《传染病学 Infectious Disease》课程教学资源（MBBS）课程参考书籍教材：Infectious Diseases, A Clinical Short Course, Second Edition

CHAPTER 1 Table 1.6. Organisms That May Be Susceptible to Cephalosporin 1st generation 2nd generation 3rd generation 4th generation (cefazolin) (cefoxitin, cefotetan) (ceftriaxone, cefotaxime) (cefepime) Methicillin-sensitive Covers same organisms Covers same organisms Covers same organisms Staphylococcus aureus as cefazolin but as cefazolin and ceftriaxon eaker gram-positive often weaker gram Excellent gram-positive and Streptococcus pyogenes positive and gram-negative activity Penicillin(PCN)-sensitive Also covers stronger gram-negative Also covers. Haemophilus influenzae activity S pneumoniae Intermediate Moraxella catarrhalis Also covers. Escherichia coli PCN-resistant (some species) H influenzae M catarrhalis Bacteroides fragilis N gonorrhoeae (some strains N. meningitidis (some species Morganella spp nigella spp required. Both agents can be used for in-hospital that, for many infections, earlier-generation, narrower aspiration pneumonia to cover for mouth flora and spectrum cephalosporins are preferred to the more serious intra-abdominal, gynecologic, and acute prostate nfections. They have been used for skin and bone infec FIRST-GENERATION CEPHALOSPORINS tions thought to be caused by a combination of gram- Pharmacokinetics--Cefazolin, the preferred parenteral egative and gram-positive organisms first-generation cephalosporin, has a longer half-life than penicillin, and it is primarily excreted by the Cephalosporins kidneys(Table 1.5). The first-generation cephalosporins penetrate most body cavities, but they fail to cross the the characteristics of the ner with Figure 1.5, summarize blood-brain barrier. Oral preparations ( cephalexin Tables 1.5 and 1.6, togetl Is cephalosporins cephradine, cefadroxil)are very well absorbed, achieving In an attempt to create some semblance of order, the excellent peak serum concentrations(0.5 g cephalexin cephalosporins have been classified into generations results in a 18 ug/mL peak). Absorption is not affected based on spectrum of activity(Table 1.5).Fi generation cephalosporins are predominantly effective against gram-positive cocci. Second-generation cepha rins demonstrate increased activity against aerobic KEY POINTS d anaerobic gram-negative bacilli, but have variable activity against gram-positive cocci. The third-genera- About First-Generation Cephalosporins tion cephalosporins demonstrate even greater activity gainst gram-negative bacilli, but only limited activity against gram-positive cocci. Finally, the fourth-genera- 1. Excellent gram-positive coverage, some gram- tion cephalosporins demonstrate the broadest specs.e of activity, being effective against both gram-positiy 2. Do not cross the blood-brain barrier occi and gram-negative baci 3. Inexpensive. of the cephalosporins by generation nat- 4. Useful for treating soft-tissue infections and for urally leads to the assumption that newer, later rgical prophylaxis Can often be used as an eneration cephalosporins are better than the older alternative to oxacillin or nafcillin cephalosporins. However, it is important to keep in mind

required. Both agents can be used for in-hospital aspiration pneumonia to cover for mouth flora and gram-negative rods alike, and they can also be used for serious intra-abdominal, gynecologic,and acute prostate infections. They have been used for skin and bone infec￾tions thought to be caused by a combination of gram￾negative and gram-positive organisms. Cephalosporins Tables 1.5 and 1.6, together with Figure 1.5, summarize the characteristics of the various cephalosporins. In an attempt to create some semblance of order, the cephalosporins have been classified into generations based on spectrum of activity (Table 1.5). First￾generation cephalosporins are predominantly effective against gram-positive cocci. Second-generation cepha￾losporins demonstrate increased activity against aerobic and anaerobic gram-negative bacilli, but have variable activity against gram-positive cocci. The third-genera￾tion cephalosporins demonstrate even greater activity against gram-negative bacilli, but only limited activity against gram-positive cocci. Finally, the fourth-genera￾tion cephalosporins demonstrate the broadest spectrum of activity, being effective against both gram-positive cocci and gram-negative bacilli. Classification of the cephalosporins by generation nat￾urally leads to the assumption that newer, later￾generation cephalosporins are better than the older cephalosporins. However, it is important to keep in mind that, for many infections, earlier-generation, narrower￾spectrum cephalosporins are preferred to the more recently developed broader-spectrum cephalosporins. FIRST-GENERATION CEPHALOSPORINS Pharmacokinetics—Cefazolin, the preferred parenteral first-generation cephalosporin, has a longer half-life than penicillin, and it is primarily excreted by the kidneys (Table 1.5). The first-generation cephalosporins penetrate most body cavities, but they fail to cross the blood–brain barrier. Oral preparations (cephalexin, cephradine, cefadroxil) are very well absorbed, achieving excellent peak serum concentrations (0.5 g cephalexin results in a 18 g/mL peak). Absorption is not affected 18 / CHAPTER 1 Table 1.6. Organisms That May Be Susceptible to Cephalosporins 1st generation 2nd generation 3rd generation 4th generation (cefazolin) (cefoxitin, cefotetan) (ceftriaxone, cefotaxime) (cefepime) Methicillin-sensitive Staphylococcus aureus (best activity) Streptococcus pyogenes Penicillin (PCN)–sensitive S. pneumoniae Escherichia coli (some species) Klebsiella pneumoniae (some species) Proteus mirabilis (some species) Covers same organisms as cefazolin, but weaker gram-positive activity. Also covers: Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae N. meningitidis Bacteroides fragilis (some strains) Covers same organisms as cefazolin, but often weaker gram￾positive and stronger gram-negative activity. Also covers: H. influenzae M. catarrhalis N. gonorrhoeae N. meningitidis Citrobacter freundii Morganella spp. Salmonella spp. Shigella spp. Covers same organisms as cefazolin and ceftriaxone. Excellent gram-positive and gram-negative activity. Also covers: Intermediate PCN-resistant S. pneumoniae Enterobacter spp. Pseudomonas aeruginosa Serratia spp. 1. Excellent gram-positive coverage, some gram￾negative coverage. 2. Do not cross the blood–brain barrier. 3. Inexpensive. 4. Useful for treating soft-tissue infections and for surgical prophylaxis. Can often be used as an alternative to oxacillin or nafcillin. KEY POINTS About First-Generation Cephalosporins

ANTI-INFECTIVE THERAPY/ 9 by food. The half-lives of cephalexin and cephradine are the newer penicillins, second-generation cephalosporins short, requiring frequent administration. These agents are rarely recommended as primary therapy. need to be corrected for renal dysfunction Because cefoxitin and cefotetan demonstrate increased Spectrum of Activity and Treatment Recommenda- aerobic coverage, including many strains of B. fragilis, The first- and also cover gonococcus, these two agents are used as active against gram-positive cocci, including MSSA, part of first-line therapy in pelvic inflammatory disease they also have moderate activity against some commu- They are also used for the treatment of moderately severe egative bacilli (Table ntra-abdominal infections and mixed aerobic-anaerobic are active against oral cavity anaerobes, soft-tissue infections, including diabetic foot infections neffective for treating B. fragilis, H. The oral preparation cefuroxime achieves serum levels L. monocytogenes, MRSA, penicillin-resistant S pneumo- that are approximately one tenth that of intravenous niae, and Enterococcus. preparations, and this agent is recommended for the out- native to nafcillin or oxacillin for soft-tissue infections tions and otitis media. Other less costly oral antibiotics thought to be caused by MSSA or S pyogenes Cefazolin effectively cover the same pathogens is also the antibiotic of choice for surgical prophylaxis Cefaclor, the other second-generation oral prepara Because of its inability to cross the blood-brain barrier, tion, is inactivated by B-lactamases produced by cefazolin should never be used to treat bacterial menin- H. influenzae and M. catarrhalis. Although cefaclor gitis. Oral preparations are commonly used to treat less has been recommended for otitis media, other oral severe soft-tissue infections, including impetigo, early antibiotics are generally preferred THIRD-GENERATION CEPHALOSPORINS SECOND-GENERATION CEPHALOSPORINS Pharmacokinetics-With the exception of ceftriaxone, Pharmacokinetics--The second-generation cephalo- the third-generation cephalosporins are excreted by the orins are cleared primarily by the kidney(Table 1. 5). kidneys(Table 1.5). Ceftriaxone is cleared primarily by They have half-lives that range from 0.8 to 3.5 hours, the liver, but high concentrations of the drug are also excreted in the biliary system. The half-lives of these tion, pectrum of Activity and Treatment Recommenda- agents vary, being as short as 1.5 hours(cefotaxime)and increased activity against some gram-negative strains, body sites effectively and they effectively treat MSSA and non-enterococcal Spectrum of Activity and Treatment Recommenda treptococci(Table 1. 6). Given the availability of the ions-As compared with the first- and second first-, third -, and fourth-generation cephalosporins and generation, third-generation rins chanced activity against many aerobic gram-negative bacilli, but they do not cover Serratia marcescens, acineto- bacter, and Enterobacter cloacae. With the exceptions of KEY POINTS ceftazidime and cefoperazone, third-generation cep losporins are ineffective against P aeruginosa. About Second-Generation Cephalosporins These agents have excellent cidal activity against S pneumoniae(including moderately penicillin-resistant strains),S. pyogenes, and other streptococci. All members 1. Improved activity against Haemophilus influen- zae, Neisseria species, and Moraxella catarrhalis. of this generation are ineffective for treating Enterococ- us,MRSA, highly penicillin-resistant pr 2. Cefoxitin and cefotetan have anaerobic activity and L. monocytogenes and are used in mixed soft-tissue infections and The ESBLs are increasing in frequency, and they pelvic inflammatory disease promise to reduce the effectiveness of the third-and 3. Cefotetan and cefamandole have a me fourth-generation cephalosporins. A number of iotetrazole ring that decreases prothr roduction vitamin K prophylaxis is third-generation cephalosporins are available, all with mended in malnourished patients. similar indications. Small deficiencies in coverage and 4. Cefuroxime-axetil is a popular oral cephalo- less-desirable pharmacokinetics have affected the popu larity of a number of these drugs sporin; less expensive alternative oral antibi ftriaxone and cefotaxime are recommended for otics are available, howeve empiric treatment of community-acquired pneumonia 5. Overall, this generation is of limited usefulness ters 4 and 6). Third-generation cephalosporins can be used

by food. The half-lives of cephalexin and cephradine are short, requiring frequent administration. These agents need to be corrected for renal dysfunction. Spectrum of Activity and Treatment Recommenda￾tions—The first-generation cephalosporins are very active against gram-positive cocci, including MSSA, and they also have moderate activity against some commu￾nity-acquired gram-negative bacilli (Table 1.6). They are active against oral cavity anaerobes, but are ineffective for treating B. fragilis, H. influenzae, L. monocytogenes, MRSA, penicillin-resistant S. pneumo￾niae, and Enterococcus. First-generation cephalosporins are an effective alter￾native to nafcillin or oxacillin for soft-tissue infections thought to be caused by MSSA or S. pyogenes. Cefazolin is also the antibiotic of choice for surgical prophylaxis. Because of its inability to cross the blood–brain barrier, cefazolin should never be used to treat bacterial menin￾gitis. Oral preparations are commonly used to treat less severe soft-tissue infections, including impetigo, early cellulitis, and mild diabetic foot ulcers. SECOND-GENERATION CEPHALOSPORINS Pharmacokinetics—The second-generation cephalo￾sporins are cleared primarily by the kidney (Table 1.5). They have half-lives that range from 0.8 to 3.5 hours, and they penetrate all body cavities. Spectrum of Activity and Treatment Recommenda￾tions—The second-generation cephalosporins possess increased activity against some gram-negative strains, and they effectively treat MSSA and non-enterococcal streptococci (Table 1.6). Given the availability of the first-, third-, and fourth-generation cephalosporins and the newer penicillins, second-generation cephalosporins are rarely recommended as primary therapy. Because cefoxitin and cefotetan demonstrate increased anaerobic coverage, including many strains of B. fragilis, and also cover gonococcus, these two agents are used as part of first-line therapy in pelvic inflammatory disease. They are also used for the treatment of moderately severe intra-abdominal infections and mixed aerobic–anaerobic soft-tissue infections, including diabetic foot infections. The oral preparation cefuroxime achieves serum levels that are approximately one tenth that of intravenous preparations, and this agent is recommended for the out￾patient treatment of uncomplicated urinary tract infec￾tions and otitis media. Other less costly oral antibiotics effectively cover the same pathogens. Cefaclor, the other second-generation oral prepara￾tion, is inactivated by
-lactamases produced by H. influenzae and M. catarrhalis. Although cefaclor has been recommended for otitis media, other oral antibiotics are generally preferred. THIRD-GENERATION CEPHALOSPORINS Pharmacokinetics—With the exception of ceftriaxone, the third-generation cephalosporins are excreted by the kidneys (Table 1.5). Ceftriaxone is cleared primarily by the liver, but high concentrations of the drug are also excreted in the biliary system. The half-lives of these agents vary, being as short as 1.5 hours (cefotaxime) and as long as 8 hours (ceftriaxone). They penetrate most body sites effectively. Spectrum of Activity and Treatment Recommenda￾tions—As compared with the first- and second￾generation, third-generation cephalosporins have enhanced activity against many aerobic gram-negative bacilli, but they do not cover Serratia marcescens, Acineto￾bacter, and Enterobacter cloacae. With the exceptions of ceftazidime and cefoperazone, third-generation cepha￾losporins are ineffective against P. aeruginosa. These agents have excellent cidal activity against S. pneumoniae (including moderately penicillin-resistant strains), S. pyogenes, and other streptococci. All members of this generation are ineffective for treating Enterococ￾cus, MRSA, highly penicillin-resistant pneumococcus, and L. monocytogenes. The ESBLs are increasing in frequency, and they promise to reduce the effectiveness of the third- and fourth-generation cephalosporins. A large number of third-generation cephalosporins are available, all with similar indications. Small deficiencies in coverage and less-desirable pharmacokinetics have affected the popu￾larity of a number of these drugs. Ceftriaxone and cefotaxime are recommended for empiric treatment of community-acquired pneumonia and community-acquired bacterial meningitis (see Chap￾ters 4 and 6). Third-generation cephalosporins can be used ANTI-INFECTIVE THERAPY / 19 1. Improved activity against Haemophilus influen￾zae, Neisseria species, and Moraxella catarrhalis. 2. Cefoxitin and cefotetan have anaerobic activity and are used in mixed soft-tissue infections and pelvic inflammatory disease. 3. Cefotetan and cefamandole have a methylth￾iotetrazole ring that decreases prothrombin production. Vitamin K prophylaxis is recom￾mended in malnourished patients. 4. Cefuroxime–axetil is a popular oral cephalo￾sporin; less expensive alternative oral antibi￾otics are available, however. 5. Overall, this generation is of limited usefulness. KEY POINTS About Second-Generation Cephalosporins

20/ CHAPTER 1 in combination with other antibiotics to empirically treat FoURTH-GENERATION CEPHALOSPORINS the septic patient. Ceftriaxone is recommended for treat- Pharmacokinetics--Clearance of the fourth-generation ment of N. gonorrhoeae Cefotaxime is cleared renally and cephalosporins is renal, and the half-lives of these agents does not form sludge in the gallbladder. For this reason, are similar to the renally cleared third-generation this agent is preferred over ceftriaxone by some pediatri cephalosporins( Table 1. 5). The R, substitution of the children--where high-dose therapy has been associated tively and negatively charged group that, together, have omatic biliary sludging. Ceftazidime is the zwitterionic properties that permit these antibiotics to only third-generation cephalosporin that has excellent penetrate the outer wall of gram-negative bacteria an activity against P aeruginosa, however, the fourth- concentrate in the periplasmic space. This characteristic generation cephalosporin cefepime(and the monobactam also allows for excellent penetration of all body com- aztreonam now more commonly utilized r antI- partments, including the cerebrospinal fuid Spectrum of Activity and Treatment Recommenda The oral third-generation cephalosporin cefixime has a tions--The fourth-generation cepl halosporins are resis- long half-life, allowing for once-daily dosing. Cefixime tant to most B-lactamases, and they only weakly induce ides eff sensitive), Pyogenes, H. influenza, M. catarrhalis, Neisse B-lactamase activity (Table 1.6, Figure 1.5).These ria species, and many gram-negative bacilli, but it is inef. agents also bind gram-positive PBPs with high affinit fective against S aureus. Its absorption is not affected b The only agent currently available in the United States is cefepime. In addition to having broad antimi- community-acquired pneumonia, and it is an alternative p aeruginosa, cefepime provides excellent coverage for other oral preparation, cefpodoxime proxetil, has an penicillin), s pyogenes, and MSSA. Cefepime and cef- taziO rable coverage for addition, it has moderate activity against S. aureus. The To maximize the likelihood of cure of serious P aerugi- indications for use are similar to those for cefixime, and nosa infection, more frequent dosing (q8h) has been rec- oxime proxetil has als ded alternative treatment for acute sinusitis Cefepime is not effective against L. monocytogenes, MRSA, or B. fragilis. As compared with third-genera tion cephalosporins, cefepime is more resistant to KEY POINTS B-lac mass, including the ESBLs. It has been effec- About the Third-Generation Cephalosporins 1. Improved gram-negative coverage. 2. Excellent activity against Neisseria gonor KEY POINTS ae, and moraxella catarrhalis. 3. Ceftriaxone has a long half-life that allows for About Fourth-Generation Cephalosporins once-daily dosing In children, acalculous chole- cystitis can occur with large doses. 1. Zwiterionic properties allow for excellent pene- 4. Cefotaxime has a shorter half-life but activity tration of the bacterial cell wall and of human identical to that of ceftriaxone does not cal tissues and fluids sludging Weakly induce B-lactamases 5. Ceftazidime has excellent activity against most 3. More resistant to e acta- Pseudomonas aeruginosa strains, but reduced activity against Staphylococcus aureus. 4. Excellent gram-positive(including methicillin 6. Extended spectrum B-lactamases are increas- ensitive Staphylococcus aureus) and gram ing in frequency and endangering the effective- negative coverage(including Pseudomonas ness of third d-generation cephalosporins aeruginosa) 7. Recommended for community-acquired pneu- 5. Excellent broad-spectrum empiric therapy Use- monia and bacterial meningitis ful in nosocomial infections

in combination with other antibiotics to empirically treat the septic patient. Ceftriaxone is recommended for treat￾ment of N. gonorrhoeae. Cefotaxime is cleared renally and does not form sludge in the gallbladder. For this reason, this agent is preferred over ceftriaxone by some pediatri￾cians, particularly for the treatment of bacterial meningitis in children—where high-dose therapy has been associated with symptomatic biliary sludging. Ceftazidime is the only third-generation cephalosporin that has excellent activity against P. aeruginosa; however, the fourth￾generation cephalosporin cefepime (and the monobactam aztreonam) are now more commonly utilized for anti￾Pseudomonas therapy in many institutions. The oral third-generation cephalosporin cefixime has a long half-life, allowing for once-daily dosing. Cefixime provides effective coverage for S. pneumoniae (penicillin￾sensitive), S. pyogenes, H. influenzae, M. catarrhalis, Neisse￾ria species, and many gram-negative bacilli, but it is inef￾fective against S. aureus. Its absorption is not affected by food. This agent is a potential second-line therapy for community-acquired pneumonia, and it is an alternative to penicillin for the treatment of bacterial pharyngitis. The other oral preparation, cefpodoxime proxetil, has an antimicrobial spectrum similar to that of cefixime. In addition, it has moderate activity against S. aureus. The indications for use are similar to those for cefixime, and cefpodoxime proxetil has also been recommended as an alternative treatment for acute sinusitis. FOURTH-GENERATION CEPHALOSPORINS Pharmacokinetics—Clearance of the fourth-generation cephalosporins is renal, and the half-lives of these agents are similar to the renally cleared third-generation cephalosporins (Table 1.5). The R2 substitution of the fourth-generation cephalosporins contains both a posi￾tively and negatively charged group that, together, have zwitterionic properties that permit these antibiotics to penetrate the outer wall of gram-negative bacteria and concentrate in the periplasmic space. This characteristic also allows for excellent penetration of all body com￾partments, including the cerebrospinal fluid. Spectrum of Activity and Treatment Recommenda￾tions—The fourth-generation cephalosporins are resis￾tant to most
-lactamases, and they only weakly induce
-lactamase activity (Table 1.6, Figure 1.5). These agents also bind gram-positive PBPs with high affinity. The only agent currently available in the United States is cefepime. In addition to having broad antimi￾crobial activity against gram-negative bacilli, including P. aeruginosa, cefepime provides excellent coverage for S. pneumoniae (including strains moderately resistant to penicillin), S. pyogenes, and MSSA. Cefepime and cef￾tazidime provide comparable coverage for P. aeruginosa. To maximize the likelihood of cure of serious P. aerugi￾nosa infection, more frequent dosing (q8h) has been rec￾ommended. Cefepime is not effective against L. monocytogenes, MRSA, or B. fragilis. As compared with third-genera￾tion cephalosporins, cefepime is more resistant to
-lactamases, including the ESBLs. It has been effec￾tively used to treat gram-negative meningitis. Cefepime is effective as a single agent in the febrile neutropenic 20 / CHAPTER 1 1. Improved gram-negative coverage. 2. Excellent activity against Neisseria gonor￾rhoeae, N. meningitidis, Haemophilus influen￾zae, and Moraxella catarrhalis. 3. Ceftriaxone has a long half-life that allows for once-daily dosing. In children, acalculous chole￾cystitis can occur with large doses. 4. Cefotaxime has a shorter half-life but activity identical to that of ceftriaxone; does not cause biliary sludging. 5. Ceftazidime has excellent activity against most Pseudomonas aeruginosa strains, but reduced activity against Staphylococcus aureus. 6. Extended spectrum
-lactamases are increas￾ing in frequency and endangering the effective￾ness of third-generation cephalosporins. 7. Recommended for community-acquired pneu￾monia and bacterial meningitis KEY POINTS About the Third-Generation Cephalosporins 1. Zwiterionic properties allow for excellent pene￾tration of the bacterial cell wall and of human tissues and fluids. 2. Weakly induce
-lactamases. 3. More resistant to extended-spectrum
-lacta￾mases and chromosomal
-lactamases. 4. Excellent gram-positive (including methicillin￾sensitive Staphylococcus aureus) and gram￾negative coverage (including Pseudomonas aeruginosa). 5. Excellent broad-spectrum empiric therapy. Use￾ful in nosocomial infections. KEY POINTS About Fourth-Generation Cephalosporins

ANTI-INFECTIVE THERAPY/ 2I patient, and it is an excellent agent for initial empiric coverage of nosocomial infections. KEY POINTS Cefpirome is available in Europe. It has an crobial spectrum similar to that of cefepime, althe About aztreonam is somewhat less active against P aeruginosa. Monobactams 1. a distinctly different structure than that of the AzTREONAM 2. No cross-reactivity with penicillin, Chemistry and Pharmacokinetics-Aztreonam was 3. Binds the penicillin-binding proteins of originally isolated from Chromobacterium violaceum and negative, but not of gram-positive bacte: gram- subsequently modified. This antibiotic has a distinctly Narrow spectrum, with excellent activity against different structure from the cephalosporins, and it is the erobic gram-negative rods only available antibiotic in its class. Rather than a cen- 5. Marketed as a non-nephrotoxic replacement for tral double ring, aztreonam has a single ring ( aminoglycosides. However, as compared with cyclic B-lactam structure"), and has been classified as a aminoglycosides, it a)has no synergy with penicillins in enterococ- Because of its unique structure, aztreonam exhibits no cal infections cross-reactivity with other B-lactam antibiotics. It can be b)is not helpful for treating Streptococcus viri- used safely in the penicillin-allergic patient. The drug pen- dans endocarditis etrates body tissue well and crosses the blood-brain barrier of inflamed meninges. Aztreonam is renally cleared and an antibiotic with good gram-positive activity. has a half-life similar toto that of the renally cleared third- Useful for the treatment of pyelonephritis. and fourth-generation cephalosporins Spectrum of Activity and Treatment Recommenda- tions--Aztreonam does not bind to the PBPs of gram positive organisms or anaerobes; rather, it binds with aztreonam is its restricted antimicrobial spectrum, which igh affinity to PBPs, particularly PBP-3(responsible allows for survival of the normal gram-positive and anaer- for septum formation during bacterial division), of obic fora that can compete with more resistant pathogens gram-negative bacilli including P aeruginosa. Gram Aztreonam can be used for the treatment of most infec negative organisms exposed to aztreonam form long tions attributable to gram-negative bacilli. It has been used filamentous structures and are killed effectively in pyelonephritis, nosocomial gram-negative Aztreonam is effective against most gram-negative pneumonia, gram-negative bacteremia, and gra aminoglycosides. However, unlike positive or anaerobic coverage glycosides, aztreonam does not provide synergy Therefore, when it is used for empiric treatment of poten penicillins for Enterococcus. A major advantage ial gram-positive pathogens in the seriously ill patient, Table 1.7. Carbapenems: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced ( trade name creatinine clearance (mL/min) enem-cilastin 0.5-1gⅣq6h 50-80:059q-8h sSS-SSSSs Very broad <10:025-0.5gq12h 1aⅣa8h 10-50:0.5gq8h Very broad (Merrem <10:05gq24h 1 gIor IM q24h <30:500mgq24h Very broad Intravenous preparations (daily cost dollars):$= 20-70; $S 71-110: SSS=111-150; SSSS= 150-200: SSSSS 2200

patient, and it is an excellent agent for initial empiric coverage of nosocomial infections. Cefpirome is available in Europe. It has an antimi￾crobial spectrum similar to that of cefepime, although it is somewhat less active against P. aeruginosa. Monobactams AZTREONAM Chemistry and Pharmacokinetics—Aztreonam was originally isolated from Chromobacterium violaceum and subsequently modified. This antibiotic has a distinctly different structure from the cephalosporins, and it is the only available antibiotic in its class. Rather than a cen￾tral double ring, aztreonam has a single ring (“mono￾cyclic
-lactam structure”), and has been classified as a monobactam. Because of its unique structure, aztreonam exhibits no cross-reactivity with other
-lactam antibiotics. It can be used safely in the penicillin-allergic patient. The drug pen￾etrates body tissue well and crosses the blood–brain barrier of inflamed meninges. Aztreonam is renally cleared and has a half-life similar to to that of the renally cleared third￾and fourth-generation cephalosporins. Spectrum of Activity and Treatment Recommenda￾tions—Aztreonam does not bind to the PBPs of gram￾positive organisms or anaerobes; rather, it binds with high affinity to PBPs, particularly PBP-3 (responsible for septum formation during bacterial division), of gram-negative bacilli including P. aeruginosa. Gram￾negative organisms exposed to aztreonam form long filamentous structures and are killed. Aztreonam is effective against most gram-negative bacilli, and this agent has been marketed as a non-nephro￾toxic replacement for aminoglycosides. However, unlike aminoglycosides, aztreonam does not provide synergy with penicillins for Enterococcus. A major advantage of aztreonam is its restricted antimicrobial spectrum, which allows for survival of the normal gram-positive and anaer￾obic flora that can compete with more resistant pathogens. Aztreonam can be used for the treatment of most infec￾tions attributable to gram-negative bacilli. It has been used effectively in pyelonephritis, nosocomial gram-negative pneumonia, gram-negative bacteremia, and gram-negative intra-abdominal infections. Importantly, though, aztre￾onam provides no gram-positive or anaerobic coverage. Therefore, when it is used for empiric treatment of poten￾tial gram-positive pathogens in the seriously ill patient, ANTI-INFECTIVE THERAPY / 21 Table 1.7. Carbapenems: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) Imipenem–cilastin 1 0.5–1 g IV q6h 50–80: 0.5 g q6–8h $$$–$$$$$ Very broad (Primaxin) 10–50: 0.5 g q8–12h 10: 0.25–0.5 g q12h Meropenem 1 1 g IV q8h 10–50: 0.5 g q8h $$$$ Very broad (Merrem) 10: 0.5 g q24h Ertapenem 4 1 g IV or IM q24h 30: 500 mg q24h $ Very broad (Invanz) Intravenous preparations (daily cost dollars): $ = 20–70; $$ 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200. 1. A distinctly different structure than that of the cephalosporins. 2. No cross-reactivity with penicillin, 3. Binds the penicillin-binding proteins of gram￾negative, but not of gram-positive bacteria. 4. Narrow spectrum, with excellent activity against aerobic gram-negative rods. 5. Marketed as a non-nephrotoxic replacement for aminoglycosides. However, as compared with aminoglycosides, it a) has no synergy with penicillins in enterococ￾cal infections. b) is not helpful for treating Streptococcus viri￾dans endocarditis. 6. Excellent empiric antibiotic when combined with an antibiotic with good gram-positive activity. Useful for the treatment of pyelonephritis. KEY POINTS About Aztreonam

22/ CHAPTER 1 aztreonam should be combined with vancomycin, cli istration with cilastatin. These drugs are all primarily damycin,erythromycin, or a penicilli cleared by the kidneys SPECTRUM OF ACTIVITY AND Carbapenems TREATMENT RECOMMENDATIONS Table 1.7, together with Figure 1.5, summarizes the char- The carbapenems have a very broad spectrum of activity, acteristics of the various carbapene negative bacteria, including anaerobes. Overall, imipenem CHEMISTRY AND PHARMACOKINETICS has slightly better activity against gram-positive organisms The carbapenems have both a modified thiazolid Meropenem and ertapenem have somewhat better activity that renders the B-lactam ring highly resistant to cleav- described later in this subsection) except Pseudomonas,as ring and a change in the configuration of the side chain against gram-negative pathogens age. Their hydroxyethyl side chain is in a trans rather These agents are cidal not only against S pneumoniae, than cis conformation, and this configuration is thought S pyogenes, and MSSA, but also against organisms that are to be responsible for the group's remarkable resistance to not covered by the cephalosporins, including Listeria, agents have zwitterionic characteristics that allow them lare(MAD). They have static activity against penicillin- to readily penetrate tissues. The carbapenems bind with sensitive enterococci; however, many penicillin-resistant gh affinity to the high molecular weight PBPs of both strains are also resistant to carbapenems. MRSA,some gram-positive and gram-negative bacteria. illin-resistant strains of S. C difficile Imipenem is combined in a 1: ratio with cilastatin Stenotropbor autophilia, and Burkholderia cepacia are block rapid breakdown by renal dehyde dase so resistant. Resistance in gram-negative bacilli is most Meropenem and ertapenem are not significantly often secondary to loss of an outer membrane protein degraded by this enzyme and do not require co-admin- called D2 that is required for intracellular penetration of the carbapenems. Increasing numbers of gram-negative strains can also produce B-lactamases called carbapene- KEY POINTS mases that can hydrolyze these drugs. mipenem and meropenem can be used as empi About the Carbapenems therapy for sepsis, and they are particularly useful if polymicrobial bacteremia is a strong possibility. They can also be used to treat severe intra-abdominal infections and 1. B-Lactam ring is highly resistant to cleavage complicated pyelonephritis. Infections attributable to 2. Have zwitterionic characteristics, and penetrate e bacilli resistant to cephalosporins and all tissues aminoglycosides may be sensitive to imipenem or 3. Frequent cross-reactivity in penicillin-allergic meropenem Imipenem or meropenem are recommended patients (7%) as primary therapy for Serratia Meropenem can be used 4. Imipenem causes seizures at high doses; be cau- for meningitis, achieving therapeutic levels in the cere- tious in renal failure patients. Meropenem is less brospinal Auid. Imipenem is not recommended for this because of i In eral, imipenem and meropenem should be reserved for the 5. Bind penicillin binding proteins of all bacteria seriously ill patient or the patient infected with a highly with high affinity. resistant bacterium that is sensitive only to this antibiotic 6. Very broad cidal activity for aerobic and anaero- Ertapenem has a longer half-life and can be given Also covers Listeria monocytogenes and Nocardia. just once daily, making it a useful agent for home intra- bic gram-positive and gram-negative bacte venous therapy. This agent is not effective against mipenem and meropenem are useful for empiric therapy of suspected mixed aerobic that of meropenem. It is recommended for complicated nd anaerobic infection or a severe nosocomial intra-abdominal infections, postpartum and postopera- infection, pending culture results. Reserve for the severely ill patient. tive acute pelvic infections, and complicated soft- infections 8. Ertapenem can be once daily. Lacks Because the carbapenems are extremely broad Pseudomonas aerugi overage pectrum agents, they kill nearly all normal f Treatment markedly the normal bacterial loss of normal fora increases the risk of nosocomial flora infections with resistant pathogens including MRSA, Pseudomonas, and candida

aztreonam should be combined with vancomycin, clin￾damycin, erythromycin, or a penicillin. Carbapenems Table 1.7, together with Figure 1.5, summarizes the char￾acteristics of the various carbapenems. CHEMISTRY AND PHARMACOKINETICS The carbapenems have both a modified thiazolidine ring and a change in the configuration of the side chain that renders the
-lactam ring highly resistant to cleav￾age. Their hydroxyethyl side chain is in a trans rather than cis conformation, and this configuration is thought to be responsible for the group’s remarkable resistance to
-lactamase breakdown. At physiologic pH, these agents have zwitterionic characteristics that allow them to readily penetrate tissues. The carbapenems bind with high affinity to the high molecular weight PBPs of both gram-positive and gram-negative bacteria. Imipenem is combined in a 1:1 ratio with cilastatin to block rapid breakdown by renal dehydropeptidase I. Meropenem and ertapenem are not significantly degraded by this enzyme and do not require co-admin￾istration with cilastatin. These drugs are all primarily cleared by the kidneys. SPECTRUM OF ACTIVITY AND TREATMENT RECOMMENDATIONS The carbapenems have a very broad spectrum of activity, effectively killing most strains of gram-positive and gram￾negative bacteria, including anaerobes. Overall, imipenem has slightly better activity against gram-positive organisms. Meropenem and ertapenem have somewhat better activity against gram-negative pathogens (except Pseudomonas, as described later in this subsection). These agents are cidal not only against S. pneumoniae, S. pyogenes, and MSSA, but also against organisms that are not covered by the cephalosporins, including Listeria, Nocardia, Legionella, and Mycobacterium avium intracellu￾lare (MAI). They have static activity against penicillin￾sensitive enterococci; however, many penicillin-resistant strains are also resistant to carbapenems. MRSA, some penicillin-resistant strains of S. pneumoniae, C. difficile, Stenotrophomonas maltophilia, and Burkholderia cepacia are also resistant. Resistance in gram-negative bacilli is most often secondary to loss of an outer membrane protein called D2 that is required for intracellular penetration of the carbapenems. Increasing numbers of gram-negative strains can also produce
-lactamases called carbapene￾mases that can hydrolyze these drugs. Imipenem and meropenem can be used as empiric therapy for sepsis, and they are particularly useful if polymicrobial bacteremia is a strong possibility. They can also be used to treat severe intra-abdominal infections and complicated pyelonephritis. Infections attributable to gram-negative bacilli resistant to cephalosporins and aminoglycosides may be sensitive to imipenem or meropenem. Imipenem or meropenem are recommended as primary therapy for Serratia. Meropenem can be used for meningitis, achieving therapeutic levels in the cere￾brospinal fluid. Imipenem is not recommended for this purpose because of its propensity to cause seizures. In gen￾eral, imipenem and meropenem should be reserved for the seriously ill patient or the patient infected with a highly resistant bacterium that is sensitive only to this antibiotic. Ertapenem has a longer half-life and can be given just once daily, making it a useful agent for home intra￾venous therapy. This agent is not effective against P. aeruginosa, but otherwise it has a spectrum similar to that of meropenem. It is recommended for complicated intra-abdominal infections, postpartum and postopera￾tive acute pelvic infections, and complicated soft-tissue infections. Because the carbapenems are extremely broad￾spectrum agents, they kill nearly all normal flora. The loss of normal flora increases the risk of nosocomial infections with resistant pathogens including MRSA, Pseudomonas, and Candida. 22 / CHAPTER 1 1.
-Lactam ring is highly resistant to cleavage. 2. Have zwitterionic characteristics, and penetrate all tissues. 3. Frequent cross-reactivity in penicillin-allergic patients (7%). 4. Imipenem causes seizures at high doses; be cau￾tious in renal failure patients. Meropenem is less epileptogenic. 5. Bind penicillin binding proteins of all bacteria with high affinity. 6. Very broad cidal activity for aerobic and anaero￾bic gram-positive and gram-negative bacteria. Also covers Listeria monocytogenes and Nocardia. 7. Imipenem and meropenem are useful for empiric therapy of suspected mixed aerobic and anaerobic infection or a severe nosocomial infection, pending culture results. Reserve for the severely ill patient. 8. Ertapenem can be given once daily. Lacks Pseudomonas aeruginosa coverage. 9. Treatment markedly alters the normal bacterial flora. KEY POINTS About the Carbapenems