A 2-Part Series on Emerging Modalities to Combat Resistant ... · sess a broad spectrum of antimicrobial activity, exceeding that of most other antimicrobial classes. Agents in the

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SPECIAL EDITIONINFECTIOUS DISEASE

A 2-Part Series on

Emerging Modalities to Combat Resistant Gram-Negative Pathogens

in Critically Ill Patients:Part 2: Focus on the Carbapenems

Date of Release: August 2007 Expiration Date: August 31, 2008

P R O G R A M O V E R V I E W Rising rates of nosocomially acquired multidrug-resistant (MDR) Gram-negative pathogens have drastically narrowed the spectrum of available therapeutic options.Resistance to antimicrobials is a mounting health concern, both in the United States and world-wide. Infections caused by resistant Gram-negative pathogens, such as Pseudomonas aeruginosaand Acinetobacter baumannii, result in higher morbidity, mortality, prolonged hospitalization, andincreased costs compared with sensitive strains. Carbapenems possess high potency against abroad spectrum of organisms and are regarded as the agents of choice for serious infections withextended-spectrum β-lactamase–producing organisms. However, increased prevalence of pan-resistant P. aeruginosa and A. baumannii strains worldwide has limited the utility even of the car-bapenems. To reduce the likelihood of emergence of resistance, clinical practice guidelines havebeen developed to direct antimicrobial treatment of nosocomial infections. Initial empiric therapyshould offer broad-spectrum coverage of Gram-negative pathogens, and therapy should be tai-lored and de-escalated after positive culture results are obtained. Although the polymyxins havebeen reintroduced, particularly as a last-line treatment of MDR Gram-negative pathogens, hetero-resistance to these agents has already been documented, highlighting the need for more appro-priate use of antimicrobials to minimize suboptimal outcomes.

Doripenem, a novel, broad-spectrum carbapenem, offers impressive in vitro activity and clinicalefficacy against P. aeruginosa and A. baumannii (including many MDR strains). Doripenem iswell tolerated and its effects on the central nervous system are negligible. This special report pro-files the properties of the carbapenem class, emphasizes key principles of clinical practice guide-lines for antimicrobial treatment selection and use, and reviews doripenem, the pending additionto the carbapenem class.

L E A R N I N G O B J E C T I V E S After reviewing this supplement, participants should be able to:

1 Discuss the impact of resistant Gram-negative organisms on outcomes and managementstrategies in critically ill patients with pneumonia and intra-abdominal infections.

2 Choose appropriate guideline-based treatments for infections caused by resistant Gram-negative pathogens in critically ill patients.

3 Review features of available carbapenem agents.

4 Evaluate the utility of new agents to combat infections resulting from P. aeruginosa and A. baumannii.

5 Weigh the benefits and risks of each carbapenem-based treatment in managing infections inthe intensive care unit.

T A R G E T A U D I E N C E This activity has been developed for critical care physicians and surgicalcritical care physicians.

A C C R E D I T A T I O N University of Kentucky College of Medicine

This activity has been planned and implemented in accordance with the Essential Areas and poli-cies of the Accreditation Council for Continuing Medical Education through the joint sponsorshipof the University of Kentucky College of Medicine and Rxperience. The University of KentuckyCollege of Medicine is accredited by the ACCME to provide continuing medical education forphysicians.

The University of Kentucky College of Medicine designates this educational activity for a maxi-mum of 1.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensuratewith the extent of their participation in the activity.

The University of Kentucky College of Medicine presents this activity for educational purposesonly. Participants are expected to utilize their own expertise and judgment while engaged in thepractice of medicine. The content of the presentation is provided solely by presenters who havebeen selected for presentations because of recognized expertise in their field.

F A C U L T Y

Lena M. Napolitano, MD,FACS, FCCP, FCCM

Professor of SurgeryDivision Chief, Acute Care Surgery

Trauma, Burn, Critical Care, Emergency Surgery

Associate Chair of Surgery for Critical Care

Department of SurgeryDirector, Surgical Critical CareUniversity of Michigan Health SystemAnn Arbor, Michigan

Robert C. Owens, Jr, PharmDCo-Director, Antimicrobial

Stewardship ProgramClinical Pharmacy Specialist,

Infectious DiseasesDepartment of Pharmacy Services

and Division of Infectious DiseasesMaine Medical CenterPortland, MaineClinical Assistant Professor Department of Medicine University of Vermont‚ College

of Medicine Burlington‚ Vermont

John P. Quinn, MD, FACPProfessor of MedicineRush UniversityStroger Hospital of Cook County Scientific DirectorChicago Infectious Disease

Research InstituteChicago, Illinois

Andrew F. Shorr, MD, MPHAssociate Director, Pulmonary and

Critical Care Medicine Associate Professor of MedicineWashington Hospital CenterWashington, DC

Introduction to Carbapenem Agents

Gram-negative pathogens belonging to the Pseudomonasand Acinetobacter species are prevalent and important caus-es of nosocomial infections among critically ill patients.Acquired mechanisms of resistance that exhibit multiple,diverse actions have caused some strains of these pathogensto be much more difficult to treat.1,2 The continuing increase inantimicrobial resistance across US hospitals remains a majorconcern for patients, clinicians, and public health officials.3

Outbreaks of nosocomial infection caused by Gram-nega-tive pathogens are not isolated, regional occurrences butrather worldwide events and have most recently reached pro-portions of a global health issue.4 Based on in vitro and clinicaldata, carbapenems have been and continue to be the agentsof choice for serious infections with extended-spectrum β-lacta-mase (ESBL)–producing organisms.5 However, resistance to β-lactam antimicrobials, including carbapenems, is increasingamong strains of Pseudomonas aeruginosa and Acinetobac-ter baumannii, leaving clinicians with a dearth of viable thera-peutic options to treat nosocomially acquired Gram-negativeinfections. Interestingly, the polymyxins have been resurrectedas last-resort treatments for patients infected with multidrug-resistant (MDR) pathogens.1 However, increased use ofpolymyxins will likely lead to emergence of resistance, thusunderscoring the immediate need for recognition of the keyrisk factors for MDR acquisition; more responsible antimicro-bial treatment selection and use; adherence to clinical practiceguidelines for initial empiric therapy and de-escalation; andgreater awareness and appreciation of the use of novel antimi-crobials for critically ill patients with nosocomial infections.1,6-9

Overview of the Carbapenemsβ-lactam antimicrobials comprise more than 50% of all

antimicrobial therapies, and their efficacy and tolerability makethem the most commonly prescribed antibiotic agents. Thecarbapenems represent one of the many antimicrobial groupsin this category.10 Carbapenems demonstrate excellent in vitroactivity because of their efficient penetration into bacteria, sta-bility to hydrolysis by nearly all clinically important serine β-lac-tamases, and high affinity for essential penicillin-bindingproteins (PBPs) of Gram-negative bacteria. These agents pos-sess a broad spectrum of antimicrobial activity, exceeding thatof most other antimicrobial classes. Agents in the carbapenem

class include doripenem, ertapenem, faropenem, imipenem,meropenem, and panipenem/betamipron.10 The molecularstructures of doripenem, ertapenem, imipenem, and meropen-em are depicted in Figure 1.

The first carbapenem that was developed, imipenem, isactive against a broad spectrum of pathogens. Imipenem iscoadministered with cilastatin—an inhibitor of human renaldehydropeptidase I—because imipenem is hydrolyzed by thisenzyme.10 Imipenem is indicated for hospitalized patients withintra-abdominal infections (IAIs), lower respiratory tract infec-tions, gynecologic and genitourinary tract infections, skin andsoft tissue infections (SSTIs), sepsis, and endocarditis. Imipen-em is considered an appropriate empirical treatment whenthere is a high likelihood of infection with resistant pathogensor multiple organisms, including aerobes and anaerobes. Theplasma half-life of imipenem is approximately 1 hour, and it is10% to 20% protein bound. The most common adverse effectsof imipenem include phlebitis, thrombophlebitis, nausea, diar-rhea, and vomiting. This agent is not indicated for central ner-vous system (CNS) infections because of its proconvulsiveactivity.13

Meropenem is a carbapenem that has activity against Gram-negative, Gram-positive, and anaerobic microorganisms. As isimipenem, meropenem is highly resistant to hydrolysis by mostof the serine-based β-lactamases produced by Gram-negativebacteria. Meropenem is effective for the treatment of seriousinfections, including those acquired in the hospital or intensivecare unit (ICU). Meropenem penetrates rapidly and widely intoa range of body fluids and tissues, including cerebrospinalfluid, and its half-life is approximately 1 hour. The most com-mon side effects associated with meropenem include diarrhea,rash, nausea, vomiting, and injection-site inflammation.Meropenem is well tolerated by the CNS in doses of 2 g every8 hours, even in patients with bacterial meningitis.14

Ertapenem is a carbapenem that shares the activity ofimipenem and meropenem against most species; however, itlacks significant activity against nonfermenters (ie, Gram-nega-tive rods, including Pseudomonas and Acinetobacter) and thushas a limited role in nosocomial infection. Ertapenem has along plasma half-life (~4 hours) that allows for once-daily dos-ing. Findings from clinical trials demonstrate equivalence withcomparators for treatment of moderate to severe IAIs, pelvicinfections, SSTIs, mild to moderate intra-abdominal sepsis, com-munity-acquired pneumonia (CAP), and complicated urinary

2

F A C U L T Y A N D S P O N S O R D I S C L O S U R E All faculty members participating in continuing medical education programs sponsoredby the University of Kentucky Colleges of Pharmacy and Medicine Continuing Education Office are expected to disclose any real orperceived conflict of interest related to the content of their presentations.

Significant relationships exist with the following companies/organizations whose products or services may be discussed:

Lena M. Napolitano, MD, FACS, FCCP, FCCM, has disclosed that she is a member of the speakers’ bureaus of and has acceptedconsultant fees from Merck & Co, Inc, Ortho-McNeil, Inc, Pfizer Inc, and Schering-Plough Corporation.

Robert C. Owens, Jr, PharmD, has disclosed that he has accepted consultant fees from Elan Corporation, plc, Ortho-McNeil, Inc,and Schering-Plough Corporation.

John P. Quinn, MD, FACP, has disclosed that he has accepted research grants and consultant fees from Roche and that he hasaccepted research grants and consultant fees from, and is a member of the speakers’ bureaus of, Cubist Pharmaceuticals, Johnson & Johnson, and Merck & Co, Inc.

Andrew F. Shorr, MD, MPH, has disclosed that he has accepted research grants and consultant fees from, and is a member of thespeakers’ bureaus of, Astellas Pharma US, Inc, AstraZeneca, GlaxoSmithKline, Ortho-McNeil, Inc, Pfizer Inc, and sanofi-aventis.Additionally, he is a member of the speakers’ bureaus of Boehringer International and Merck & Co, Inc.

The University of Kentucky is an equal opportunity university.

The content for this activity was provided by Rxperience.

3

tract infections (UTIs). Side effects include diarrhea, nausea,headache, and infusion-site reaction. Lastly, the risk of seizureis small, although definite.12

Clinical Practice Guidelines forSelection of Antimicrobial Therapy

HAP Guidelines

The American Thoracic Society (ATS) and the Infectious Dis-eases Society of America (IDSA) offer joint guidelines (2005)

on the management of adults with hospital-acquired pneumonia(HAP), ventilator-associated pneumonia (VAP), and healthcare-associated pneumonia (HCAP). These guidelines recommendprompt, empiric, and broad-spectrum therapy for patients withHAP who are at risk for MDR pathogens. Broad-spectrumempiric antimicrobial therapy should be accompanied by a de-escalation commitment based on serial clinical and microbio-logic data. In addition, there is minimal support for combinationtherapy in managing infection with P. aeruginosa, and car-bapenems should be used at optimal doses to prevent emer-gence of resistance in Acinetobacter. Figure 2 summarizes theinitial treatment strategies based on clinical responses of a

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FIGURE 1. MOLECULAR STRUCTURE OF SELECT CARBAPENEMS

Adapted from references 11-14.

O O

O

O

O

OH

HH HH H

HO

N

HN

N

NS

H

H

HHOH

COOH

NHCH

NH

N

NHHS

SS

N

CO2H

H3C CH3

CH3

CH3

CH3

CH3

CON

NH

COOH

OH

O

H

H H

NS

NH2

CH3

CO2NaCO2Na

H3C

•H2O

•H2O

HO

12

345

6 7

Doripenem Ertapenem

Imipenem Meropenem

FIGURE 2. INITIAL MANAGEMENT BASED ON CLINICAL RESPONSE OF THE PATIENT WITH SUSPECTED HAP

HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; LRT, lower respiratory tract; VAP, ventilator-associated pneumonia; WBC, white blood cell count

Adapted from reference 15.

HAP, VAP, or HCAP suspectedHAP, VAP, or HCAP suspected

Unless there are both a low clinical suspicion for pneumonia and negative microscopy of LRT sample, begin empiric antimicrobial therapy using algorithm for initiating antimicrobial therapy

for HAP, VAP, and HCAP (Figure 3) and local microbiologic data

Unless there are both a low clinical suspicion for pneumonia and negative microscopy of LRT sample, begin empiric antimicrobial therapy using algorithm for initiating antimicrobial therapy

for HAP, VAP, and HCAP (Figure 3) and local microbiologic data

Days 2 and 3: Check cultures and assess clinical response (temperature, WBC, chest X-ray, oxygenation, purulent sputum,

hemodynamic changes, and organ function)

Days 2 and 3: Check cultures and assess clinical response (temperature, WBC, chest X-ray, oxygenation, purulent sputum,

hemodynamic changes, and organ function)

Clinical improvement at 48-72 hoursClinical improvement at 48-72 hours

Cultures –Cultures –

Search for other pathogens, complications, other

diagnoses, or other site of infection

Search for other pathogens, complications, other

diagnoses, or other site of infection

Adjust antibiotic therapy; search for other pathogens,

complications, other diagnoses, or other sites of infection

Adjust antibiotic therapy; search for other pathogens,

complications, other diagnoses, or other sites of infection

Consider stopping antibiotics

Consider stopping antibiotics

De-escalate antibiotics, if possible. Treat selected

patients for 7-8 days and reassess

De-escalate antibiotics, if possible. Treat selected

patients for 7-8 days and reassess

Cultures –Cultures –Cultures +Cultures + Cultures +Cultures +

NoNo YesYes

Obtain LRT sample for culture (quantitative or semiquantitative) and microscopyObtain LRT sample for culture (quantitative or semiquantitative) and microscopy

patient with suspected HAP, VAP, or HCAP. Figure 3 provides atreatment algorithm to guide clinicians in the initiation of antimi-crobial therapy.

Antimicrobial selection should be based on risk factors forMDR pathogens, such as antimicrobial therapy within the past90 days, time of current hospitalization, frequency of resistancein the hospital or community, risk factors for HCAP (eg, resi-dence in nursing home, home infusion therapy), and immuno-suppressive disease or therapy. Table 1 provides guidance onthe recommended initial empiric antimicrobial for HAP or VAPpatients without known risk factors for MDR pathogens (earlyonset and any disease severity).15 It is important to note thatother antibiotics are also indicated for treatment of HAP, inaddition to those stated in the guidelines. Table 2 summarizesthe recommended, initial, broad-spectrum combination thera-

pies for late-onset disease, risk factors, or MDR pathogens.15

Other key principles discussed in the ATS/IDSA guidelinesfor management of HAP, VAP, and HCAP include the following:• Early, appropriate, broad-spectrum antimicrobial therapy

should be initiated with adequate dosing to optimize antimi-crobial therapy.

• An empiric therapy regimen should include agents fromantibiotic classes different from those the patient hasrecently received.

• Combination therapy for a specific pathogen should beused judiciously for treatment of HAP.

Initial, Broad-Spectrum,Combination Antibiotic Therapy

Antipseudomonal cephalosporinor

Antipseudomonal carbapenemor

β-lactam/β-lactamase inhibitor plus

Antipseudomonal fluoroquinolone*or

Aminoglycoside

Linezolid or vancomycin†

Recommended Antibiotic

Ceftriaxone

or

Levofloxacin, moxifloxacin, orciprofloxacin

or

Ampicillin-sulbactam

or

Ertapenem

4

TABLE 1. INITIAL EMPIRIC THERAPY IN PATIENTSWITHOUT RISK FACTORS FOR MDR PATHOGENS

*The frequency of penicillin-resistant S. pneumoniae and MDR S. pneumoniaeis increasing. Levofloxacin or moxifloxacin is preferred to ciprofloxacin, and therole of other new quinolones, such as gatifloxacin, has not been established.

MDR, multidrug-resistant


Potential Pathogens

Streptococcus pneumoniae*

Haemophilus influenzae

Methicillin-sensitive Staphylococcus aureus

Antibiotic-sensitive entericGram-negative bacilliEscherichia coliKlebsiella pneumoniaeEnterobacter speciesProteus speciesSerratia marcescens

FIGURE 3. ALGORITHM FOR INITIATING EMPIRIC ANTIMICROBIAL THERAPY FOR HAP, VAP, AND HCAP

HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; MDR, multidrug-resistant; VAP, ventilator-associated pneumonia


Late onset (>5 days) or risk factors for MDR pathogensLate onset (>5 days) or risk factors for MDR pathogens

Limited-spectrum antibiotic therapy (Table 1)

Limited-spectrum antibiotic therapy (Table 1)

Broad-spectrum antibiotic therapy for MDR pathogens (Table 2)

Broad-spectrum antibiotic therapy for MDR pathogens (Table 2)

NoNo YesYes

HAP, VAP, or HCAP suspected (all disease severity)HAP, VAP, or HCAP suspected (all disease severity)

*If an ESBL strain such as K. pneumoniae or an Acinetobacter species issuspected, a carbapenem is a reliable choice. If L. pneumophila is suspected,the combination antibiotic regimen should include a macrolide (eg,azithromycin), or a fluoroquinolone (eg, ciprofloxacin or levofloxacin) should beused rather than an aminoglycoside.†If MRSA risk factors are present or there is a high incidence locally.

ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant


Potential Pathogens

Pathogens listed in Table 1 andMDR pathogens

Pseudomonas aeruginosa

Klebsiella pneumoniae(ESBL+)*

Acinetobacter species*

Methicillin-resistantStaphylococcus aureus

Legionella pneumophila*

TABLE 2. INITIAL EMPIRIC THERAPY FOR LATE-ONSET DISEASE, RISK FACTORS, OR MDR PATHOGENS

• De-escalation of antibiotics should be considered based onculture results and clinical response.

• A shorter duration of antibiotic therapy (ie, 7 to 8 days) isrecommended in patients with uncomplicated HAP, VAP, orHCAP who have received appropriate initial therapy anddemonstrated a good clinical response, with no evidence ofinfection with nonfermenting Gram-negative bacilli.15

IAI/Complicated IAI (cIAI) GuidelinesBoth the IDSA (2003) and the Surgical Infection Society

(SIS; 2002) have issued guidelines on the management of IAIs.A cIAI extends beyond the hollow viscus of origin into the peri-toneal space and is associated with either abscess formationor with peritonitis. Antimicrobial therapy should be initiated assoon as a cIAI is suspected. In some instances, a multidrugregimen (eg, aminoglycoside plus fluoroquinolone or car-bapenem plus vancomycin) is recommended. Only carbapen-ems and broad-spectrum penicillins (combined with aβ-lactamase inhibitor) are recommended for monotherapy

treatment of cIAIs,9,16 because only these agents have a spec-trum that effectively covers both aerobes and anaerobes.17

Tables 3 and 4 compare IDSA and SIS recommendations withregard to severity and risk status of patients with cIAIs, respec-tively.9,16

Therapy With Carbapenem Agents

Clinicians who treat documented resistant Gram-negativeinfections must consider the role of monotherapy (eg, car-bapenems or colistin) and the possibility of combination thera-py, as well as factors related to empiric treatment andde-escalation. The therapies of choice for treatment of infec-tions with ESBL-producing organisms include fluoroquinolones(for UTIs), carbapenems (bacteremia, HAP, and IAI), andmeropenem (meningitis).15

Multiple studies highlight the efficacy of carbapenems asmonotherapy for the treatment of ESBL-producing Klebsiella

IDSA

5


TABLE 3. IDSA- AND SIS-RECOMMENDED ANTIMICROBIAL REGIMENS: MILD TO MODERATE/LOWER RISKIDSA SIS

• Ampicillin/sulbactam*

• Ticarcillin/clavulanic acid

• Ertapenem

• Cefotetan

• Cefoxitin

• Ertapenem

• Meropenem

• Ampicillin/sulbactam*

• Imipenem/cilastatin

• Piperacillin/tazobactam

• Ticarcillin/clavulanate

• Cefazolin or cefuroxime +metronidazole

• Fluoroquinolone-based therapy +metronidazole†

• Ciprofloxacin + metronidazole

• Aminoglycoside + antianaerobe

• Aztreonam + clindamycin

• Cefuroxime + metronidazole

• Third-/fourth-generation cephalosporin + anti-anaerobe

*Because increasing resistance of E. coli to ampicillin and to ampicillin/sulbactam has been reported, local susceptibility profiles should be reviewed before use.†Fluoroquinolone=ciprofloxacin, levofloxacin, moxifloxacin, or gatifloxacin. Because increasing resistance of Bacteroides fragilis group isolates to available quinoloneshas been reported, these agents should be used in combination with metronidazole.

IDSA, Infectious Diseases Society of America; SIS, Surgical Infection Society

Adapted from references 9 and 16.

Mild to Moderate Infections Lower-Risk Patients

Single-Agent Regimen

Combination Regimen

TABLE 4. IDSA- AND SIS-RECOMMENDED ANTIMICROBIAL REGIMENS: HIGH SEVERITY/HIGHER RISKSIS



• Meropenem



• Meropenem

• Third/fourth-generation cephalosporin + metronidazole

• Aztreonam + metronidazole



• Aminoglycoside + anti-anaerobe

• Aztreonam + clindamycin

• Third-/fourth-generation cephalosporin + anti-anaerobe

IDSA, Infectious Diseases Society of America; SIS, Surgical Infection Society

Adapted from references 9 and 16.

High-Severity Infections Higher-Risk Patients

Single-Agent Regimen

Combination Regimen

pneumoniae and Escherichia coli infections. In a prospective,observational study of patients with K. pneumoniae bacteremia(455 episodes in 440 patients; 85 episodes caused by ESBL-producing organisms), use of a carbapenem, mainly imipenem,was associated with lower 14-day mortality compared with otherantimicrobials (OR, 0.173; 95% CI, 0.039-0.755; P=0.012).5

Du and colleagues demonstrated lower mortality withimipenem than with cephalosporins for the treatment of ESBL-producing E. coli or K. pneumoniae bloodstream infection.ESBLs were produced by 27% of isolates. Patients treated withimipenem were more likely to survive, whereas those receivingcephalosporin treatment tended to have poorer outcomes(1/19 vs 14/40; P=0.023). In addition, compared withmonotherapy, combination therapy neither resulted in treat-ment success nor improved patient outcome.18

In a multicenter, open-label, randomized, parallel-group trial,the Belgian Multicenter Study Group compared the efficacyand tolerability of meropenem and imipenem/cilastatin (both 1 g/8 h intravenously) as empirical monotherapy in 212 ICUpatients (n=107 meropenem; n=105 imipenem/cilastatin) withserious bacterial infections, including lower respiratory tractinfection in ventilated patients, IAI, and sepsis. Predominantpathogens included E. coli, Enterobacter species, and P.aeruginosa.19 Both treatments demonstrated similar satisfacto-ry clinical and bacteriologic response rates, as illustrated inFigure 4.19

There has been renewed interest in the use of polymyxins asalternative treatments for critically ill patients infected withstrains of A. baumannii, P. aeruginosa, and K. pneumoniae thatare resistant to almost all available antimicrobials. Polymyxinsare a group of polypeptide cationic antimicrobials that includecolistin (polymyxin E) and polymyxin B. Both of these agentswere discovered in the 1940s and were widely used parenter-ally for approximately 20 years. They fell out of use after reportsof neurologic and renal adverse effects. Currently, these med-ications are viewed as last-resort agents in patients infectedwith MDR pathogens.20

A retrospective case series study by Michalopoulos and col-leagues examined the efficacy and safety of colistin in 43 criti-

cally ill patients with ICU-acquired infection (primarily VAP andbacteremia) characterized by MDR P. aeruginosa and/or A.baumannii. Clinical cure of infection was achieved in 69.8% ofpatients (30/43); 25.6% (11/43) did not respond to treatment,and all of these patients died. Deterioration of renal functionoccurred in 18.6% (8/43) of patients.21

In a retrospective chart review of 37 ICU patients with MDRA. baumannii, clinical cure was observed in 22 of 29 (76%) ofpatients treated with polymyxin B. Crude mortality was 27%(9/33), with 3 deaths attributed to polymyxin B treatment fail-ure. Nephrotoxicity was observed in 21% and neurotoxicity in6% of patients treated with polymyxin B. Generalizability of find-ings may be limited by the relatively young age of patients inthis study, as well as by the large number of trauma patientswith few comorbidities.22

Colistin was also evaluated by Reina and colleagues in aprospective cohort study of 185 patients infected with A. bau-mannii and P. aeruginosa after an ICU stay of more than 48hours. Fifty-five patients were treated with colistin. Of 130patients in the noncolistin group, 81% were treated with car-bapenems. There were no differences between groups in thefrequency of clinical cure on day 6 of treatment (15% vs 17%) ornumber alive at discharge (71% vs 74%). Overall, outcomes withcolistin were the same as outcomes for carbapenems, andmean creatinine levels remained normal throughout treatment.23

A recent review of 5 studies of treatment with I.V. colistin ofVAP resulting from P. aeruginosa or A. baumannii reportedclinical cure rates ranging from 25% to 62%, despite highseverity of illness at baseline. De novo nephrotoxicity ratesranged from 8% to 36%, despite close attention to appropriatedosing and duration of treatment. Neurotoxicity was reportedin only 1 patient across the 5 studies, and this was the onlypatient for whom colistin treatment was discontinued in thesestudies.24

Now that colistin has re-emerged as acceptable therapy forMDR A. baumannii infections, its use has increased worldwideand heteroresistance has since been recorded. Recently, ateam of investigators became the first to report heteroresis-tance to colistin in clinical isolates of A. baumannii obtained

6

FIGURE 4. SATISFACTORY RESPONSE RATES AT END OF TREATMENT

CI, confidence interval


0

40

80

Clinical Response RateDiff 8.9%; 95% CI, -4.2–+21.9%;

P=0.185

Pat

ien

ts (

%)

Bacteriologic Response RateDiff 6.9%; 95% CI, -8.7–+22.4%;

P=0.389

Meropenem

Imipenem-cilastatin

77.0%

68.1% 67.1%

60.3%

67/87 49/73 44/7362/91

7

from an Australian hospital (14 from patients admitted to theICU) that were apparently susceptible to colistin based onMICs. Population analysis profiles demonstrated that het-eroresistance to colistin occurred in 15 of the 16 A. bauman-nii clinical isolates; most clinical isolates grew in the presenceof 3 to 10 µg/mL of colistin. These findings send a clear mes-sage to clinicians: If colistin is used inappropriately, rapiddevelopment of resistance and treatment failures may eventu-ally follow.7

Doripenem: Safety, Efficacy, andComparative Data

Doripenem is a novel, broad-spectrum parenteral carba-penem. Doripenem’s molecular structure (see Figure 1 onpage 3) confers β-lactamase stability and resistance to inacti-vation by renal dehydropeptidases. This new addition to thecarbapenem class has demonstrated impressive in vitro activi-ty against P. aeruginosa and A. baumannii isolates, includingmany MDR strains. In vitro studies have established the uniquecharacteristics of doripenem, including a spectrum and poten-cy against Gram-negative cocci similar to that of imipenem andactivity against Gram-negative bacteria similar to that of mero-penem. One key feature of doripenem, attributed to the sidechain at position 2, is greater activity against MDR, nonfermenta-tive, Gram-negative bacilli. Furthermore, as does meropenem,doripenem exhibits favorable pharmacokinetic, pharmaco-dynamic, and toxicologic features.25 As do other carbapenems,doripenem remains vulnerable to class B enzymes, also knownas metallo-β-lactamases, which represent significant threats totreatment by all β-lactams.26

Doripenem possesses high affinity for PBP targets that arespecies-specific. Doripenem has low serum protein binding(8% to 9%), a half-life of approximately 1 hour, and endotoxinrelease comparable with that of other carbapenems. Thisagent has synergy with glycopeptides when tested againstoxacillin-resistant S. aureus, and it has documented successwithin in vivo animal models and in clinical trials.11

In Vitro ActivityIn a global surveillance report, Fritsche and colleagues

evaluated the antimicrobial activity results of doripenem andcomparator agents against 16,008 Gram-positive and Gram-negative isolates, including 829 P. aeruginosa and 155 Acine-tobacter species isolates. Nonduplicate, consecutive clinicalisolates were collected from more than 70 medical centersworldwide and were either community- or nosocomiallyacquired.25 Of all the carbapenems, doripenem was shown tobe the most active agent (Table 5). Doripenem was also asso-ciated with the lowest rate of spontaneous resistance amongthe antipseudomonal agents tested, including other car-bapenems .

Doripenem and meropenem were most active among all β-lactams against P. aeruginosa, and doripenem and imipenemwere most active against Acinetobacter species.25

In another in vitro study by Jones and colleagues, onlydoripenem (75.8% inhibited at ≤4 µg/mL), imipenem, andmeropenem demonstrated activity against wild-type A. bau-mannii isolates. Doripenem and imipenem were the mostpotent agents (MIC50, 0.5 µg/mL) and inhibited strains atpotentially achievable breakpoint concentrations. Moreover,doripenem was 2- and 4-fold more potent than meropenemand imipenem against P. aeruginosa, respectively.11

Doripenem: Reducing/Preventing Emergence of Resistance

Use of doripenem may reduce emergence of resistantpathogens, as evidenced in a number of studies. Sakyo andcolleagues examined the potency of doripenem, meropenem,and imipenem in preventing the emergence of carbapenem-resistant P. aeruginosa mutants. In total, 140 P. aeruginosa iso-lates were investigated for carbapenem resistance. Theisolation frequency of each mutant was examined at concen-trations of one half or one quarter MIC of each carbapenemfor that mutant. Mutants were not selected on agar containingdoripenem at more than 10–9 per cell per generation; howev-er, mutants were selected on agar containing meropenem orimipenem at frequencies of approximately 10–9 to 10–7. Thesedata indicate that of all the carbapenems, doripenem exhibit-ed the lowest drug concentration and the narrowest range ofdrug concentration for selection of carbapenem-resistantmutants, and doripenem therefore had the greatest ability toprevent the emergence of mutants.27

β-lactams used in combination with aminoglycosides mayprovide synergistic activity against Gram-negative pathogens.In an in vitro study, doripenem was tested in combination withgentamicin to determine resistance selection during subin-hibitory passaging using P. aeruginosa isolates with elevatedMIC values (n=6). Doripenem MIC values increased 2- to 8-fold and higher in 4 isolates, whereas 2 strains maintained thebaseline doripenem MIC. When doripenem plus gentamicinwas tested, 3 strains maintained the original doripenem MICvalues, 2 strains had a 2-fold increase, and only 1 strainshowed a 4-fold increase in doripenem MIC values. Thus, thecombination of doripenem plus an aminoglycoside may be aneffective treatment of infections caused by P. aeruginosa withelevated carbapenem MIC values, with lower risk of selectingfurther resistance.28

Mushtaq and colleagues evaluated in vitro resistance selec-tion potential of antimicrobial agents versus characterized iso-lates, mutants, and transconjugants of P. aeruginosa.Doripenem MICs were lower than meropenem for strains withelevated intrinsic resistance. Furthermore, mutant selection(single step) with doripenem occurred with fewer strains thanwith other agents. The final multiple of the MIC achieved was


TABLE 5. DORIPENEM IN VITRO ACTIVITY VERSUS OTHER CARBAPENEMS

CarbapenemActivity Against P. aeruginosa;

MIC90, µg/mLAgainst Acinetobacter species;

MIC90, µg/mL

Doripenem 8 4

Ertapenem >8 >8.

Meropenem 16 8

Imipenem >8 2


lower for doripenem than for other agents and never exceeded4 times the starting MIC. Other carbapenems selected mutantsfrom among more test strains.29

Doripenem Clinical EfficacyAt the 2006 Annual Interscience Conference on Antimicro-

bial Agents and Chemotherapy (ICAAC) meeting, Malafaiaand colleagues presented findings from a large, randomized,double-dummy, multicenter Phase III trial comparing the effi-cacy and safety of doripenem (500 mg I.V. infusion every 8hours over 60 minutes) versus meropenem (1 g I.V. bolusevery 8 hours over 3-5 minutes) for treatment of adult patients(n=486) with cIAIs.30 Patients could be switched to oral amox-icillin-clavulanate after 9 or more doses of doripenem ormeropenem. Table 6 summarizes patient characteristics ofthe microbiologically evaluable population at test-of-cure(TOC) analysis. The total duration of study therapy was 5 to14 days. The primary end point was clinical response at theTOC visit 21 to 60 days post-therapy. Figure 5 illustrates theclinical cure rate for both agents at the TOC visit for the micro-biologically evaluable population. Doripenem was noninferiorto meropenem for the treatment of cIAI. Also illustrated in Fig-ure 5 are the clinical cures for the microbiologic modifiedintent-to-treat population. In this study, doripenem was effec-tive against major causative organisms (E. coli, K. pneumoni-ae, P. aeruginosa, S. intermedius, Bacteroides caccae, B.thetaiotaomicron, B. fragilis, and B. uniformis) and was gen-erally well tolerated. Nausea occurred in 3.7% and 2.6% in thedoripenem and meropenem groups, respectively, and diar-rhea occurred in 2.5% and 3.0% in each group, respectively.

Optimizing Treatment WithCarbapenems

For β-lactams, the best predictor of bacterial killing is thetime during which drug concentration exceeds the MIC of theorganism. Lodise and colleagues evaluated an extended-infu-sion dosing scheme for piperacillin-tazobactam therapy, usinga Monte Carlo simulation, to improve clinical outcomes in criti-cally ill patients with P. aeruginosa infections. Among patientswith APACHE-II scores of 17 or greater, the 14-day mortality ratewas significantly lower among patients who received extended-infusion therapy (4 hours) than among patients who receivedintermittent-infusion therapy (30 minutes), and the medianduration of hospital stay was significantly shorter.31

Likewise, extending infusion time may confer advantages intreatment with carbapenems. In healthy volunteers, a 2-hourinfusion of imipenem resulted in serum concentrationsexceeding organism MIC for extended time periods,compared with a half-hour infusion.32 The advantages ofprolonged infusion with meropenem were demonstrated in anin vitro hollow-fiber infection model by Tam and colleagues. Inthis study, selective amplification of resistant subpopulationsof P. aeruginosa was reduced with extended meropeneminfusion.33

Adverse CNS effects, particularly the lower seizure thresh-old, of β-lactam antimicrobials are well known, although thedata on seizure activity are somewhat inconclusive. In the lit-erature, imipenem has been associated with a 3% incidenceof seizures. The mechanism of seizure action of imipenem ismultifactorial and believed to be related to the agent’s abilityto reduce inhibition of epileptic discharges by blocking γ-aminobutyric acid (GABA)-A receptor, to its action onα–amino-3-hydroxy-5-methyl-isoxazoleproprionate (AMPA)and N-methyl-D-aspartate (NDMA) receptor complexes, orpossibly to its penicillin-like activity.34

Wong and colleagues evaluated the efficacy and safety ofcombination imipenem/cilastatin in 21 young children withbacterial meningitis. The study was terminated when 7patients (33%) developed seizure activity after antibiotic ther-apy was given, leading investigators to conclude that the util-ity of imipenem/cilastatin for bacterial meningitis in childrenmay be limited by a possible increased incidence of drug-related seizure activity.35

Observations from 1,754 patients treated with imipenem/cilastatin in Phase III dose-ranging studies in the United Statesdemonstrated that 52 patients (3%) had seizures, of which 16(0.9%) were considered to be associated with imipenem. Of the1,754 patients, 946 (54%) were treated with 2 g of imipenem/cilastin per day for serious infections. The majority of seizuretypes were generalized tonic-clonic (n=37), with the rest dividedbetween focal seizures and myoclonus. Imipenem dosages inexcess of manufacturer recommendations were associated withincreased risk of seizures.36 A possible clinical concern is thatphysicians may use suboptimal doses in an effort to avoid pos-sible seizures with imipenem, thereby complicating overall treat-ment outcomes.

A medical chart review of 75 patients receiving imipenem ina municipal hospital during a 6-month interval was conductedby Koppel and colleagues. Findings from this study demon-strated that imipenem use is safe and is not associated with

8

TABLE 6. PATIENT CHARACTERISTICS OF THE ME AT TOC ANALYSIS

Primary Site of Infection I.V. Doripenem; n=162 (%) I.V. Meropenem; n=153 (%)

Complicated localized appendicitis 57 (35.2) 42 (27.5)

Other sites of IAI 105 (64.8) 111 (72.5)

Generalized peritonitis 76 (46.9) 81 (52.9)

Localized infection 46 (28.4) 30 (19.6)

Multiple abscess 5 (3.1) 4 (2.6)

Single abscess 33 (20.4) 36 (23.5)

Postoperative infection 10 (6.2) 12 (7.8)

IAI, intra-abdominal infection; ME, microbiologically evaluable; TOC, test of cure


Infection Process (%)

9

increased risk of seizure. Of the 75 charts reviewed, only 4patients had seizures during imipenem treatment and 8patients had seizures before or after imipenem use. Althoughthe incidence of seizure was greater among critically illpatients, it did not differ with use of imipenem. Determiningthe proper dose of imipenem at initiation of therapy andavoiding dosing at more than 2 g per day appears to mitigatethe risk for seizures related to imipenem.34

In an animal model study, doripenem showed no convul-sive activity when administered via I.V. or intracerebroventric-ular route. Furthermore, this agent did not potentiate seizuresin the pentylenetetrazol (PTZ)-induced convulsive model, hada low affinity for GABA receptors compared with other β-lac-tams, did not induce seizure discharges when used concomi-tantly with valproic acid in the PTZ- or bicuculine-inducedseizure model, and caused no changes in electroencephalo-gram (EEG) or behavior in any animal studied. These findingssuggest that doripenem neurotoxicity may be negligible inclinical use settings. Conversely, imipenem produced seizuredischarges on EEG and/or convulsive activity in rats, mice,and dogs; and meropenem caused shaking behavior in ratsand spikes or seizure discharges in dogs.37

Summary

The carbapenem class of antimicrobials is characterized byexcellent in vitro activity and broad-spectrum antimicrobial activ-ity. These agents are considered to be the therapy of choice forinfection with ESBL-producing pathogens. Doripenem repre-sents a novel, broad-spectrum carbapenem with impressive non-clinical activity and documented success in clinical trials. Theunique characteristics of doripenem, including greater activityagainst Gram-negative MDR pathogens and a favorable toxicol-ogy profile, offer clinicians a practical treatment to combat thesepathogens in critically ill patients. Use of polymyxins has resur-faced for those patients infected with A. baumannii, P. aerugi-nosa, or other isolates that are resistant to virtually all availableantimicrobial agents. However, heteroresistance to colistin hasrecently been documented; thus, overuse or misuse of theseagents can rapidly lead to development of resistance and nega-tive outcomes. Adherence to clinical practice guidelines for thetreatment of nosocomially acquired Gram-negative pathogensensures appropriate antimicrobial selection and judicious use ofavailable agents for MDR pathogens, and can reduce emer-gence of resistance.


FIGURE 5. DORIPENEM EFFICACY NONINFERIOR TO MEROPENEM FOR TREATMENT OF CIAI

CI, confidence interval; cIAI, complicated intra-abdominal infection; ITT, intent to treat


0

10

20

30

40

50

60

70

80

90

100

Microbiologically Evaluable95% CI, -8.6 –+9.2

Microbiological Modified ITT95% CI, -10.3 –+8.0

Doripenem

Meropenem83.3% 83.0%

74.5% 75.7%

135/162 149/200 140/185127/153

Clin

ical

Cu

re (

%)

References1. Landman D, Bratu S, Alam M, Quale J. Citywide emergence of Pseudomonas

aeruginosa strains with reduced susceptibility to polymyxin B. J AntimicrobChemother. 2005;55:954-957.

2. Fournier PE, Vallenet D, Barbe V, et al. Comparative genomics in multidrugresistance in Acinetobacter baumannii. PLoS Genet. 2006;2:e7.

3. National Nosocomial Infections Surveillance System. National NosocomialInfections Surveillance (NNIS) System Report, data summary from January1992 through June 2004, issued October 2004. Am J Infect Control.2004;32:470-485.

4. Garnacho-Montero J, Ortiz-Leyba C, Fernandez-Hinojosa E, et al. Acinetobac-ter baumannii ventilator-associated pneumonia: epidemiological and clinicalfindings. Intensive Care Med. 2005;31:649-655.

5. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinicalupdate. Clin Microbiol Rev. 2005;18:657-686.

6. Dellit TH, Owens RC, McGowan JE Jr, et al, and the Infectious Diseases Soci-

ety of America and Society for Healthcare Epidemiology of America. Infec-tious Diseases Society of America and the Society for Healthcare Epidemiol-ogy of America guidelines for developing an institutional program to enhanceantimicrobial stewardship. Clin Infect Dis. 2007;44:159-177.

7. Li J, Rayner CR, Nation RL, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother.2006;50:2946-2950.

8. Dodek P, Keenan S, Cook D, et al, and the Canadian Critical Care Society. Evi-dence-based clinical practice guideline for the prevention of ventilator-associ-ated pneumonia. Ann Intern Med. 2004;141:305-313.

9. Solomkin JS, Mazuski JE, Baron EJ, et al, and the Infectious Diseases Soci-ety of America. Guidelines for the selection of anti-infective agents for compli-cated intra-abdominal infections. Clin Infect Dis. 2003;37:997-1005.

10. Bonfiglio G, Russo G, Nicoletti G. Recent developments in carbapenems.Expert Opin Investig Drugs. 2002;11:529-544.

11. Jones RN, Huynh HK, Biedenbach DJ, Fritsche TR, Sader HS. Doripenem (S-4661), a novel carbapenem: comparative activity against contemporarypathogens including bactericidal action and preliminary in vitro methods eval-uations. J Antimicrob Chemother. 2004;54:144-154.

12. Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem.J Antimicrob Chemother. 2003;52:331-344.

13. Rodloff AC, Goldstein EJ, Torres A. Two decades of imipenem therapy. JAntimicrob Chemother. 2006;58:916-929.

14. Hurst M, Lamb HM. Meropenem: a review of its use in patients in intensivecare. Drugs. 2000;59:653-680.

15. American Thoracic Society; Infectious Diseases Society of America. Guide-lines for the management of adults with hospital-acquired, ventilator-associat-ed, and healthcare-associated pneumonia. Am J Respir Crit Care Med.2005;171:388-416.

16. Mazuski JE, Sawyer RG, Nathens AB, et al, for the Therapeutic Agents Com-mittee of the Surgical Infections Society. The Surgical Infection Society guide-lines on antimicrobial therapy for intra-abdominal infections: evidence for therecommendations. Surg Infect (Larchmt). 2002;3:175-233.

17. Tellado JM, Wilson SE. Empiric treatment of nosocomial intra-abdominal infec-tions: a focus on the carbapenems. Surg Infect (Larchmt). 2005;6:329-343.

18. Du B, Long Y, Liu H, et al. Extended-spectrum beta-lactamase-producingEscherichia coli and Klebsiella pneumoniae bloodstream infection: risk fac-tors and clinical outcome. Intensive Care Med. 2002;28:1718-1723.

19. Verwaest C, on behalf of the Belgian Multicenter Study Group. Meropenemversus imipenem/cilastatin as empirical monotherapy for serious bacterialinfections in the intensive care unit. Clin Microbiol Infect. 2000;6:294-302.

20. Falagas ME, Kasiakou SK, Tsiodras S, Michalopoulos A. The use of intra-venous and aerosolized polymyxins for the treatment of infections in criticallyill patients: a review of the recent literature. Clin Med Res. 2006;4:138-146.

21. Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S, Falagas ME. Col-istin treatment in patients with ICU-acquired infections caused by multiresis-tant gram-negative bacteria: the renaissance of an old antibiotic. ClinMicrobiol Infect. 2005;11:115-121.

22. Holloway KP, Rouphael NG, Wells JB, King MD, Blumberg HM. Polymyxin B anddoxycycline use in patients with multidrug-resistant Acinetobacter baumanniiinfections in the intensive care unit. Ann Pharmacother. 2006;40:1939-1945.

23. Reina R, Estenssoro E, Sáenz G, et al. Safety and efficacy of colistin in Acine-tobacter and Pseudomonas infections: a prospective cohort study. IntensiveCare Med. 2005;31:1058-1065.

24. Linden PK, Paterson DL. Parenteral and inhaled colistin for treatment of ven-tilator-associated pneumonia. Clin Infect Dis. 2006;43(suppl 2):S89-S94.

25. Fritsche TR, Stilwell MG, Jones RN. Antimicrobial activity of doripenem (S-4661):a global surveillance report (2003). Clin Microbiol Infect. 2005;11:974-984.

26. Jones RN, Sader HS, Fritsche TR. Comparative activity of doripenem andthree other carbapenems tested against Gram-negative bacilli with variousbeta-lactamase resistance mechanisms. Diagn Microbiol Infect Dis.2005;52:71-74.

27. Sakyo S, Tomita H, Tanimoto K, Fujimoto S, Ike Y. Potency of carbapenemsfor the prevention of carbapenem-resistant mutants of Pseudomonas aerugi-nosa: the high potency of a new carbapenem doripenem. J Antibiot (Tokyo).2006;59:220-228.

28. Huynh HK, Biedenbach DJ, Jones RN. Delayed resistance selection fordoripenem when passaging Pseudomonas aeruginosa isolates with doripen-em plus an aminoglycoside. Diagn Microbiol Infect Dis. 2006;55:241-243.

29. Mushtaq S, Ge Y, Livermore DM. Doripenem versus Pseudomonas aerugi-nosa in vitro: activity against characterized isolates, mutants, and transconju-gants and resistance selection potential. Antimicrob Agents Chemother.2004;48:3086-3092.

30. Malafaia O, Umeh O, Jiang J. Doripenem versus meropenem for the treat-ment of complicated intra-abdominal infections. Poster presented at: 46thAnnual Interscience Conference on Antimicrobial Agents and Chemotherapy(ICAAC). September 27-30, 2006; San Francisco, Calif. Poster L-1564b.

31. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam forPseudomonas aeruginosa infection: clinical implications of an extended-infu-sion dosing strategy. Clin Infect Dis. 2007;44:357-363.

32. Jaruratanasirikul S, Raungsri N, Punyo J, Sriwiriyajan S. Pharmacokinetics ofimipenem in healthy volunteers following administration by 2 h or 0.5 h infu-sion. J Antimicrob Chemother. 2005;56:1163-1165.

33. Tam VH, Schilling AN, Neshat S, Poole K, Melnick DA, Coyle EA. Optimizationof meropenem minimum concentration/MIC ratio to suppress in vitro resis-tance of Pseudomonas aeruginosa. Antimicrob Agents Chemother.2005;49:4920-4927.

34. Koppel BS, Hauser WA, Politis C, van Duin D, Daras M. Seizures in the criti-cally ill: the role of imipenem. Epilepsia. 2001;42:1590-1593.

35. Wong VK, Wright HT Jr, Ross LA, Mason WH, Inderlied CB, Kim KS. Imipen-em/cilastatin treatment of bacterial meningitis in children. Pediatr Infect DisJ. 1991;10:122-125.

36. Calandra G, Lydick E, Carrigan J, Weiss L, Guess H. Factors predisposing toseizures in seriously ill infected patients receiving antibiotics: experience withimipenem/cilastatin. Am J Med. 1988;84:911-918.

37. Horiuchi M, Kimura M, Tokumura M, Hasebe N, Arai T, Abe K. Absence ofconvulsive liability of doripenem, a new carbapenem antibiotic, in comparisonwith beta-lactam antibiotics. Toxicology. 2006;222:114-124.

10

Post-testChoose the single-letter response that best answers the question or completes the sentence.

1. β-lactam antimicrobials, the most commonlyprescribed antimicrobial agents because of theirefficacy and tolerability, comprise _____.a. 10% to 25% of all antimicrobial therapiesb. <15% of all antimicrobial therapies c. >50% of all antimicrobial therapiesd. >80% of all antimicrobial therapies

2. Which of the following statements does not explainwhy carbapenems demonstrate excellent in vitroactivity?a. Carbapenems efficiently penetrate bacteria.b. Carbapenems offer narrow-spectrum antimicrobial

activity.c. Carbapenems have a high affinity for essential PBPs of

Gram-negative bacteria.d. Carbapenems offer stability to hydrolysis by nearly all

clinically important serine β-lactamases.

3. In an animal model study, which agent(s) caused NOseizure discharges or shaking behavior in rats, mice,or dogs?a. Meropenem and doripenemb. Meropenem and imipenemc. Meropenem onlyd. Doripenem only

4. In the case of HAP, VAP, or HCAP, when MDR Gram-negative infection is suspected, guidelines recom-mend _____.a. Isolation of patients to prevent the spread of bacteriab. Monotherapy up front with an antimicrobial that targets

specific bacteriac. Empiric therapy with doripenem, followed by imipenemd. Empiric therapy with an antipseudomonal carbapenem

or β-lactam/β-lactamase inhibitor plus an anti-pseudomonal fluoroquinolone or an aminoglycoside

11


5. For adult patients with HAP, ATS and IDSArecommend _____.a. broad-spectrum therapy for patients at risk for MDR

pathogensb. combination antimicrobial therapyc. aggressive monotherapy treatment that targets

P. aeruginosad. ceftriaxone/metronidazole for the treatment of mild to

moderate infections

6. Which of the following statements is true based onthe ATS/IDSA guidelines for the management of HAP?a. Antimicrobial de-escalation should be conducted based

solely on the patient’s clinical response.b. An empiric therapy regimen should include agents from

different antimicrobial classes than the patient hasrecently received.

c. A shorter duration of therapy is pertinent in patientswith complicated HAP who have received initiallyappropriate therapy and have experienced a goodclinical response.

d. Combination antimicrobial therapy is required in allpatients with HAP.

7. Which of the following statements is true based on the IDSA and SIS guidelines for the managementof cIAIs?a. Antimicrobial therapy should commence once cIAI is

confirmed.b. Broad-spectrum penicillins are the only recommended

monotherapy for cIAIs because their spectrum ofactivity effectively covers aerobes and anaerobes.

c. Multidrug regimens are not indicated for the treatmentof cIAIs.

d. Only carbapenems and broad-spectrum penicillins arerecommended monotherapy for the treatment of cIAIssince their spectrum of activities effectively coveraerobes and anaerobes.

8. Based on SIS guidelines, it is recommended that apatient at lower risk for cIAI be treated with ______.a. ciprofloxacin monotherapyb. aztreonam monotherapyc. meropenem monotherapyd. clindamycin monotherapy

9. In a prospective, observational study of patientswith K. pneumoniae bacteremia, multivariateanalysis and other predictors of mortality demon-strated that use of a carbapenem during the 5-dayperiod after onset of bacteremia resulting from anESBL-producing organism was independentlyassociated with ______.a. neither treatment success nor improved patient

outcomeb. lower mortalityc. a 30% mortality rated. lower morbidity and mortality

10. The Belgian Multicenter Study Group compared theefficacy and tolerability of meropenem andimipenem/cilastatin as empirical monotherapy in 212 ICU patients with serious bacterial infections.Results demonstrated that ______.a. meropenem was significantly more clinically and

bacteriologically efficacious than imipenem/cilastatinfor the empirical monotherapy of serious bacterialinfections in ICU patients

b. the clinical response rate of meropenem surpassed theclinical response rate of imipenem-cilastatin

c. meropenem was at least as clinically and bacteriologi-cally efficacious as imipenem/cilastatin for theempirical monotherapy of serious bacterial infections inICU patients

d. imipenem/cilastatin was significantly more efficaciousthan meropenem when used as empirical monotherapyfor serious bacterial infections in ICU patients

11. Based on a retrospective chart review of 37 ICUpatients with MDR A. baumannii who receivedpolymyxin B ______.a. neurotoxicity was more common than nephrotoxicity b. generalizability of findings may be limited by older age

of patientsc. crude mortality for these patients was 17%d. clinical cure rate for these patients was 76%

12. In an in vitro study by Jones and colleagues, which ofthe following demonstrated activity against wild-typeA. baumannii isolates?a. Imipenem and meropenemb. Meropenem and doripenemc. Doripenemd. Doripenem, imipenem, and meropenem

13. Sakyo and colleagues examined the potency of 3 antimicrobials and their ability to prevent theemergence of carbapenem-resistant P. aeruginosamutants. Based on their findings, these investigatorsdetermined that ______.a. doripenem and meropenem had equal ability to prevent

the emergence of mutantsb. doripenem had the greatest ability to prevent

emergence of mutants c. imipenem had the greatest ability to prevent emergence

of mutantsd. meropenem had the greatest ability to prevent

emergence of mutants

14. Clinically, the efficacy of doripenem for treatment ofcIAIs is comparable with that of ______.a. meropenemb. ertapenemc. faropenemd. imipenem

15. In an animal model study evaluating the effects ofdoripenem on CNS activity, which of the followingwere evident?a. Doripenem, compared with other β-lactams, had a high

affinity for GABA receptors.b. Doripenem potentiated seizures in the PTZ-induced

convulsive model.c. Doripenem caused no changes in EEG or behavior in

any animal studied.d. Doripenem demonstrated convulsive activity only in rats.

12

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Emerging Modalities to Combat Resistant Gram-Negative Pathogens in Critically Ill Patients: Part 2: Focus on the Carbapenems

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A 2-Part Series on Emerging Modalities to Combat Resistant ... · sess a broad spectrum of antimicrobial activity, exceeding that of most other antimicrobial classes. Agents in the