1.Infectious DiseasesA Clinical Short Course

2. NoticeMedicine is an ever-changing science. As new research and clinical experience broadenour Despite dire warnings that we are approaching the end of the antibiotic era, the inci-dence of antibiotic-resistant bacteria continues to rise. The proportions of penicillin-resis-tant Streptococcus pneumoniae, hospital-acquired methicillin-resistant Staphylococcusaureus (MRSA), and vancomycin-resistant Enterococcus (VRE) strains continue toincrease. Community-acquired MRSA (cMRSA) is now common throughout the world.Multiresistant Acinetobacter and Pseudomonas are everyday realities in many of our hos-pitals. The press is now warning the lay public of the existence of dirty hospitals. Asnever before, it is critical that health care providers understand the principles of properanti-infective therapy and use anti-infective agents judiciously. These agents need to bereserved for treatable infections-not used to calm the patient or the patients family. Toooften, patients with viral infections that do not warrant anti-infective therapy arrive at thephysicians ofce expecting to be treated with an antibiotic. And health care workers toooften prescribe antibiotics to fulll those expectations. Physicians unschooled in the prin-ciples of microbiology utilize anti-infective agents just as they would more conventionalmedications, such as anti-inammatory agents, anti-hypertensive medications, and car-diac drugs. They use one or two broad-spectrum antibiotics to treat all patients with.They use one or two broad-spectrum antibiotics to treat all patients with. 3. Infectious DiseasesA Clinical Short CourseSecond EditionFREDERICK S. SOUTHWICK, M.D. Professor of Medicine Chief of Infectious Diseases Vice Chairman of Medicine University of Florida College of MedicineGainesville, Florida McGraw-Hill Medical Publishing DivisonNew York Chicago San Fracisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto 4. Copyright 2007 by The McGraw-Hill Companies, Inc. All rights reserved. Manufactured in the United States of America. Except as permittedunder the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or storedin a database or retrieval system, without the prior written permission of the publisher.0-07-159378-0The material in this eBook also appears in the print version of this title: 0-07-147722-5.All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we usenames in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where suchdesignations appear in this book, they have been printed with initial caps.McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs.For more information, please contact George Hoare, Special Sales, at george_hoare@mcgraw-hill.com or (212) 904-4069.TERMS OF USEThis is a copyrighted work and The McGraw-Hill Companies, Inc. (McGraw-Hill) and its licensors reserve all rights in and to the work. Use ofthis work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work,you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit,distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hills prior consent. You may use the work for yourown noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail tocomply with these terms.THE WORK IS PROVIDED AS IS. McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THEACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANYINFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIMANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY ORFITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the workwill meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you oranyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has noresponsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liablefor any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any ofthem has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claimor cause arises in contract, tort or otherwise.DOI: 10.1036/0071477225 5. ProfessionalWant to learn more?We hope you enjoy thisMcGraw-Hill eBook! Ifyoud like more information about this book,its author, or related books and websites,please click here. 6. Dedication To my mother and father, Ann and Wayne Southwick, and to my beautiful wife, Kathie Southwick for all their loving encouragementCopyright 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. 7. This page intentionally left blank 8. For more information about this title, click hereContentsContributorsixPreface xiAcknowledgmentsxiii1 ANTI-INFECTIVE THERAPY 12 THE SEPSIS SYNDROME 573 THE FEBRILE PATIENT 664 PULMONARY INFECTIONS795 EYE, EAR NOSE, AND THROAT INFECTIONS 1206 CENTRAL NERVOUS SYSTEM INFECTIONS1397 CARDIOVASCULAR INFECTIONS1678 GASTROINTESTINAL AND HEPATOBILIARY INFECTIONS1909 GENITOURINARY TRACT INFECTIONS AND SEXUALLY TRANSMITTED DISEASES (STDs)23110 SKIN AND SOFT TISSUE INFECTIONS 25611 BONE AND JOINT INFECTIONS 27312 PARASITIC INFECTIONS28813 ZOONOTIC INFECTIONS 32214 BIOTERRORISM34915 SERIOUS ADULT VIRAL ILLNESSES OTHER THAN HIV36516 INFECTIONS IN THE IMMUNOCOMPROMISED HOST38417 HIV INFECTION 397Index435 9. This page intentionally left blank 10. Contributors Bernard Hirschel, M.D.Frederick S. Southwick, M.D. Professor of Medicine Professor of Medicine Division of Infectious Diseases Chief of Infectious Diseases University of GenevaVice Chairman of Medicine Geneva, Switzerland University of Florida College of Medicine P. Daniel Lew, M.D. Gainesville, Florida Professor of Medicine and Chiefof Infectious Diseases Sankar Swaminathan, M.D. University of GenevaAssociate Professor of Medicine Geneva, Switzerland Division of Infectious Diseases University of Florida College Reuben Ramphal, M.D.of Medicine Professor of Medicine Gainesville, Florida Division of Infectious Diseases University of Florida College of Medicine Gainesville, FloridaCopyright 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. 11. This page intentionally left blank 12. Preface THE END OF THE FEATURES OF THE SECOND ANTIBIOTIC ERA? EDITION Time and Newsweek magazines have heralded the This is the second edition of a textbook envisioned as End of the Antibiotic Era. Echoing the concerns ofa 30-day tutorial designed to provide a solid ground- many infectious disease and health policy experts,ing in the principles of clinical infectious diseases. The Chicago Tribunes feature on Unhealthy Hospi-The title has been changed from infectious Diseases in tals warns that the overuse of antibiotics are spawn- 30 Days to Infectious Diseases: A Clinical Short Course; ing drug-resistant germs that are spreading from hos- however the design and intention of our book has not pitals into the community at unprecedented rates.changed. As our title emphasizes we have created a Vancomycin resistant enterococcus (VRE), methicillin- concise overview of this important field that will resistant Staphylococcus aureus (MRSA) are now com- allow the busy physician, medical student, nurse monly found in our hospitalized patients and a newpractioner, and physician assistant to understand, highly virulent community-acquired methicillindiagnose and treat common infectious diseases. resistant Staphylococcus aureus (cMRSA) is infectingMastering the eld of infectious diseases seems high school and college athletes. Extensively drug- daunting, and many textbooks in the eld are over a resistant tuberculosis (XDR-TB) has resulted in nearthousand pages in length. Our goal has been to make 100% mortality in an outbreak in South Africa.this task easier and more enjoyable. By indicating the Newly discovered infectious diseases such as SARS,number of days that should be allotted to the study Avian Inuenza, Ehrlichia, Lyme Disease, and West of each chapter, we have a created a schedule for com- Nile Encephalitis are emerging as threats to our well-pletion of each lesson. By taking one small step at a being. Malaria remains a leading cause of death intime, a seemingly difcult task can be more readily many parts of the world. The 2001 bioterrorist attack achieved. The book has been shortened to make launched by mailing anthrax spores illustrates thecompletion within 30 days feasible. This has been critical need for all health providers to recognize the made possible by creating a wide array of tables that manifestations of this nearly forgotten pathogen andsummarize the methods of clinical assessment, anti- others that can be used as weapons of mass destruc- infective agent doses, and drug toxicities; facts that tion. The AIDS epidemic continues to devastate sub- do not require memorization, but do need to be Saharan Africa, and is spreading at an alarming ratereferred to when caring for patients. in Asia and the former Soviet Union. HIV strainsChapters are organized by organ system when pos- resistant to antiretroviral therapy are increasingsible, because this is how clinicians encounter infec- throughout the United States and Europe. Diseases tious diseases. As in the last edition, guiding ques- long believed to have non-infectious etiologies are tions begin each chapter to encourage the reader to now conrmed as having microbial origins. Infec-actively inquire as he or she reads the text. The poten- tious diseases have re-emerged as one of the worldstial severity of each disease is assessed to give the inex- top healthcare priorities, and to meet the needs of the perienced clinician a sense of the speed with which 21st Century, health care providers must possess acare must be initiated. Key points are included in solid grounding in clinical infectious diseases.shaded areas to emphasize the most important factsCopyright 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. 13. xii / PREFACEthe clinician should know when managing eachimprove healthcare providers understanding of infec-infection. When possible simple diagrams summarizetious diseases and provide them with the latestmanagement approaches, as well as principles of approaches managing infections. It is our rm beliefpathogenesis. All chapters have been updated to that only through a concerted educational campaignreect the current treatment and diagnostic guide-to teach the principles of infectious diseases and thelines of the Infectious Disease Society of Americajudiciously use anti-infective agents we can help to(IDSA) and up-to-date references have beenprevent the End of the Antibiotic Era.included at the end of each chapter. Our goal is to 14. Acknowledgments I wish to thank Dr. Morton Swartz who rst inspired want to thank the many medical students at the Uni- my love for Infectious Diseases. I will always be grate-versity of Florida who provided helpful feedback on ful to Drs. James McGuigan, and Tom Stossel for the rst edition. Their input has guided many of the serving as my mentors throughout my career. Thank improvements in the second edition. you to my contributors, Drs. P. Daniel Lew, Reuben A special thanks to James Shanahan of McGraw- Ramphal, Sankar Swaminathan, and BernardHill who has been my sounding board throughout Hirschel for their prompt and well written submis-the writing process, and was instrumental making the sions. Dr. Hirschel and I want to acknowledge the second edition a Lange series publication. Finally, I assistance of Drs. Markus Flepp, Vronique Schiffer,wish to acknowledge the excellent artwork of Roger and Rainer Weber with sections of Chapter 17. I alsoHoover.Copyright 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. 15. This page intentionally left blank 16. Anti-Infective Therapy 1Time Recommended to complete: 3 daysFrederick Southwick, M.D. GUIDING QUESTIONS1. Are we at the end of the antibiotic era? 6. Does one antibiotic cure all infections?2. Why are superbugs suddenly appearing in our7. What are the strategies that underlie optimal hospitals?antibiotic usage?3. How do bacteria become resistant to antibiotics? 8. How is colonization distinguished from infection, and why is this distinction important?4. How can the continued selection of highly resis- 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 the antibiotic era, the incidence of antibiotic-resistantall patients with suspected infections. bacteria continues to rise. The proportions of penicillin- Many excellent broad-spectrum antibiotics can resistant Streptococcus pneumoniae, hospital-acquiredeffectively treat most bacterial infections without requir- methicillin-resistant Staphylococcus aureus (MRSA), anding a specic causative diagnosis. However, overuse of vancomycin-resistant Enterococcus (VRE) strains continue empiric broad-spectrum antibiotics has resulted in the to increase. Community-acquired MRSA (cMRSA) isselection of highly resistant pathogens. A simplistic now common throughout the world. Multiresistantapproach to anti-infective therapy and establishment of Acinetobacter and Pseudomonas are everyday realities ina xed series of simple rules concerning the use of these many of our hospitals. The press is now warning the layagents is unwise and has proved harmful to patients. public of the existence of dirty hospitals. As never Such an approach ignores the remarkable adaptability of before, 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 usethese more primitive life forms have survived for anti-infective agents judiciously. These agents need to be millions of years, far longer than the human race. reserved for treatable infectionsnot used to calm the The rules for the use of anti-infective therapy are patient or the patients family. Too often, patients withdynamic and must take into account the ability of these viral infections that do not warrant anti-infective therapypathogens to adapt to the selective pressures exerted by arrive at the physicians ofce expecting to be treated with the overuse of antibiotic, antifungal, and antiviral agents. an antibiotic. And health care workers too often prescribe The days of the shotgun approach to infectious diseases antibiotics to fulll those expectations.must end, or more and more patients will become Physicians unschooled in the principles of microbiol-infected with multiresistant organisms that cannot be ogy utilize anti-infective agents just as they would moretreated. Only through the judicious use of anti-infective conventional medications, such as anti-inammatory therapy can we hope to slow the arrival of the end of the agents, anti-hypertensive medications, and cardiac drugs.antibiotic era.1Copyright 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. 17. 2 / CHAPTER 1KEY POINTS About Anti-Infective Therapy 1. Too often, antibiotics are prescribed to fulll thepatients expectations, rather than to treat a truebacterial infection. 2. A single antibiotic cannot meet all infectiousdisease needs. 3. Physicians ignore the remarkable adaptabilityof bacteria, fungi, and viruses at their patientsperil. 4. Anti-infective therapy is dynamic and requires abasic understanding of microbiology. 5. The shotgun approach to infectious diseasesmust end, or we may truly experience the end ofthe antibiotic era. ANTIBIOTIC RESISTANCEGENETIC MODIFICATIONS LEADING TOFigure 11. Mechanisms by which bacteria transferANTIMICROBIAL RESISTANCEantibiotic 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. Pointsecond bacterium and serves as bridge for themutations can develop in the DNA of bacteria as they transfer of the plasmid DNA from the donor toreplicate. These mutations occur in the natural envi-the recipient bacterium. Using this mechanism, aronment, but are of no survival advantage unless the single resistant bacterium can transfer resistancebacteria are placed under selective pressures. In theto other bacteria.case of a mutation that renders a bacterium resistant to2. Transduction. Bacteriophages are protein-coateda specic antibiotic, exposure to the specic antibiotic DNA segments that attach to the bacterial wall andallows the bacterial clone that possesses the antibiotic inject DNA in a process called transduction.resistance mutation to grow, while bacteria without theThese 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 releaserial ora. In addition to point mutations bacteria can linear segments of chromosomal DNA, which isalso use three major mechanisms to transfer geneticthen taken up by recipient bacteria and incorpo-material among themselves: rated into the recipients genome. This process is1. 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-ient bacteria is called a transposon (Figure 1.1). terial genome (Figure 1.1). Plasmids often carryNatural 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 plasmidtance 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 vancomycin resis- bacterias outer surface. The pilus attaches to a tance in enterococci. 18. ANTI-INFECTIVE THERAPY / 3-lactamase activity occurs primarily through plasmidsKEY POINTSand transposons.Multiple classes of -lactamases exist. Some preferen-About Antibiotic Resistance tially break down penicillins; others preferentially destroyspecic cephalosporins or carbenicillin. Extended-spec- 1. Bacteria can quickly alter their genetic makeup bytrum -lactamases (ESBLs) readily destroy most cepha-losporins. Another class of -lactamase is resistant toa) point mutation.clavulanate, an agent added to numerous antibiotics tob) transfer of DNA by plasmid conjugation.inhibit -lactamase activity. Some bacteria are able to pro-c) transfer of DNA by bacteriophage trans-duce -lactamases called carbapenemases that are capable duction. of inactivating imipenem and meropenem.d) transfer of naked DNA by transposon trans- Gram-negative bacilli produce a broader spectrum formation. of -lactamases than do gram-positive organisms, and 2. The ability of bacteria to share DNA provides a therefore infections with gram-negative organismssurvival advantage, allowing them to quicklymore commonly arise in patients treated for pro-adapt to antibiotic exposure. longed periods with broad-spectrum antibiotics. In 3. Biochemical alterations leading to antibiotic some instances, -lactamase activity is low before theresistance includebacterium is exposed to antibiotics; however, follow-a) degradation or modication of the antibiotic.ing exposure, -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 pumps. initial testing. Following cephalosporin treatment,c) modication of the antibiotic target.-lactamase activity increases, resistance develops,and the patients infection relapses. For this reason, 4. Under the selection pressure of antibiotics, thethird-generation cephalosporins are not recom-question is not whether, but when resistantbacteria will take over.mended for serious Enterobacter infections.OTHER ENZYME MODIFICATIONS OF ANTIBIOTICSErythromycin is readily inactivated by an esterase thathydrolyzes the lactone ring of the antibiotic. ThisThus bacteria possess multiple ways to transfer their esterase has been identied in Escherichia coli. OtherDNA, and they promiscuously share genetic informa-plasmid-mediated erythromycin inactivating enzymestion. This promiscuity provides a survival advantage, have been discovered in Streptococcus species andallowing bacteria to quickly adapt to their environment.S. aureus. Chloramphenicol is inactivated by chloram-phenicol acetyltransferase, which has been isolated fromboth gram-positive and gram-negative bacteria. Simi-BIOCHEMICAL MECHANISMS FORlarly, aminoglycosides can be inactivated by acetyltrans-ANTIMICROBIAL RESISTANCEferases. Bacteria also inactivate this class of antibiotics byWhat are some of the proteins that these resistant genesphosphorylation and adenylation.encode for, and how do they work? These resistance enzymes are found in many gram- The mechanisms by which bacteria resist antibioticsnegative strains and are increasingly detected in entero-can be classied into three major groups: cocci, S. aureus and S. epidermidis. Degradation or modication of the antibioticReduction of the Bacterial Reduction of the bacterial antibiotic concentration Antibiotic Concentration Modication of the antibiotic targetINTERFERENCE WITH ANTIBIOTIC ENTRYFor an antibiotic to work, it must be able to penetrateDegradation or Modicationthe bacterium and reach its biochemical target. Gram-of the Antibiotic negative bacteria contain an outer lipid coat thatimpedes penetration by hydrophobic reagents (such as -LACTAMASESmost antibiotics). The passage of hydrophobic antibi-Many bacteria synthesize one or more enzymes called otics is facilitated by the presence of porinssmall -lactamases that inactivate antibiotics by breaking thechannels in the cell walls of gram-negative bacteria thatamide bond on the -lactam ring. Transfer of allow the passage of charged molecules. Mutations 19. 4 / CHAPTER 1leading to the loss of porins can reduce antibiotic pene-Ribosomal resistance to gentamicin, tobramycin, andtration and lead to antibiotic resistance. amikacin is less common because these aminoglyco- sides have several binding sites on the bacterial ribo-PRODUCTION OF EFFLUX PUMPS some and require multiple bacterial mutations beforeTransposons have been found that encode for an their binding is blocked.energy-dependent pump that can actively pumptetracycline out of bacteria. Active efux of antibioticsCONCLUSIONShas been observed in many enteric gram-negativebacteria, and this mechanism is used to resist Bacteria can readily transfer antibiotic resistance genes.tetracycline, macrolide, and fluoroquinolone Bacteria have multiple mechanisms to destroy antibi-antibiotic treatment. S. aureus, S. epidermidis, otics, lower the antibiotic concentration, and interfereS. pyogenes, group B streptococci, and S. pneumoniae with antibiotic binding. Under the selective pressures ofalso can utilize energy-dependent efflux pumps toprolonged antibiotic treatment, the question is notresist antibiotics.whether, but when resistant bacteria will take over.Modication of the Antibiotic TargetALTERATIONS OF CELL WALL PRECURSORS ANTI-INFECTIVE AGENT DOSINGAlteration of cell wall precursors is the basis for VRE.Vancomycin and teicoplanin binding requires that D-The characteristics that need to be considered whenalanine-D-alanine be at the end of the peptidoglycan celladministering antibiotics include absorption (when deal-wall precursors of gram-positive bacteria. Resistant ing with oral antibiotics), volume of distribution, metab-strains of Enterococcus faecium and Enterococcus faecalisolism, and excretion. These factors determine the dose ofcontain the vanA plasmid, which encodes a protein that each drug and the time interval of administration. Tosynthesizes D-alanine-D-lactate instead of D-alanine-D-effectively clear a bacterial infection, serum levels of thealanine at the end of the peptidoglycan precursor. Lossantibiotic need to be maintained above the minimumof the terminal D-alanine markedly reduces vancomycininhibitory concentration (MIC) for a signicant period.and teicoplanin binding, allowing the mutant bac-For each pathogen, the MIC is determined by seriallyterium to survive and grow in the presence of thesediluting the antibiotic into liquid medium containing 104antibiotics. bacteria per milliliter. Inoculated tubes are incubated overnight until broth without added antibiotic hasCHANGES IN TARGET ENZYMESbecome cloudy or turbid as a result of bacterial growth.Penicillins and cephalosporins bind to specic proteinsThe lowest concentration of antibiotic that preventscalled penicillin-binding proteins (PBPs) in the bacter- active bacterial growththat is, the liquid media remainsial cell wall. Penicillin-resistant S. pneumoniae demon- clearconstitutes the MIC (Figure 1.2). Automatedstrate decreased numbers of PBPs or PBPs that bind analyzers can now quickly determine, for individualpenicillin with lower afnity, or both. Decreased peni-pathogens, the MICs for multiple antibiotics, and thesecillin binding reduces the ability of the antibiotic to kill data serve to guide the physicians choice of antibiotics.the targeted bacteria. The mean bactericidal concentration (MBC) is deter-The basis for antibiotic resistance in MRSA is pro-mined by taking each clear tube and inoculating a plateduction of a low afnity PBP encoded by the mecA of solid medium with the solution. Plates are then incu-gene. Mutations in the target enzymes dihydropteroatebated to allow colonies to form. The lowest concentra-synthetase and dihydrofolate reductase cause sulfon- tion of antibiotic that blocks all growth of bacteriathatamide and trimethoprim resistance respectively. Single is, no colonies on solid mediumrepresents the MBC.amino-acid mutations that alter DNA gyrase functionSuccessful cure of an infection depends on multiplecan result in resistance to uoroquinolones. host factors in addition to serum antibiotic concentration. However, investigators have attempted to predict success-ALTERATIONS IN RIBOSOMAL BINDING SITEful treatment by plotting serum antibiotic levels againstTetracyclines, macrolides, lincosamides, and amino-time. Three parameters can be assessed (Figure 1.3): timeglycosides all act by binding to and disrupting theabove the MIC (T>MIC), ratio of the peak antibiotic con-function of bacterial ribosomes (see the descriptionscentration to the MIC (Cmax/MIC), and the ratio of theof individual antibiotics later in this chapter). A num- area under the curve (AUC) to the MIC (AUC/MIC).ber of resistance genes encode for enzymes thatCure rates for -lactam antibiotics are maximized bydemethylate adenine residues on bacterial ribosomalmaintaining serum levels above the MIC for >50% ofRNA, inhibiting antibiotic binding to the ribosome.the time. Peak antibiotic concentrations are of less 20. ANTI-INFECTIVE THERAPY / 5exceed the MIC. High peak levels of these antibiotics maybe more effective than low peak levels at curing infec-tions. Therefore, for treatment with aminoglycosides anduoroquinolones Cmax/MIC and AUC/MIC are morehelpful for maximizing effectiveness. In the treatment ofgram-negative bacteria, aminoglycosides have been sug-gested to achieve maximal effectiveness when Cmax/MICis 10 to 12. For uoroquinolones, best outcomes in com-munity-acquired pneumonia may be achieved when theAUC/MIC is 34. To prevent the development of uo-roquinolone resistance to S. pneumoniae, in vitro studieshave suggested that AUC/MIC should be 50. ForP. aeruginosa, an AUC/MIC of 200 is required. In vitro studies also demonstrate that aminoglycosidesand uoroquinolones demonstrate a post-antibiotic effect:when the antibiotic is removed, a delay in the recovery ofbacterial growth occurs. Gram-negative bacteria demon-strate a delay of 2 to 6 hours in the recovery of activegrowth after aminoglycosides and uoroquinolones, butno delay after penicillins and cephalosporins. But peni-cillins and cephalosporins generally cause a 2-hour delayin the recovery of gram-positive organisms. Investigatorssuggest that antibiotics with a signicant post-antibioticFigure 12. Understanding the minimum inhibitoryeffect can be dosed less frequently; those with no post-concentration and the minimal bactericidalantibiotic effect should be administered by constantconcentration.infusion. Although these in vitro effects suggest certaintherapeutic approaches, it must be kept in mind that con-centration-dependent killing and post-antibiotic effect areimportance for these antibiotics, and serum concentra-both in vitro phenomena, and treatment strategies basedtions above 8 times the MIC are of no benet other than on these effects have not been substantiated by controlledto enhance penetration into less permeable body sites.human clinical trials.Unlike -lactam antibiotics, aminoglycosides and u-oroquinolones demonstrate concentration-dependentkilling. In vitro studies show that these antibioticsdemonstrate greater killing the more their concentrations KEY POINTSAbout Antibiotic Dosing 1. Absorption, volume of distribution, metabolism,and excretion all affect serum antibiotic levels. 2. Mean inhibitory concentration (MIC) is helpfulin guiding antibiotic choice. 3. To maximize success with -lactam antibiotics,serum antibiotic levels should be above the MICfor at least 50% of the time (T>MIC 50%). 4. To maximize success with aminoglycosides andfluoroquinolones, high peak concentration,Cmax/MIC, and high AUC/MIC ratio are recom-mended. 5. The clinical importance of concentration-dependent killing and post-antibiotic effect foraminoglycosides and uoroquinolones remainto be proven by clinical trials.Figure 13. Pharmacokinetics of a typical antibiotic. 21. 6 / CHAPTER 1BASIC STRATEGIES Does the Patient have aFOR ANTIBIOTIC THERAPY Bacterial Infection?WBC with DifferentialThe choice of antibiotics should be carefully consi-Assess Severity of Illnessdered. A step-by-step logical approach is helpful(Figure 1.4).1. Decide Whether The Patient Has a No,Bacterial Infection YesObserve CloselyObtain Cultures.One test that has traditionally been used to differentiatean acute systemic bacterial infection from a viral illness isthe peripheral white blood cell (WBC) count. In patientswith serious systemic bacterial infections, the peripheral Obtain Cultures If Patient worsensWBC count may be elevated and may demonstrate an including bloodclinicallyincreased percentage of neutrophils. On occasion, lessmature neutrophils such as band forms and, less com-monly, metamyelocytes are observed on peripheral bloodsmear. Most viral infections fail to induce a neutrophilDecide onresponse. Viral infections, particularly EpsteinBarr virus, Probable Site ofinduce an increase in lymphocytes or monocytes (orInfection & Beginboth) and may induce the formation of atypical mono-Empiric Therapycytes. Unfortunately, the peripheral WBC count is only arough guideline, lacking both sensitivity and specicity.Recently, serum procalcitonin concentration has beenfound to be a far more accurate test for differentiating At 3 Days Review Culturebacterial from viral infection. In response to bacterial and Graminfection, this precursor of calcitonin is synthesized and Stain Resultsreleased into the serum by many organs of the body; pro-duction of interferon in response to viral infectioninhibits its synthesis. The serum procalcitonin test mayalso be of prognostic value, serum procalcitonin levelsPositive & Gram stainbeing particularly high in severe sepsis (see Chapter 2). consistent with InfectionNegative or ColonizationReview sensitivities and2. Make a Reasonable Statistical GuessReturn to topstreamline antibioticsas to the Possible Pathogens (narrowest spectrum andfewest drugs possible)Based on the patients symptoms and signs, as well as onlaboratory tests, the anatomic site of the possible infec-Figure 1.4. Algorithm for the initial use oftion can often be determined. For example, burning on anti-infective therapy.urination, associated with pyuria on urinalysis, suggests aurinary tract infection. The organisms that cause uncom-plicated urinary tract infection usually arise from thebowel ora. They include E. coli, Klebsiella, and Proteus.ora associated with the hospital and the oor where theAntibiotic treatment needs to cover these potential patient became ill. Many hospitals have a high incidencepathogens. Later chapters review the pathogens com- of MRSA and therefore empiric antibiotic treatment formonly associated with infections at specic anatomica possible staphylococcal infection must include van-sites and the recommended antibiotic coverage for those comycin, pending culture results. Other hospitals have apathogens.large percentage of Pseudomonas strains that are resistantto gentamicin, eliminating that antibiotic from consid-3. Be aware of the Antibiotic Susceptibility Patterns eration as empiric treatment of possible gram-negativein Your Hospital and Communitysepsis. In many communities, individuals who havenever been hospitalized are today presenting with soft-In patients that develop infection while in hospitaltissue infections caused by cMRSA, and physicians in(nosocomial infection), empiric therapy needs to takethese communities must adjust their empiric antibioticinto account the antibiotic susceptibility patterns of theselection (see Chapter 10). 22. ANTI-INFECTIVE THERAPY / 74. Take into Account Previous Antibiotic Treatmenttic. The use of rifampin combined with oxacillin isantagonistic in some strains of S. aureus, for exam-The remarkable adaptability of bacteria makes itple. Many combination regimens have not beenhighly likely that a new pathogen will be resistant tocompletely studied, and the natural assumption thatpreviously administered antibiotics. If the onset of themore antibiotics lead to more killing power oftennew infection was preceded by a signicant interval does not apply.when antibiotics were not given, the resident ora mayhave recolonized with less resistant ora. However, theb. Use of multiple antibiotics increases the risk ofre-establishment of normal ora can take weeks, and adverse reactions. Drug allergies are common.patients in hospital are likely to recolonize with highly When a patient on more than one antibiotic devel-resistant hospital ora.ops an allergic reaction, all antibiotics becomepotential offenders, and these agents can no longer5. Take into Consideration Important Host Factors be used. In some instances, combination therapycan increase the risk of toxicity. The combination ofa. Penetration into the site of infection. For example, gentamicin and vancomycin increases the risk of patients with bacterial meningitis should not be nephrotoxicity, for example. treated with antibiotics that fail to cross the c. Use of multiple antibiotics often increases costs bloodbrain barrier (examples include 1st-generationand the risk of administration errors. Administra- cephalosporins, gentamicin, and clindamycin).tion of two or more intravenous antibiotics requiresb. Peripheral WBC count. Patients with neutropeniamultiple intravenous reservoirs, lines, and pumps. have a high mortality rate from sepsis. ImmediateNurses and pharmacists must dispense each antibi- broad-spectrum, high-dose intravenous antibiotic otic dose, increasing labor costs. The more drugs a treatment is recommended as empiric therapy forpatient receives, the higher the probability of an these patients.administration error. Use of two or more drugs usu-c. Age and underlying diseases (hepatic and renal ally increases the acquisition costs. dysfunction). Elderly patients tend to metabolize d. Use of multiple antibiotics increases the risk of and excrete antibiotics more slowly; longer dosing infection with highly resistant organisms. Pro- intervals are therefore often required. Agents withlonged use of broad-spectrum antibiotic coverage significant toxicity (such as aminoglycosides) increases the risk of infection with MRSA, VRE, should generally be avoided in elderly patientsmultiresistant gram-negative bacilli, and fungi. because they exhibit greater toxicity. Antibiotics When multiple antibiotics are used, the spectrum metabolized primarily by the liver should generallyof bacteria killed increases. Killing most of the be avoided or reduced in patients with signicantnormal ora in the pharynx and gastrointestinal cirrhosis. In patients with significant renal dys- tract is harmful to the host. The normal flora function, antibiotic doses need to be modied. compete for nutrients, occupy binding sites thatd. Duration of hospitalization. Patients who have could otherwise be used by pathogenic bacteria, just arrived in the hospital tend to be colonized with and produce agents that inhibit the growth of community-acquired pathogens; patients who havecompetitors. Loss of the normal ora allows resis- been in the hospital for prolonged periods and havetant pathogens to overgrow. received several courses of antibiotics tend to be col- onized with highly resistant bacteria and with fungi. 7. Switch to Narrower-Spectrum Antibiotic Coveragee. Severity of the patients illness. The severely ill Within 3 Days patient who is toxic and hypotensive requires broad-(Table 1.1, Figure 1.5). Within 3 days following the spectrum antibiotics; the patient who simply has aadministration of antibiotics, sequential cultures of new fever without other serious systemic complaints mouth ora reveal that the numbers and types of bac- can usually be observed off antibiotics.teria begin to change signicantly. The normal ora6. Use the Fewest Drugs Possible die, and resistant gram-negative rods, gram-positive cocci, and fungi begin to predominate. The morea. Multiple drugs may lead to antagonism ratherquickly the selective pressures of broad-spectrum than synergy. Some regimens, such as penicillin antibiotic coverage can be discontinued, the lower the and an aminoglycoside for Enterococcus, have been risk of selecting for highly resistant pathogens. Broad shown to result in synergythat is, the combinedcoverage is reasonable as initial empiric therapy until effects are greater than simple addition of the MBCscultures are available. By the 3rd day, the microbiology of the two agents would suggest. In other instances,laboratory can generally identify the pathogen or certain combinations have proved to be antagonis- pathogens, and a narrower-spectrum, specic antibiotic 23. 8 / CHAPTER 1Table 1.1. Classication of Antibiotics by Spectrum of Activity Narrow Moderately Broad Broad Very Broad Penicillin Ampicillin AmpicillinsulbactamTicarcillinclavulinate Oxacillin/NafcillinTicarcillinAmoxicillinclavulanate Piperacillintazobactam CefazolinPiperacillin Ceftriaxone,Cefepime Cephalexin/CephradineCefoxitinCefotaximeImipenem AztreonamCefotetanCeftizoxime Meropenem AminoglycosidesCefuroximeaxetilCeftazidime Ertapenem Vancomycin Cefaclor Cexime Gatioxacin Macrolides Ciprooxacin Cefpodoxime proxetilMoxioxacin ClindamycinAzithromycin TetracyclineTigecycline LinezolidClarithromycin Doxycycline Quinupristin/dalfopristinTalithromycinChloramphenicol Daptomycin TrimethoprimLevooxacinsulfamethoxazole Metronidazoleregimen can be initiated. Despite the availability of cul- gentamicin is low, but when blood-level monitoring,ture results, clinicians too often continue the same the requirement to closely follow blood urea nitrogenempiric broad-spectrum antibiotic regimen, and thatbehavior is a critical factor in explaining subsequentinfections with highly resistant superbugs. Figure 1.5graphically illustrates the spectrum of available antibi- KEY POINTSotics as a guide to the antibiotic choice.Obey the 3-day rule. Continuing broad-spectrum About the Steps Required to Designantibiotics beyond 3 days drastically alters the hostsan Antibiotic Regimenresident ora and selects for resistant organisms. After3 days, streamline antibiotic coverage. Use narrower-spectrum antibiotics to treat the specific pathogens1. Assess the probability of bacterial infection.identied by culture and Gram stain. (Antibiotics should be avoided in viral infections.)2. Be familiar with the pathogens primarily8. All Else Being Equal, Choose The Leastresponsible for infection at each anatomic site.Expensive Drug3. Be familiar with the bacterial ora in the local hospital and community.As is discussed in later chapters, more than one antibi-4. Take into account previous antibiotic treatment.otic regimen can often be used to successfully treat aspecic infection. Given the strong economic forces dri-5. Take into account the specic host factors (age,ving medicine today, the physician needs to consider the immune status, hepatic and renal function, duration of hospitalization, severity of illness).cost of therapy whenever possible. Too often, new, moreexpensive antibiotics are chosen over older generic 6. Use the minimum number and narrowest spec-antibiotics that are equally effective. In this book, thetrum of antibiotics possible.review of each specic antibiotic tries to classify that7. Switch to a narrower-spectrum antibiotic regi-antibiotics cost range to assist the clinician in makingmen based on culture results.cost-effective decisions. 8. Take into account acquisition cost and the costs However, in assessing cost, factoring in toxicity isof toxicity.also important. For example, the acquisition cost of 24. Figure 15. Antibiogram of all major antibiotics.9 25. 10 / CHAPTER 1and serum creatinine, and the potential for an culture). However, because the sputum culture wasextended hospital stay because of nephrotoxicity are positive for a resistant E. coli, the physician switchedfactored into the cost equation, gentamicin is often to a broader-spectrum antibiotic. The correct decisionnot cost-effective.should have been to continue cefazolin.Obey the 3-day rule. Continuing broad-spectrum One of the most difcult and confusing issues forantibiotics beyond 3 days drastically alters the hosts nor- many physicians is the interpretation of culture results.mal ora and selects for resistant organisms. AfterWound cultures and sputum cultures are often misin-3 days streamline the antibiotics. Use narrower-spectrum terpreted. Once a patient has been started on an antibi-antibiotics to treat the specic pathogens identied byotic, the bacterial ora on the skin and in the mouthculture and Gram stain.and sputum will change. Often these new organisms do not invade the host, but simply represent new ora that have colonized these anatomic sites. Too often, physi-COLONIZATION VERSUS INFECTIONcians try to eradicate the new ora by adding new more- powerful antibiotics. The result of this strategy is to select for organisms that are multiresistant. The eventual CASE 1.1outcome can be the selection of a bacterium that is resis- tant to all antibiotics.Following a motor vehicle accident, a 40-year-oldNo definitive method exists for differentiatingman was admitted to the intensive care unit with between colonization and true infection. However, several clinical findings are helpful in guiding the4 fractured ribs and a severe lung contusion on the physician. Evidence supporting the onset of a newright side. Chest X-ray (CXR) demonstrated an inl- infection include a new fever or a change in fever pat-trate in the right lower lobe. Because of depressedtern, a rise in the peripheral WBC with a increase inmental status, this man required respiratory the percentage of PMNs and band forms (left shift),support. Gram stain demonstrating an increased number ofInitially, Gram stain of the sputum demonstrated PMNs in association with predominance of bacteriafew polymorphonuclear leukocytes (PMNs) and no that are morphologically consistent with the cultureorganisms. On the third hospital day, this patient results. In the absence of these ndings, colonizationdeveloped a fever to 103 F (39.5 C), and his periph- is more likely, and the current antibiotic regimeneral WBC increased to 17,500 from 8000 (80% PMNs,should be continued.15% band forms). A new CXR demonstrated exten-sion of the right lower lobe inltrate. Gram stain ofsputum revealed abundant PMNs and 20 to 30gram-positive cocci in clusters per high-power eld.KEY POINTSHis sputum culture grew methicillin-sensitiveS. aureus. Intravenous cefazolin (1.5 g every 8 hours) About Differentiating Colonizationwas initiated. He defervesced, and secretions from from Infectionhis endotracheal tube decreased over the next 3days. On the fourth day, a repeat sputum samplewas obtained. Gram stain revealed a moderate1. Growth of resistant organisms is the rule in thenumber of PMNs and no organisms; however,patient on antibiotics.culture grew E. coli resistant to cefazolin. The physi- 2. Antibiotics should be switched only on evi-cian changed the antibiotic to intravenous cefepimedence of a new infection.(1 g every 8 hours).3. Evidence for a new superinfection includes a) new fever or a worsening fever pattern, b) increased peripheral leukocyte count withleft shift, c) increased inammatory exudate at the origi- Case 1.1 represents a very typical example of hownal site of infection,antibiotics are misused. The initial therapy for a prob- d) increased polymorphonuclear leukocytes onable early S. aureus pneumonia was appropriate, and Gram stain, andthe patient responded (fever resolved, sputum pro- e) correlation between bacterial morphologyduction decreased, gram-positive cocci disappearedand culture on Gram stain.from the Gram stain, and S. aureus no longer grew on 26. ANTI-INFECTIVE THERAPY / 11new anti-infectives are frequently being introduced, pre- SPECIFIC ANTI-INFECTIVE scribing physicians should also take advantage of hand-held devices, online pharmacology databases, andAGENTSantibiotic manuals so as to provide up-to-date treatment(see Further Reading at the end of the current chapter).ANTIBIOTICS When the proper therapeutic choice is unclear, on-the-Before prescribing a specic antibiotic, clinicians shouldjob training can be obtained by requesting a consulta-be able to answer these questions:tion with an infectious disease specialist. Anti-infectiveagents are often considered to be safe; however, the mul- How does the antibiotic kill or inhibit bacterial growth? tiple potential toxicities outlined below, combined with What are the antibiotics 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 dosingrecommendations? Does the dosing schedule need to -Lactam Antibioticsbe modied in patients with renal dysfunction? What are the indications for using each specificCHEMISTRY AND MECHANISMS OF ACTIONantibiotic? The -Lactam antibiotics have a common central How broad is the antibiotics antimicrobial spectrum? structure (Figure 1.6) consisting of a -lactam ring anda thiazolidine ring [in the penicillins and carbapenems, How much does the antibiotic cost?Figure 1.6(A)] or a -lactam ring and a dihydrothiazineClinicians should be familiar with the general classes of ring [in the cephalosporins, Figure 1.6(B)]. The sideantibiotics, their mechanisms of action, and their majorchain attached to the -lactam ring (R1) determinestoxicities. The differences between the specic antibiotics many of the antibacterial characteristics of the specicin each class can be subtle, often requiring the expertise of antibiotic, and the structure of the side chain attachedan infectious disease specialist to design the optimalto the dihydrothiazine ring (R2) determines the phar-anti-infective regimen. The general internist or physician- macokinetics and metabolism.in-training should not attempt to memorize all the facts The -lactam antibiotics bind to various PBPs.outlined here, but rather should read the pages that follow The PBPs represent a family of enzymes important foras 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, andtreatment indications, pharmacokinetics, dosing regimens, transpeptidases. Strong binding to PBP-1, a celland cost are reviewed. The specic indications for each wall transpeptidase and transglycolase causes rapidanti-infective are briey covered here. A more complete bacterial death. Inhibition of this transpeptidasediscussion of specic regimens is included in the later prevents the cross-linking of the cell wall peptido-chapters that cover infections of specic anatomic sites. glycans, resulting in a loss of integrity of the bacterialUpon prescribing a specic antibiotic, physicians cell wall. Without its protective outer coat, theshould reread the specic sections on toxicity, spectrumhyperosmolar intracellular contents swell, and theof activity, pharmacokinetics, dosing, and cost. Becausebacterial cell membrane lyses. Inhibition of PBP-3, aFigure1.6. Basic structure of the A penicillins and B the cephalosporins. 27. 12 / CHAPTER 1and bacterial death. Inhibition of other PBPs blocks KEY POINTS cell wall synthesis in other ways, and activates bacter-ial lysis. About -Lactam AntibioticsThe activity of all -lactam antibiotics requires activebacterial growth and active cell wall synthesis. There-fore, bacteria in a dormant or static phase will not be 1. Penicillins, cephalosporins, and carbapenemsare all b-lactam antibiotics:killed, but those in an active log phase of growth arequickly lysed. Bacteriostatic agents slow bacteriala) All contain a -lactam ring.growth and antagonize -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 be combined with -lactam antibiotics. bacterial cell wall peptidoglycans.c) All require active bacterial growth for bacte- TOXICITY riocidal action. Table 1.2 summarizes the toxicities of the -lactamd) All are antagonized by bacteriostatic anti-antibiotics. biotics. Hypersensitivity reactions are the most commonside effects associated with the -lactam antibiotics.Penicillins are the agents that most commonly causeallergic reactions, at rates ranging from 0.7% to 10%.transpeptidase and transglycolase that acts at the sep- Allergic reactions to cephalosporins have beentum of the dividing bacterium, causes the formation reported in 1% to 3% of patients, and similar percent-of long filamentous chains of non-dividing bacteria ages have been reported with carbapenems. However,Table 1.2. Toxicities of -Lactam AntibioticsClinical symptom Antibiotic Meropenem CeftriaxoneAztreonamImipenem Penicillins Cefotetan Cefepime CefazolinAllergic skin rashAnaphylaxisStevenJohnsonSeizuresEncephalopathy aDiarrhea (Clostridium difcile)CholelithiasisPhlebitisLaboratory tests: Coagulation Creatinine Cytopenias EosinophiliaAST/ALTa 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 veryrare; = rise; AST/ALT = aspartate aminotransferase/ alanine transaminase. 28. ANTI-INFECTIVE THERAPY / 13the incidence of serious, immediate immunoglobulinOther less common toxicities are associated withE (IgE)mediated hypersensitivity reactions is much individual -lactam antibiotics. Natural penicillins andlower with cephalosporins than with penicillins.imipenem lower the seizure threshold and can result inApproximately 1% to 7% of patients with penicillingrand mal seizures. Ceftriaxone is excreted in high con-allergies also prove to be allergic to cephalosporins and centrations in the bile and can crystallize, causing biliarycarbapenems.sludging and cholecystitis. Antibiotics containing a spe-Penicillins are the most allergenic of the -lactamcic 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 withantigens increase the probability of a host immuneencephalopathy and myoclonus in elderly individuals.response. Patients who have been sensitized by previ- All broad-spectrum antibiotics increase the risk ofous exposure to penicillin may develop an immediate pseudomembranous colitis (see Chapter 8). In combi-IgE-mediated hypersensitivity reaction that can resultnation with aminoglycosides, cephalosporins demon-in anaphylaxis and urticaria. In the United States, strate increased nephrotoxicity.penicillin-induced allergic reactions result in 400 to800 fatalities annually. Because of the potential dan-ger, patients with a history of an immediate hypersen-Penicillinssitivity reaction to penicillin should never be given Tables 1.3 and 1.4, together with Figure 1.5, summarizeany -lactam antibiotic, including a cephalosporin orthe characteristics of the various penicillins.carbapenem. High levels of immunoglobulin G anti- Penicillins vary in their spectrum of activity. Naturalpenicillin antibodies can cause serum sickness, a syn-penicillins have a narrow spectrum. The aminopeni-drome resulting in fever, arthritis, and arthralgias, cillins have an intermediate spectrum, and combinedurticaria, and diffuse edema. with -lactamase inhibitors, the carboxy/ureidopeni-cillins have a very broad spectrum of activity.NATURAL PENICILLINS KEY POINTS PharmacokineticsAll natural penicillins are rapidlyexcreted by the kidneys, resulting in short half-livesAbout -Lactam Antibiotic Toxicity (Table 1.3). As a consequence, the penicillins must bedosed frequently, and dosing must be adjusted in patientswith 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 immediatehypersensitivity reactions. 2. Allergy to penicillins (PCNs) seen in 1% to10% of patients; 1% to 3% are allergic to KEY POINTScephalosporins and carbapenems. 1% to 7% ofpatients with a PCN allergy are also allergic tocephalosporins and carbapenems. About the Natural Penicillins 3. Seizures are associated with PCNs andimipenem, primarily in patients with renal dys-1. Very short half-life (1530 minutes).function.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 inamed body cavities. 5. Cephalosporins with methylthiotetrazole rings4. Narrow spectrum. Indicated for Streptococcus(cefamandole, cefoperazone, moxalactam, pyogenes, S. viridans Gp., mouth ora, Clostridiacefotetan) can interfere with vitamin K and perfringens, Neisseria meningitidis, Pasteurella,increase prothrombin time.and spirochetes. 6. Pseudomembranous colitis can develop as a5. Recommended for penicillin-sensitive S. pneu-result of overgrowth of Clostridium difcile. moniae [however, penicillin resistant strains are 7. Nephrotoxicity sometimes occurs whennow frequent ( 30%)]; infections caused bycephalosporins are given in combination withmouth flora; Clostridium perfringens or spiro-aminoglycosides.chetes. 29. 14 /CHAPTER 1Table 1.3. Penicillins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum AntibioticHalf-life Dose Dose for reduced CostaSpectrum (trade name)(h)creatinine clearance(mL/min) Natural penicillins (PCNs) PCN G 0.52 4 106 U IV q4h