrow spectrum. The aminopeni drome resulting in fever, arthritis, and arthralgia cillins have an intermediate spectrum, and combined urticaria, and diffuse edema with B-lactamase inhibitors, the carboxy/ureidopeni cillin have a very broad spectrum of activity. NATURAL PENICILLINS KEY POINTS Pharmacokinetics--All natural penicillins are rapidly excreted by the kidneys, resulting in short half-live About B-Lactam Antibiotic Toxicity (Table 1.3). As a consequence, the penicillins must be dosed frequently, and dosing must be adjusted in patients with renal dysfunction. Probenecid slows renal excretion, 1. Allergic reactions are most common toxicity, and this agent can be used to sustain higher serum levels and they include both delayed and immediate ypersensitivity reactions. 2. Allergy to penicillins(PCNs)seen in 1%to 10% of patients: 1% to 3% are allergic to KEY POINTS cephalosporins and carbapenems. 1% to 7% of tients with a pcn allergy are also allergic to ephalosporins and carbapenems. About the natural penicillins imipenem, primarily in patients with renal dys- 1. Very short half-life(15-30 minutes) 2. Excreted renally; adjust for renal dysfunction; 4. Ceftriaxone is excreted in the bile and can crys- probenecid delays excretion. tallize to form biliary sludge. 3. Penetrates most inflamed body cavities. 4. Narrow spectrum Indicated for Streptococcu efamandole, cefoperazone, moxalactam pyogenes, S viridans Gp, mouth flora, Clostridia efotetan )can interfere with vitamin K and meningitidis, Pasteurella increase prothrombin time and spirochetes 6. Pseudomembranous colitis can develop as a result of overgrowth of Clost 5. Recommended for penicillin-sensitive S pneu- moniae [however, penicillin resistant strains are Nephrotoxicity sometimes occurs when now frequent (>30%)]; infections caused by cephalosporins are given in combination with mouth flora; Clostridium perfringens or spiro- aminoglycosides. hetes

the incidence of serious, immediate immunoglobulin E (IgE)–mediated hypersensitivity reactions is much lower with cephalosporins than with penicillins. Approximately 1% to 7% of patients with penicillin allergies also prove to be allergic to cephalosporins and carbapenems. Penicillins are the most allergenic of the
-lactam antibiotics because their breakdown products, partic￾ularly penicilloyl and penicillanic acid, are able to form amide bonds with serum proteins. The resulting antigens increase the probability of a host immune response. Patients who have been sensitized by previ￾ous exposure to penicillin may develop an immediate IgE-mediated hypersensitivity reaction that can result in anaphylaxis and urticaria. In the United States, penicillin-induced allergic reactions result in 400 to 800 fatalities annually. Because of the potential dan￾ger, patients with a history of an immediate hypersen￾sitivity reaction to penicillin should never be given any
-lactam antibiotic, including a cephalosporin or carbapenem. High levels of immunoglobulin G anti￾penicillin antibodies can cause serum sickness, a syn￾drome resulting in fever, arthritis, and arthralgias, urticaria, and diffuse edema. Other less common toxicities are associated with individual
-lactam antibiotics. Natural penicillins and imipenem lower the seizure threshold and can result in grand mal seizures. Ceftriaxone is excreted in high con￾centrations in the bile and can crystallize, causing biliary sludging and cholecystitis. Antibiotics containing a spe￾cific methylthiotetrazole ring (cefamandole, cefopera￾zone, cefotetan) can induce hypoprothrombinemia and, in combination with poor nutrition, may increase post￾operative bleeding. Cefepime has been associated with encephalopathy and myoclonus in elderly individuals. All broad-spectrum antibiotics increase the risk of pseudomembranous colitis (see Chapter 8). In combi￾nation with aminoglycosides, cephalosporins demon￾strate increased nephrotoxicity. Penicillins Tables 1.3 and 1.4, together with Figure 1.5, summarize the characteristics of the various penicillins. Penicillins vary in their spectrum of activity. Natural penicillins have a narrow spectrum. The aminopeni￾cillins have an intermediate spectrum, and combined with
-lactamase inhibitors, the carboxy/ureidopeni￾cillins have a very broad spectrum of activity. NATURAL PENICILLINS Pharmacokinetics—All natural penicillins are rapidly excreted by the kidneys, resulting in short half-lives (Table 1.3). As a consequence, the penicillins must be dosed frequently, and dosing must be adjusted in patients with renal dysfunction. Probenecid slows renal excretion, and this agent can be used to sustain higher serum levels. ANTI-INFECTIVE THERAPY / 13 1. Allergic reactions are most common toxicity, and they include both delayed and immediate hypersensitivity reactions. 2. Allergy to penicillins (PCNs) seen in 1% to 10% of patients; 1% to 3% are allergic to cephalosporins and carbapenems. 1% to 7% of patients with a PCN allergy are also allergic to cephalosporins and carbapenems. 3. Seizures are associated with PCNs and imipenem, primarily in patients with renal dys￾function. 4. Ceftriaxone is excreted in the bile and can crys￾tallize to form biliary sludge. 5. Cephalosporins with methylthiotetrazole rings (cefamandole, cefoperazone, moxalactam, cefotetan) can interfere with vitamin K and increase prothrombin time. 6. Pseudomembranous colitis can develop as a result of overgrowth of Clostridium difficile. 7. Nephrotoxicity sometimes occurs when cephalosporins are given in combination with aminoglycosides. KEY POINTS About
-Lactam Antibiotic Toxicity 1. Very short half-life (15–30 minutes). 2. Excreted renally; adjust for renal dysfunction; probenecid delays excretion. 3. Penetrates most inflamed body cavities. 4. Narrow spectrum. Indicated for Streptococcus pyogenes, S. viridans Gp., mouth flora, Clostridia perfringens, Neisseria meningitidis, Pasteurella, and spirochetes. 5. Recommended for penicillin-sensitive S. pneu￾moniae [however, penicillin resistant strains are now frequent (30%)]; infections caused by mouth flora; Clostridium perfringens or spiro￾chetes. KEY POINTS About the Natural Penicillins