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ANTIMICROBIALTHERAPY
CONTENTS
Preface xiii
Burke A. Cunha
Antibiotics–Past, Present, and Future 1049
Nancy Khardori
Thedrugtherapyfordiseasesotherthanthosecausedbymicrobial
agentsinvolvestreatingthehost.Ininfectiousdiseasestherapy,the
goalistoridthehostofthepathogen.Hence,drugtherapyisaimed
atthepathogen.Becauseasecondlivingagentisinvolvedinthetri-
angle,drugtherapyisaffectedbythepathogen’snature,itstissue
specificity,and,mostimportantly,thechangesitundergoestosur-
vive.Thehistoryofantimicrobialtherapyhasclearlydemonstrated
thatthedrugsthatareusedtotreatinfectionsarealsoresponsiblefor
makingthemmoredifficulttotreatinthefuture.Theonlywayto
keepantimicrobial agentsuseful isto usethem appropriately and
judiciously.
In Vitro Susceptibility Testing Versus In Vivo Effectiveness 1077
Charles W. Stratton
The clinical relevance of susceptibility testing has always been
questionedbecauseofthedifficultyofcorrelatinginvitrosuscept-
ibilitytestingwithinvivoclinicaleffectiveness.Clearlytherehave
always been host/pathogen factors that influence the clinical out-
comethatcannot bepredicted bytheresultsofsusceptibility test-
ing.However,improvedunderstandingofpharmacodynamicand
pharmacokineticparametershasgreatlyimprovedtheuseofanti-
microbial agents. Most importantly, the integration of these phar-
macodynamic and pharmacokinetic indices has greatly improved
the correlation between in vitro susceptibility testing and in vivo
clinicaleffectivenessandallowsmorerealisticbreakpoints.Finally,
the clinical microbiology laboratory has advanced with improved
methods to detect resistance as well as the adaptation of break-
points thataremore realistic.
Æ Æ
VOLUME90 NUMBER6 NOVEMBER2006 vii
New Uses for Older Antibiotics: Nitrofurantoin, Amikacin,
Colistin, Polymyxin B, Doxycycline, and Minocycline Revisited 1089
Burke A. Cunha
Nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and
minocycline are antibiotics with proven effectiveness against se-
lected pathogens. These antibiotics have not developed resistance
over time. As ‘‘low-resistance-potential antibiotics’’ that are effec-
tive against an increasing number of infections due to resistant
gram-positiveorgram-negativepathogens,theseantimicrobialsre-
mainanimportantpartoftheantibioticarmamentarium.Theywill
be used increasingly in the future, as highly resistant organisms
continuetobeimportantclinicallyandtherapeuticoptionsremain
limited.
Macrolide and Ketolide Resistance with Streptococcus
pneumoniae 1109
Gary V. Doern
Antimicrobialagentsinthemacrolidefamilyhavelongbeenconsid-
ered drugs of potential utility in the management of infections
causedbyStreptococcuspneumoniae.However,withtheemergence
ofmacrolideresistance,theclinicalvalueofmacrolidesinpneumo-
coccalinfectionsisthreatened.Inpart,asaconsequenceofthedevel-
opment of macrolide resistance, recently the first agent in the
ketolideantimicrobialclass,telithromycin,wasdevelopedandintro-
ducedintoclinicalpractice.Theketolidesaremacrolideantimicro-
bialswhosechemistryhasbeenmodifiedsoastoavoidtheeffects
of the most common mechanisms of macrolide resistance with S
pneumoniae. This discussion reviews the current state of resistance
tomacrolidesandketolideswithSpneumoniaeinNorthAmerica.
Antibiotic Therapy for Helicobacter pylori 1125
Jason Collins, Amira Ali-Ibrahim, and Duane T. Smoot
Helicobacterpyloriisoneofthemostcommonbacterialinfectionsin
theworld.Hpyloriinfectionofthegastricmucosaisthemostcom-
moncauseofpepticulcersandisbelievedtoberesponsiblefor50%
to 60% of all gastric carcinomas. This infection is difficult to treat
becausethebacteriumislocatedwithinthegastriclumeninthemu-
cusandnotwithinthegastrictissue.AntimicrobialtherapyforHpy-
lori includes two or three antibiotics plus either a proton pump
inhibitororahistaminereceptorantagonist.Hpylorireadilydevel-
ops resistance to antibiotics; therefore, if the initial treatment is
unsuccessful,repeattreatmentshouldincludedifferentantibiotics.
Antimicrobial Therapy of Clostridium difficile-Associated
Diarrhea 1141
Emilio Bouza, Almudena Burillo, and Patricia Mun˜oz
Clostridium difficile-associated diarrhea (CDAD) is the most com-
mon etiologically defined cause of hospital-acquired diarrhea.
viii CONTENTS
Caused by the toxins of certain strains of C difficile, CDAD repre-
sents a growing concern, with epidemic outbreaksin some hospi-
tals where very aggressive and difficult-to-treat strains have
recentlybeenfound.IncidenceofCDADvariesordinarilybetween
1to10inevery1,000admissions.EvidenceshowsthatCDADin-
creases morbidity, lengths of stay, and costs. This article describes
theclinicalmanifestationsofCDAD,relatedriskfactors,considera-
tions for confirming CDAD, antimicrobial and nonantimicrobial
treatmentofCDAD,andissuesrelatedtorelapses.Thearticlecon-
cludes with a discussion of recent epidemic outbreaks involving
CDAD.
Antimicrobial Therapy of Multidrug-Resistant Streptococcus
pneumoniae, Vancomycin-Resistant Enterococci, and
Methicillin-Resistant Staphylococcus aureus 1165
Burke A. Cunha
Antibioticresistanceamongpneumococci,enterococci,andstaphy-
lococcihasbecomeincreasinglyimportantinrecentdecades.Clin-
icians should be familiar with the nuances of antibiotic
susceptibility testing and interpretation in selecting antibiotics for
these infections. The clinical significance of penicillin-resistant
Streptococcus pneumoniae, macrolide-resistant S pneumoniae, and
multidrug-resistant S pneumoniae is discussed. The clinical spec-
trum and therapeutic approach to Enterococcus faecalis (ie,
vancomycin-sensitive enterococci) and E faecium (ie, vancomycin-
resistant enterococci) are discussed. Differences in therapeutic ap-
proach between methicillin-sensitive Staphylococcus aureus and
methicillin-resistant Saureus(MRSA)infections are reviewed.Dif-
ferences between in vitro susceptibility testing and in vivo effec-
tiveness of antibiotics for hospital-acquired MRSA (HA-MRSA)
are described. Lastly, the clinical features of infection and therapy
of HA-MRSA and community-acquired MRSA (CA-MRSA) infec-
tionsare compared.
Monotherapy Versus Combination Therapy 1183
Shilpa M. Patel and Louis D. Saravolatz
Thescienceofantibiotictherapyforinfectiousdiseasescontinuesto
evolve. In many instances where empiric coverage is necessary,
treatment with more than one agent is considered prudent. If an
etiology is identified, antibiotics are modified based on culture
and susceptibility data. Even when the organism is known, more
than one antibiotic may be needed. Decisions about antibiotics
shouldbemadeafterassessmentsofpertinentclinicalinformation,
laboratory and microbiology information, ease of administration,
patient compliance, potential adverse effects, cost, and available
evidence supporting various treatment options. Clinicians also
needtoconsidersynergyandlocalresistancepatternsinselecting
therapeutic options. In this article, the authors outline monother-
apy and combination therapy options for several common infec-
tiousdiseases.
CONTENTS ix
Oral Antibiotic Therapy of Serious Systemic Infections 1197
Burke A. Cunha
Traditionally, antibiotics have been administered intravenously
(IV)forserioussystemicinfections.Asmorepotentoralantibiotics
wereintroduced,andtheirpharmacokineticaspectsstudied,orally
administered antibiotics have been increasingly used for serious
systemic infections was appreciated. Antibiotics ideal for oral ad-
ministrationarethosethathavetheappropriatespectrum,highde-
gree of activity against the presumed or known pathogen, and
havegoodbioavailability.Oralantibioticswithhighbioavailability,
thatis,R90%absorbed,achieveserum/tissueconcentrationscom-
parableto IVadministeredantibiotic at the samedose.The popu-
larity of ‘‘IV to PO switch therapy’’ is possible because of the
availabilityofmanypotentoralantibioticswithhighbioavailabil-
ity.InitialIVtherapyisappropriateinpatientswhoareinshock/
have impaired intestinal absorption, but after clinical deferves-
cence, completion of therapy should be accomplished with oral
antibiotics.Asexperiencewith‘‘IVtoPOswitchtherapy’’hasaccu-
mulated, confidence in oral antimicrobics for therapy of serious
systemicinfectionshascontinuedtoincrease.Thetrendintreating
serioussystemicinfectionsentirelywithoralantimicrobialtherapy
will continue,and isclearly thewave ofthe future.
Antibiotic Drug Interactions 1223
Manjunath P. Pai, Kathryn M. Momary, and
Keith A. Rodvold
Drug–druginteractionsinthefieldofinfectiousdiseasescontinueto
expandasnewdrugsareapproved,metabolicenzymesandtrans-
portersareidentified,andrecommendationsforcoadministrationof
drugsarerevised.Thisarticleprovidesanoverviewoftheprinciples
andmechanismsofdrug–druginteractionsanddescribespharma-
cokinetic-pharmacodynamic interactions commonly associated
with antibacterial therapy, antiviral agents (nonretroviral), and
drugsfortuberculosis.
Antibiotic Selection in the Penicillin-Allergic Patient 1257
Burke A. Cunha
Cliniciansshouldbefamiliarwithwhichantibioticsaresafetouse
for different types of penicillin-allergic reactions. Clinically, it is
convenienttodividepatientswithpenicillinallergyintothreecate-
gories: those with unknown or possible reactions to penicillin,
thosewithadrugfeverorrash,andthosewithhivesoranaphylac-
tic reactions. b-lactam antibiotics may be used safely for patients
with unknown/possible penicillin allergy and drug fever or rash.
Penicillinsorb-lactamsshouldnotbeusedforpatientswithhives
or anaphylactic reactions. For all patients, clinicians should con-
sider antimicrobial therapy with an antibiotic that does not cross-
react with penicillins or b-lactams. This article reviews how
cliniciansshouldselectantimicrobialsinpenicillin-allergicpatients.
x CONTENTS
Clinical Approach to Antibiotic Failure 1265
David Schlossberg
A systematic approach is presented for the patient with antibiotic
failure. Noninfectious mimics of infection and nontreatable infec-
tionsmustfirstbeexcluded.Then,theclinicianmustidentifythose
patients who have responded but have a surgical component of
their infection or have complications separate from their initial
infection. Such complications could include drug fever, phlebitis,
decubiti,urinarytractinfection,aspiration,andpulmonaryembo-
lism.Otherpatientsmaydeteriorateclinicallybecauseofincorrect
antibiotic coverage, failure of antibiotic to reach the site of infec-
tion,localinactivationofantibiotic,paradoxicalresponse,immune
compromise,orbecausetheyhavereachedthepointofnoreturn.
Index 1279
CONTENTS xi
MedClinNAm90(2006)xiii–xiv
Preface
BurkeA.Cunha,MD,MACP
GuestEditor
Since the author first edited a volume of the Medical Clinics of North
America on Antimicrobial Therapy in 1982, the ensuing decades have wit-
nessedaconceptualevolutioninantimicrobialtherapy.Emergingpathogens
and antibiotic resistance have fueled the search for new antibiotics to cope
with these ongoing challenges. Over the years, additional antimicrobial
agents have been introduced to clinical use. Because the number of newly
introduced antibiotics has been limited, clinicians have re-evaluated older
agentswithactivityagainstnewlyresistantorganisms.Recentdecadeshave
also witnessed an increase in the appreciation of the pharmacokinetic as-
pects of antimicrobials, which has led to an increase in the use of oral anti-
biotics to treat more and more infectious diseases. This volume of the
Medical Clinics of North America on Antimicrobial Therapy builds on the
previous volumes of 1995 and 2001, edited by the author, and focuses on
the currently most relevant topics relating to antimicrobial therapy.
This issue contains articles written by recognized authorities on antibi-
otics from the United States and Europe. The contributors have been se-
lected on the basis of their clinical experiences and expertise. The issue
consists of 12 articles covering the most important aspects of antimicrobial
therapy at the present time. It begins with an overview by Dr. Nancy
Khardori of antimicrobial therapy past, present, and future, which places
today’s antimicrobial therapy in perspective. Dr. Charles Stratton contrib-
utes an article reviewing in vitro susceptibility testing versus in vivo clinical
effectiveness of antibiotics. Other antibiotic concepts that are problematic
for many physicians include the relative merits of monotherapy and
0025-7125/06/$-seefrontmatter(cid:2)2006ElsevierInc.Allrightsreserved.
doi:10.1016/j.mcna.2006.07.001 medical.theclinics.com
xiv PREFACE
combinationtherapyforvariousinfectiousdiseases,whichareablyreviewed
byDr.LouisSaravoltaz.Olderantibioticsarebeing‘‘rediscovered’’fornew
uses against resistant organisms. An article by the author focusing on new
uses for older antibiotics is also included in this issue.
Antibioticresistanceamonggram-positivecocciisaproblemworldwide.
Multidrug-resistant Streptococcus pneumonia, vancomycin-resistant entero-
cocci,andmethicillin-resistantStaphylcoccusaureusarethemostfrequently
encountered gram-positive therapeutic challenges for physicians. Nation-
ally, there is an underrecognized and underappreciated epidemic of macro-
lide-resistantSpneumoniae,andthisimportanttopiciswellreviewedbyDr.
Gary Doern.
The antimicrobial therapies for Helicobacter pylori and Clostridium diffi-
cile diarrhea/colitis remain thorny therapeutic problems. Key components
ofthisissuearearticlesreviewingthecurrentstateoftheartfortheantimi-
crobialtherapyofHpylori,byDr.DuaneSmoot,andforthatofCdifficile
diarrhea/colitis, by Dr. Emilio Bouza.
The remaining articles are devoted to potential problems related to anti-
microbial prescription. The common dilemma of selecting an antibiotic in
thepenicillin-allergicpatientisreviewedbytheauthor.Theimportanttopic
of antibiotic drug interactions is carefully covered by Dr. Keith Rodvold.
The issue concludes with the important subject of apparent antibiotic fail-
ure, covered by Dr. David Schlossberg.
This issue of the Medical Clinics of North America on Antimicrobial
Therapyisanup-to-datedeskreferencesourcedealingwiththemostimpor-
tant clinical problems related to antimicrobial therapy that are currently
faced by physicians.
Burke A. Cunha, MD, MACP
Chief, Infectious Disease Division
Winthrop-University Hospital
Minneola, NY 11501
MedClinNAm90(2006)1049–1076
AntibioticsdPast, Present, and Future
Nancy Khardori, MD, PhD*
DepartmentofInternalMedicine,SouthernIllinoisUniversitySchoolofMedicine,
POBox19636,Springfield,IL62794-9636,USA
Thedrugtherapyfordiseasesotherthanthosecausedbymicrobialagents
involvestreatingthehost.Ininfectiousdiseasestherapy,thegoalistoridthe
hostofthepathogen.Hence,drugtherapyisaimedatthepathogen.Because
asecondlivingagentisinvolvedinthetriangle,drugtherapyisaffectedbythe
pathogen’snature,itstissuespecificity,and,mostimportantly,thechangesit
undergoestosurvive.Thehistoryofantimicrobialtherapy hasclearlydem-
onstratedthatthedrugsthatareusedtotreatinfectionsarealsoresponsible
for making them more difficult to treat in the future. The only way to keep
antimicrobialagentsusefulistousethemappropriatelyandjudiciously.
The slow but glorious beginning
The ‘‘Ice Man,’’ whose mummified body was retrieved from underneath
a receded glacier in northern Italy in 1991, had lived about 5310 years ago
[1].Thedeadbodyhadbeendriedquicklybyalpinewinds,thenfrozenand
enclosed in the perennial icedexplaining its extraordinarily well-preserved
state. The study of this mummy has produced important archaeologic and
medical findings. Among them are the presence of Trichuris trichura eggs
in his rectum and his probable use of a fungus, Piptoporus betulinus, for
these intestinal parasites. The toxic oils in the fungus were probably the
onlyremedyavailableinEuropeuntiltheintroductionofmoretoxiccheno-
pod oil from the Americas. The efficacy of chenopod oil was increased by
a strong laxative, resulting in expulsion of the dead and dying worms and
eggs. Piptoporus betulinus contains oils that are toxic against metazoans
andhaveknownantimicrobialpropertiesagainstmycobacteria.Thefungus
alsocontainstoxicresinsandagaricacid,whicharepowerfullaxatives.For
* Infectious Disease Division, PO Box 19636, 701 North First Street, Room A-478,
Springfield,IL62794-9636.
E-mailaddress:[email protected]
0025-7125/06/$-seefrontmatter(cid:2)2006ElsevierInc.Allrightsreserved.
doi:10.1016/j.mcna.2006.06.007 medical.theclinics.com
1050 KHARDORI
morethanfivemillennia,humanbeingshavetreatedtheirailmentswithex-
traordinary creativity. For example, in 2000 BC, Assyrian and Babylonian
doctors used a salve made of frog bile and sour milk for treating infected
eyes, but this concoction was considered effective only after the patient
took a swig of beer and a sliced onion [2].
It was in the mid-nineteenth century that Louis Pasteur observed that
some micro-organisms destroy othersdthe phenomenon that later came
to be known as antibiosis or ‘‘against life.’’ The search for antimicrobial
chemicalagentsrevealedthatantisepticsweretootoxicforanythingbutsur-
face use on wounds. German bacteriologist Paul Ehrlich systematically
testedchemicalagents,searchingforthe‘‘magicbullet’’thatcouldbetaken
internally,butheendedupwithonlyahigh-riskarsenic-basedtreatmentfor
syphilis. Alexander Fleming in London had been looking for antibacterial
agents in human secretions. The discovery of the antibacterial activity of
the enzyme lysozyme was made because of an accidental sneeze on a petri
dish [3]. Fleming observed that, when bacteria later formed colonies on
the plate, none developed in the spots occupied by mucus. Further tests
showed that lysozyme acted mostly against harmless organisms. In 1928,
serendipitymadeanothernotablevisittoFleming’slaboratoryatSt.Mary’s
Hospital inLondon.Hehadleftacultureplate ofStaphylococciuncovered
inhislaboratorywhileonavacation.Onhisreturn,henoticedmoldinthe
petri dish along with a clear space between the Staphylococci and the blue-
greenspottedmold.ItwastheclassicexampleofwhatPasteurhadreferred
to as fortune’s accommodating a willing mind.
Fleming identified the mold as Penicillium natatum, a culture filtrate of
whichwasabletokillbacteria.Henamedtheagentinthefiltratepenicillin.
BecauseofapaucityoffinancialresourcesandFleming’smodestambitions
(according to some historians), it took another 12 years for penicillin to
emerge as the greatest medical advance of the twentieth (or any other) cen-
tury. But the golden age of anti-infective medicine actually began in 1934.
Gerhard Domagk, a German pharmacologist, discovered that a dye used
totintclothcuredstreptococcalinfectionsinmice.Hisowndyingdaughter
survived a streptococcal infection after he injected her with the dye. Daniel
Bovert, a Swiss-born scientist, identified the active compound as sulfanil-
amide. Domagk was awarded the Nobel Prize in Medicine in 1939.
FloreyandChain,workingatOxfordUniversity,wereinterestedtonote
thatstaphylococci,thoughresistanttosulfanamidesandlysozyme,wereap-
parentlysensitivetothepenicilliummold[4].WorldWarIIprovidedacru-
cial spur to and much-needed resources for research on antimicrobial
agents. Staphylococcal infections and gas gangrene were killing more men
than the immediate organ damage caused by shell and bullet wounds. In
the spring of 1940, Florey and Chain were able to make a small amount
ofyellowish-brownpowderfromFleming’smold.Thisfirstsampleof‘‘pen-
icillin powder’’ was a million times more potent than Fleming’s original fil-
trate. In 1941, the Fermentation Division of the newly created Northern
