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 Gram-Negative Pathogens in Critically Ill Patients: Part 2: Focus on the Carbapenems

Date of Release: August 2007 Expiration Date: August 31, 2008 FACULTY Lena M. Napolitano, MD, PROGRAM OVERVIEW Rising rates of nosocomially acquired multidrug-resistant (MDR) Gram- negative pathogens have drastically narrowed the spectrum of available therapeutic options. FACS, FCCP, FCCM Resistance to antimicrobials is a mounting health concern, both in the United States and world- Professor of Surgery wide. Infections caused by resistant Gram-negative pathogens, such as Pseudomonas aeruginosa Division Chief, Acute Care Surgery and Acinetobacter baumannii, result in higher morbidity, mortality, prolonged hospitalization, and Trauma, Burn, Critical Care, increased costs compared with sensitive strains. Carbapenems possess high potency against a Emergency Surgery broad spectrum of organisms and are regarded as the agents of choice for serious infections with Associate Chair of Surgery for extended-spectrum β-lactamase–producing organisms. However, increased prevalence of pan- Critical Care resistant P. aeruginosa and A. baumannii strains worldwide has limited the utility even of the car- Department of Surgery bapenems. To reduce the likelihood of emergence of resistance, clinical practice guidelines have Director, Surgical Critical Care been developed to direct antimicrobial treatment of nosocomial infections. Initial empiric therapy University of Michigan Health System should offer broad-spectrum coverage of Gram-negative pathogens, and therapy should be tai- Ann Arbor, Michigan lored and de-escalated after positive culture results are obtained. Although the polymyxins have been reintroduced, particularly as a last-line treatment of MDR Gram-negative pathogens, hetero- Robert C. Owens, Jr, PharmD resistance to these agents has already been documented, highlighting the need for more appro- Co-Director, Antimicrobial priate use of antimicrobials to minimize suboptimal outcomes. Stewardship Program Doripenem, a novel, broad-spectrum carbapenem, offers impressive in vitro activity and clinical Clinical Pharmacy Specialist, efficacy against P. aeruginosa and A. baumannii (including many MDR strains). Doripenem is Infectious Diseases well tolerated and its effects on the central nervous system are negligible. This special report pro- Department of Pharmacy Services files the properties of the carbapenem class, emphasizes key principles of clinical practice guide- and Division of Infectious Diseases lines for antimicrobial treatment selection and use, and reviews doripenem, the pending addition Maine Medical Center to the carbapenem class. Portland, Maine Clinical Assistant Professor LEARNING OBJECTIVES After reviewing this supplement, participants should be able to: Department of Medicine 1 Discuss the impact of resistant Gram-negative organisms on outcomes and management University of Vermont‚ College strategies in critically ill patients with pneumonia and intra-abdominal infections. of Medicine 2 Choose appropriate guideline-based treatments for infections caused by resistant Gram- Burlington‚ Vermont negative pathogens in critically ill patients. John P. Quinn, MD, FACP 3 Review features of available carbapenem agents. Professor of Medicine 4 Evaluate the utility of new agents to combat infections resulting from P. aeruginosa and Rush University A. baumannii. Stroger Hospital of Cook County 5 Weigh the benefits and risks of each carbapenem-based treatment in managing infections in Scientific Director the intensive care unit. Chicago Infectious Disease Research Institute TARGET AUDIENCE This activity has been developed for critical care physicians and surgical Chicago, Illinois critical care physicians. Andrew F. Shorr, MD, MPH ACCREDITATION University of Kentucky College of Medicine Associate Director, Pulmonary and This activity has been planned and implemented in accordance with the Essential Areas and poli- Critical Care Medicine cies of the Accreditation Council for Continuing Medical Education through the joint sponsorship Associate Professor of Medicine of the University of Kentucky College of Medicine and Rxperience. The University of Kentucky Washington Hospital Center College of Medicine is accredited by the ACCME to provide continuing medical education for Washington, DC physicians. 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 commensurate with the extent of their participation in the activity. The University of Kentucky College of Medicine presents this activity for educational purposes only. Participants are expected to utilize their own expertise and judgment while engaged in the practice of medicine. The content of the presentation is provided solely by presenters who have been selected for presentations because of recognized expertise in their field.

Supported by an educational grant Jointly sponsored by the Distribution via: from Ortho-McNeil, Inc. University of Kentucky College of Medicine and Rxperience.

INFECTIOUS DISEASE SPECIAL EDITION FACULTY AND SPONSOR DISCLOSURE All faculty members participating in continuing medical education programs sponsored by the University of Kentucky Colleges of Pharmacy and Medicine Continuing Education Office are expected to disclose any real or perceived 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 accepted consultant 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 has accepted 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 the speakers’ 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.

Introduction to Carbapenem Agents class include doripenem, ertapenem, faropenem, imipenem, meropenem, and panipenem/betamipron.10 The molecular Gram-negative pathogens belonging to the Pseudomonas structures of doripenem, ertapenem, imipenem, and meropen- and Acinetobacter species are prevalent and important caus- em are depicted in Figure 1. es of nosocomial infections among critically ill patients. The first carbapenem that was developed, imipenem, is Acquired mechanisms of resistance that exhibit multiple, active against a broad spectrum of pathogens. Imipenem is diverse actions have caused some strains of these pathogens coadministered with cilastatin—an inhibitor of human renal to be much more difficult to treat.1,2 The continuing increase in dehydropeptidase I—because imipenem is hydrolyzed by this antimicrobial resistance across US hospitals remains a major enzyme.10 Imipenem is indicated for hospitalized patients with concern for patients, clinicians, and public health officials.3 intra-abdominal infections (IAIs), lower respiratory tract infec- Outbreaks of nosocomial infection caused by Gram-nega- tions, gynecologic and genitourinary tract infections, skin and tive pathogens are not isolated, regional occurrences but soft tissue infections (SSTIs), sepsis, and endocarditis. Imipen- rather worldwide events and have most recently reached pro- em is considered an appropriate empirical treatment when portions of a global health issue.4 Based on in vitro and clinical there is a high likelihood of infection with resistant pathogens data, carbapenems have been and continue to be the agents or multiple organisms, including aerobes and anaerobes. The of choice for serious infections with extended-spectrum β-lacta- plasma half-life of imipenem is approximately 1 hour, and it is mase (ESBL)–producing organisms.5 However, resistance to β- 10% to 20% protein bound. The most common adverse effects lactam antimicrobials, including carbapenems, is increasing of imipenem include phlebitis, thrombophlebitis, nausea, diar- among strains of Pseudomonas aeruginosa and Acinetobac- rhea, and vomiting. This agent is not indicated for central ner- ter baumannii, leaving clinicians with a dearth of viable thera- vous system (CNS) infections because of its proconvulsive peutic options to treat nosocomially acquired Gram-negative activity.13 infections. Interestingly, the polymyxins have been resurrected Meropenem is a carbapenem that has activity against Gram- as last-resort treatments for patients infected with multidrug- negative, Gram-positive, and anaerobic microorganisms. As is resistant (MDR) pathogens.1 However, increased use of imipenem, meropenem is highly resistant to hydrolysis by most polymyxins will likely lead to emergence of resistance, thus of the serine-based β-lactamases produced by Gram-negative underscoring the immediate need for recognition of the key bacteria. Meropenem is effective for the treatment of serious risk factors for MDR acquisition; more responsible antimicro- infections, including those acquired in the hospital or intensive bial treatment selection and use; adherence to clinical practice care unit (ICU). Meropenem penetrates rapidly and widely into guidelines for initial empiric therapy and de-escalation; and a range of body fluids and tissues, including cerebrospinal greater awareness and appreciation of the use of novel antimi- fluid, and its half-life is approximately 1 hour. The most com- crobials for critically ill patients with nosocomial infections.1,6-9 mon side effects associated with meropenem include diarrhea, rash, nausea, vomiting, and injection-site inflammation. Overview of the Carbapenems Meropenem is well tolerated by the CNS in doses of 2 g every β-lactam antimicrobials comprise more than 50% of all 8 hours, even in patients with bacterial meningitis.14 antimicrobial therapies, and their efficacy and tolerability make Ertapenem is a carbapenem that shares the activity of them the most commonly prescribed antibiotic agents. The imipenem and meropenem against most species; however, it carbapenems represent one of the many antimicrobial groups lacks significant activity against nonfermenters (ie, Gram-nega- in this category.10 Carbapenems demonstrate excellent in vitro tive rods, including Pseudomonas and Acinetobacter) and thus activity because of their efficient penetration into bacteria, sta- has a limited role in nosocomial infection. Ertapenem has a bility to hydrolysis by nearly all clinically important serine β-lac- long plasma half-life (~4 hours) that allows for once-daily dos- tamases, and high affinity for essential penicillin-binding ing. Findings from clinical trials demonstrate equivalence with proteins (PBPs) of Gram-negative bacteria. These agents pos- comparators for treatment of moderate to severe IAIs, pelvic sess a broad spectrum of antimicrobial activity, exceeding that infections, SSTIs, mild to moderate intra-abdominal sepsis, com- of most other antimicrobial classes. Agents in the carbapenem munity-acquired pneumonia (CAP), and complicated urinary

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Doripenem Ertapenem HO CH3 CO2H O O O 7 1 6 2 H N 5 4 S HO S S N 3 H N NH O CO2Na H H 2 N H CO2Na N H3C H H NH H •H2O H CH3 O Imipenem Meropenem NH OH CH3 OH H H CH3 CON H H NHCH CH S CH3 3 H3C •H O H S H N 2 N NH O O COOH COOH

FIGURE 1. MOLECULAR STRUCTURE OF SELECT CARBAPENEMS

Adapted from references 11-14. tract infections (UTIs). Side effects include diarrhea, nausea, on the management of adults with hospital-acquired pneumonia headache, and infusion-site reaction. Lastly, the risk of seizure (HAP), ventilator-associated pneumonia (VAP), and healthcare- is small, although definite.12 associated pneumonia (HCAP). These guidelines recommend prompt, empiric, and broad-spectrum therapy for patients with HAP who are at risk for MDR pathogens. Broad-spectrum Clinical Practice Guidelines for empiric antimicrobial therapy should be accompanied by a de- Selection of Antimicrobial Therapy escalation commitment based on serial clinical and microbiologic data. In addition, there is minimal support for combination HAP Guidelines therapy in managing infection with P. aeruginosa, and carbapenems should be used at optimal doses to prevent emer- The American Thoracic Society (ATS) and the Infectious Dis- gence of resistance in Acinetobacter. Figure 2 summarizes the eases Society of America (IDSA) offer joint guidelines (2005) initial treatment strategies based on clinical responses of a

HAP, VAP, or HCAP suspected

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

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)

Clinical improvement at 48-72 hours No Yes

Cultures – Cultures + Cultures – Cultures +

Search for other pathogens, Adjust antibiotic therapy; Consider De-escalate antibiotics, complications, other search for other pathogens, stopping if possible. Treat selected diagnoses, or other site complications, other diagnoses, antibiotics patients for 7-8 days of infection or other sites of infection and reassess

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

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

No Yes

Limited-spectrum Broad-spectrum antibiotic antibiotic therapy (Table 1) therapy for MDR pathogens (Table 2)

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 Adapted from reference 15.

patient with suspected HAP, VAP, or HCAP. Figure 3 provides a pies for late-onset disease, risk factors, or MDR pathogens.15 treatment algorithm to guide clinicians in the initiation of antimi- Other key principles discussed in the ATS/IDSA guidelines crobial therapy. for management of HAP, VAP, and HCAP include the following: Antimicrobial selection should be based on risk factors for • Early, appropriate, broad-spectrum antimicrobial therapy MDR pathogens, such as antimicrobial therapy within the past should be initiated with adequate dosing to optimize antimi- 90 days, time of current hospitalization, frequency of resistance crobial therapy. in the hospital or community, risk factors for HCAP (eg, resi- • An empiric therapy regimen should include agents from dence in nursing home, home infusion therapy), and immuno- antibiotic classes different from those the patient has suppressive disease or therapy. Table 1 provides guidance on recently received. the recommended initial empiric antimicrobial for HAP or VAP • Combination therapy for a specific pathogen should be patients without known risk factors for MDR pathogens (early used judiciously for treatment of HAP. onset and any disease severity).15 It is important to note that other antibiotics are also indicated for treatment of HAP, in TABLE 2. INITIAL EMPIRIC THERAPY FOR addition to those stated in the guidelines. Table 2 summarizes LATE-ONSET DISEASE, RISK FACTORS, the recommended, initial, broad-spectrum combination thera- OR MDR PATHOGENS Potential Pathogens Initial, Broad-Spectrum, TABLE 1. INITIAL EMPIRIC THERAPY IN PATIENTS Combination Antibiotic Therapy WITHOUT RISK FACTORS FOR MDR PATHOGENS Pathogens listed in Table 1 and Antipseudomonal cephalosporin Potential Pathogens Recommended Antibiotic MDR pathogens or Pseudomonas aeruginosa Streptococcus pneumoniae* Ceftriaxone Antipseudomonal carbapenem Klebsiella pneumoniae or Haemophilus influenzae or (ESBL+)* β-lactam/β-lactamase inhibitor Methicillin-sensitive Levofloxacin, moxifloxacin, or Acinetobacter species* plus Staphylococcus aureus ciprofloxacin Antipseudomonal fluoroquinolone* Antibiotic-sensitive enteric or Methicillin-resistant or Gram-negative bacilli Ampicillin-sulbactam Escherichia coli Staphylococcus aureus Aminoglycoside or Klebsiella pneumoniae Legionella pneumophila* Linezolid or vancomycin† Enterobacter species Ertapenem Proteus species Serratia marcescens *If an ESBL strain such as K. pneumoniae or an Acinetobacter species is suspected, a carbapenem is a reliable choice. If L. pneumophila is suspected, the combination antibiotic regimen should include a macrolide (eg, *The frequency of penicillin-resistant S. pneumoniae and MDR S. pneumoniae azithromycin), or a fluoroquinolone (eg, ciprofloxacin or levofloxacin) should be is increasing. Levofloxacin or moxifloxacin is preferred to ciprofloxacin, and the used rather than an aminoglycoside. role of other new quinolones, such as gatifloxacin, has not been established. †If MRSA risk factors are present or there is a high incidence locally. MDR, multidrug-resistant ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant Adapted from reference 15. Adapted from reference 15. 4 Why wait? Access this program and post-test @ CMEZone.com

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

Mild to Moderate Infections Lower-Risk Patients Single-Agent Regimen • Ampicillin/sulbactam* • Cefotetan • Ampicillin/sulbactam* • Ticarcillin/clavulanic acid • Cefoxitin • Imipenem/cilastatin • Ertapenem • Ertapenem • Piperacillin/tazobactam • Meropenem • Ticarcillin/clavulanate

Combination Regimen • Cefazolin or cefuroxime + • Ciprofloxacin + metronidazole metronidazole • Aminoglycoside + antianaerobe • Fluoroquinolone-based therapy + • Aztreonam + clindamycin metronidazole† • 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 quinolones has 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.

• De-escalation of antibiotics should be considered based on treatment of cIAIs,9,16 because only these agents have a spec- culture results and clinical response. trum that effectively covers both aerobes and anaerobes.17 • A shorter duration of antibiotic therapy (ie, 7 to 8 days) is Tables 3 and 4 compare IDSA and SIS recommendations with recommended in patients with uncomplicated HAP, VAP, or regard to severity and risk status of patients with cIAIs, respec- HCAP who have received appropriate initial therapy and tively.9,16 demonstrated a good clinical response, with no evidence of infection with nonfermenting Gram-negative bacilli.15 Therapy With Carbapenem Agents IAI/Complicated IAI (cIAI) Guidelines Both the IDSA (2003) and the Surgical Infection Society Clinicians who treat documented resistant Gram-negative (SIS; 2002) have issued guidelines on the management of IAIs. infections must consider the role of monotherapy (eg, car- A cIAI extends beyond the hollow viscus of origin into the peri- bapenems or colistin) and the possibility of combination thera- toneal space and is associated with either abscess formation py, as well as factors related to empiric treatment and or with peritonitis. Antimicrobial therapy should be initiated as de-escalation. The therapies of choice for treatment of infec- soon as a cIAI is suspected. In some instances, a multidrug tions with ESBL-producing organisms include fluoroquinolones regimen (eg, aminoglycoside plus fluoroquinolone or car- (for UTIs), carbapenems (bacteremia, HAP, and IAI), and bapenem plus vancomycin) is recommended. Only carbapen- meropenem (meningitis).15 ems and broad-spectrum penicillins (combined with a Multiple studies highlight the efficacy of carbapenems as β-lactamase inhibitor) are recommended for monotherapy monotherapy for the treatment of ESBL-producing Klebsiella

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

High-Severity Infections Higher-Risk Patients Single-Agent Regimen • Piperacillin/tazobactam • Piperacillin/tazobactam • Imipenem/cilastatin • Imipenem/cilastatin • Meropenem • Meropenem

Combination Regimen • Third/fourth-generation cephalosporin + metronidazole • Ciprofloxacin + metronidazole • Aztreonam + metronidazole • Aminoglycoside + anti-anaerobe • Ciprofloxacin + metronidazole • Aztreonam + clindamycin • Third-/fourth-generation cephalosporin + anti-anaerobe

IDSA, Infectious Diseases Society of America; SIS, Surgical Infection Society Adapted from references 9 and 16. 5 80 77.0% Meropenem 68.1% 67.1% Imipenem-cilastatin 60.3%

40 Patients (%) Patients

67/8762/91 49/73 44/73 0 Clinical Response Rate Bacteriologic Response Rate Diff 8.9%; 95% CI, -4.2–+21.9%; Diff 6.9%; 95% CI, -8.7–+22.4%; P=0.185 P=0.389

FIGURE 4. SATISFACTORY RESPONSE RATES AT END OF TREATMENT

CI, confidence interval Adapted from reference 19.

pneumoniae and Escherichia coli infections. In a prospective, cally ill patients with ICU-acquired infection (primarily VAP and observational study of patients with K. pneumoniae bacteremia bacteremia) characterized by MDR P. aeruginosa and/or A. (455 episodes in 440 patients; 85 episodes caused by ESBL- baumannii. Clinical cure of infection was achieved in 69.8% of producing organisms), use of a carbapenem, mainly imipenem, patients (30/43); 25.6% (11/43) did not respond to treatment, was associated with lower 14-day mortality compared with other and all of these patients died. Deterioration of renal function antimicrobials (OR, 0.173; 95% CI, 0.039-0.755; P=0.012).5 occurred in 18.6% (8/43) of patients.21 Du and colleagues demonstrated lower mortality with In a retrospective chart review of 37 ICU patients with MDR imipenem than with cephalosporins for the treatment of ESBL- A. baumannii, clinical cure was observed in 22 of 29 (76%) of producing E. coli or K. pneumoniae bloodstream infection. patients treated with polymyxin B. Crude mortality was 27% ESBLs were produced by 27% of isolates. Patients treated with (9/33), with 3 deaths attributed to polymyxin B treatment fail- imipenem were more likely to survive, whereas those receiving ure. Nephrotoxicity was observed in 21% and neurotoxicity in cephalosporin treatment tended to have poorer outcomes 6% of patients treated with polymyxin B. Generalizability of find- (1/19 vs 14/40; P=0.023). In addition, compared with ings may be limited by the relatively young age of patients in monotherapy, combination therapy neither resulted in treat- this study, as well as by the large number of trauma patients ment success nor improved patient outcome.18 with few comorbidities.22 In a multicenter, open-label, randomized, parallel-group trial, Colistin was also evaluated by Reina and colleagues in a the Belgian Multicenter Study Group compared the efficacy prospective cohort study of 185 patients infected with A. bau- and tolerability of meropenem and imipenem/cilastatin (both mannii and P. aeruginosa after an ICU stay of more than 48 1 g/8 h intravenously) as empirical monotherapy in 212 ICU hours. Fifty-five patients were treated with colistin. Of 130 patients (n=107 meropenem; n=105 imipenem/cilastatin) with patients in the noncolistin group, 81% were treated with car- serious bacterial infections, including lower respiratory tract bapenems. There were no differences between groups in the infection in ventilated patients, IAI, and sepsis. Predominant frequency of clinical cure on day 6 of treatment (15% vs 17%) or pathogens included E. coli, Enterobacter species, and P. number alive at discharge (71% vs 74%). Overall, outcomes with aeruginosa.19 Both treatments demonstrated similar satisfacto- colistin were the same as outcomes for carbapenems, and ry clinical and bacteriologic response rates, as illustrated in mean creatinine levels remained normal throughout treatment.23 Figure 4.19 A recent review of 5 studies of treatment with I.V. colistin of There has been renewed interest in the use of polymyxins as VAP resulting from P. aeruginosa or A. baumannii reported alternative treatments for critically ill patients infected with clinical cure rates ranging from 25% to 62%, despite high strains of A. baumannii, P. aeruginosa, and K. pneumoniae that severity of illness at baseline. De novo nephrotoxicity rates are resistant to almost all available antimicrobials. Polymyxins ranged from 8% to 36%, despite close attention to appropriate are a group of polypeptide cationic antimicrobials that include dosing and duration of treatment. Neurotoxicity was reported colistin (polymyxin E) and polymyxin B. Both of these agents in only 1 patient across the 5 studies, and this was the only were discovered in the 1940s and were widely used parenter- patient for whom colistin treatment was discontinued in these ally for approximately 20 years. They fell out of use after reports studies.24 of neurologic and renal adverse effects. Currently, these med- Now that colistin has re-emerged as acceptable therapy for ications are viewed as last-resort agents in patients infected MDR A. baumannii infections, its use has increased worldwide with MDR pathogens.20 and heteroresistance has since been recorded. Recently, a A retrospective case series study by Michalopoulos and col- team of investigators became the first to report heteroresis- leagues examined the efficacy and safety of colistin in 43 criti- tance to colistin in clinical isolates of A. baumannii obtained 6 Why wait? Access this program and post-test @ CMEZone.com

TABLE 5. DORIPENEM IN VITRO ACTIVITY VERSUS OTHER CARBAPENEMS Activity Against P. aeruginosa; Against Acinetobacter species; Carbapenem MIC90, µg/mL MIC90, µg/mL

Doripenem 8 4

Meropenem 16 8

Ertapenem >8 >8.

Imipenem >8 2

Adapted from reference 25. from an Australian hospital (14 from patients admitted to the Doripenem and meropenem were most active among all β- ICU) that were apparently susceptible to colistin based on lactams against P. aeruginosa, and doripenem and imipenem MICs. Population analysis profiles demonstrated that het- were most active against Acinetobacter species.25 eroresistance to colistin occurred in 15 of the 16 A. bauman- In another in vitro study by Jones and colleagues, only nii clinical isolates; most clinical isolates grew in the presence doripenem (75.8% inhibited at ≤4 µg/mL), imipenem, and of 3 to 10 µg/mL of colistin. These findings send a clear mes- meropenem demonstrated activity against wild-type A. bau- sage to clinicians: If colistin is used inappropriately, rapid mannii isolates. Doripenem and imipenem were the most development of resistance and treatment failures may eventu- potent agents (MIC50, 0.5 µg/mL) and inhibited strains at ally follow.7 potentially achievable breakpoint concentrations. Moreover, doripenem was 2- and 4-fold more potent than meropenem and imipenem against P. aeruginosa, respectively.11 Doripenem: Safety, Efficacy, and Comparative Data Doripenem: Reducing/Preventing Emergence of Resistance Doripenem is a novel, broad-spectrum parenteral carba- Use of doripenem may reduce emergence of resistant penem. Doripenem’s molecular structure (see Figure 1 on pathogens, as evidenced in a number of studies. Sakyo and page 3) confers β-lactamase stability and resistance to inacti- colleagues examined the potency of doripenem, meropenem, vation by renal dehydropeptidases. This new addition to the and imipenem in preventing the emergence of carbapenem- carbapenem class has demonstrated impressive in vitro activi- resistant P. aeruginosa mutants. In total, 140 P. aeruginosa iso- ty against P. aeruginosa and A. baumannii isolates, including lates were investigated for carbapenem resistance. The many MDR strains. In vitro studies have established the unique isolation frequency of each mutant was examined at concen- characteristics of doripenem, including a spectrum and poten- trations of one half or one quarter MIC of each carbapenem cy against Gram-negative cocci similar to that of imipenem and for that mutant. Mutants were not selected on agar containing activity against Gram-negative bacteria similar to that of mero- doripenem at more than 10–9 per cell per generation; howev- penem. One key feature of doripenem, attributed to the side er, mutants were selected on agar containing meropenem or chain at position 2, is greater activity against MDR, nonfermenta- imipenem at frequencies of approximately 10–9 to 10–7. These tive, Gram-negative bacilli. Furthermore, as does meropenem, data indicate that of all the carbapenems, doripenem exhibit- doripenem exhibits favorable pharmacokinetic, pharmaco- ed the lowest drug concentration and the narrowest range of dynamic, and toxicologic features.25 As do other carbapenems, drug concentration for selection of carbapenem-resistant doripenem remains vulnerable to class B enzymes, also known mutants, and doripenem therefore had the greatest ability to as metallo-β-lactamases, which represent significant threats to prevent the emergence of mutants.27 treatment by all β-lactams.26 β-lactams used in combination with aminoglycosides may Doripenem possesses high affinity for PBP targets that are provide synergistic activity against Gram-negative pathogens. species-specific. Doripenem has low serum protein binding In an in vitro study, doripenem was tested in combination with (8% to 9%), a half-life of approximately 1 hour, and endotoxin gentamicin to determine resistance selection during subin- release comparable with that of other carbapenems. This hibitory passaging using P. aeruginosa isolates with elevated agent has synergy with glycopeptides when tested against MIC values (n=6). Doripenem MIC values increased 2- to 8- oxacillin-resistant S. aureus, and it has documented success fold and higher in 4 isolates, whereas 2 strains maintained the within in vivo animal models and in clinical trials.11 baseline doripenem MIC. When doripenem plus gentamicin was tested, 3 strains maintained the original doripenem MIC In Vitro Activity values, 2 strains had a 2-fold increase, and only 1 strain In a global surveillance report, Fritsche and colleagues showed a 4-fold increase in doripenem MIC values. Thus, the evaluated the antimicrobial activity results of doripenem and combination of doripenem plus an aminoglycoside may be an comparator agents against 16,008 Gram-positive and Gram- effective treatment of infections caused by P. aeruginosa with negative isolates, including 829 P. aeruginosa and 155 Acine- elevated carbapenem MIC values, with lower risk of selecting tobacter species isolates. Nonduplicate, consecutive clinical further resistance.28 isolates were collected from more than 70 medical centers Mushtaq and colleagues evaluated in vitro resistance selec- worldwide and were either community- or nosocomially tion potential of antimicrobial agents versus characterized iso- acquired.25 Of all the carbapenems, doripenem was shown to lates, mutants, and transconjugants of P. aeruginosa. be the most active agent (Table 5). Doripenem was also asso- Doripenem MICs were lower than meropenem for strains with ciated with the lowest rate of spontaneous resistance among elevated intrinsic resistance. Furthermore, mutant selection the antipseudomonal agents tested, including other car- (single step) with doripenem occurred with fewer strains than bapenems . with other agents. The final multiple of the MIC achieved was 7 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)

Infection Process (%) Generalized peritonitis 76 (46.9) 81 (52.9)

Localized infection 46 (28.4) 30 (19.6)

Single abscess 33 (20.4) 36 (23.5)

Multiple abscess 5 (3.1) 4 (2.6)

Postoperative infection 10 (6.2) 12 (7.8)

IAI, intra-abdominal infection; ME, microbiologically evaluable; TOC, test of cure Adapted from reference 30.

lower for doripenem than for other agents and never exceeded Likewise, extending infusion time may confer advantages in 4 times the starting MIC. Other carbapenems selected mutants treatment with carbapenems. In healthy volunteers, a 2-hour from among more test strains.29 infusion of imipenem resulted in serum concentrations exceeding organism MIC for extended time periods, Doripenem Clinical Efficacy compared with a half-hour infusion.32 The advantages of At the 2006 Annual Interscience Conference on Antimicro- prolonged infusion with meropenem were demonstrated in an bial Agents and Chemotherapy (ICAAC) meeting, Malafaia in vitro hollow-fiber infection model by Tam and colleagues. In and colleagues presented findings from a large, randomized, this study, selective amplification of resistant subpopulations double-dummy, multicenter Phase III trial comparing the effi- of P. aeruginosa was reduced with extended meropenem cacy and safety of doripenem (500 mg I.V. infusion every 8 infusion.33 hours over 60 minutes) versus meropenem (1 g I.V. bolus Adverse CNS effects, particularly the lower seizure thresh- every 8 hours over 3-5 minutes) for treatment of adult patients old, of β-lactam antimicrobials are well known, although the (n=486) with cIAIs.30 Patients could be switched to oral amox- data on seizure activity are somewhat inconclusive. In the lit- icillin-clavulanate after 9 or more doses of doripenem or erature, imipenem has been associated with a 3% incidence meropenem. Table 6 summarizes patient characteristics of of seizures. The mechanism of seizure action of imipenem is the microbiologically evaluable population at test-of-cure multifactorial and believed to be related to the agent’s ability (TOC) analysis. The total duration of study therapy was 5 to to reduce inhibition of epileptic discharges by blocking γ- 14 days. The primary end point was clinical response at the aminobutyric acid (GABA)-A receptor, to its action on TOC visit 21 to 60 days post-therapy. Figure 5 illustrates the α–amino-3-hydroxy-5-methyl-isoxazoleproprionate (AMPA) clinical cure rate for both agents at the TOC visit for the micro- and N-methyl-D-aspartate (NDMA) receptor complexes, or biologically evaluable population. Doripenem was noninferior possibly to its penicillin-like activity.34 to meropenem for the treatment of cIAI. Also illustrated in Fig- Wong and colleagues evaluated the efficacy and safety of ure 5 are the clinical cures for the microbiologic modified combination imipenem/cilastatin in 21 young children with intent-to-treat population. In this study, doripenem was effec- bacterial meningitis. The study was terminated when 7 tive against major causative organisms (E. coli, K. pneumoni- patients (33%) developed seizure activity after antibiotic ther- ae, P. aeruginosa, S. intermedius, Bacteroides caccae, B. apy was given, leading investigators to conclude that the util- thetaiotaomicron, B. fragilis, and B. uniformis) and was gen- ity of imipenem/cilastatin for bacterial meningitis in children erally well tolerated. Nausea occurred in 3.7% and 2.6% in the may be limited by a possible increased incidence of drug- doripenem and meropenem groups, respectively, and diar- related seizure activity.35 rhea occurred in 2.5% and 3.0% in each group, respectively. Observations from 1,754 patients treated with imipenem/ cilastatin in Phase III dose-ranging studies in the United States demonstrated that 52 patients (3%) had seizures, of which 16 Optimizing Treatment With (0.9%) were considered to be associated with imipenem. Of the Carbapenems 1,754 patients, 946 (54%) were treated with 2 g of imipenem/ cilastin per day for serious infections. The majority of seizure For β-lactams, the best predictor of bacterial killing is the types were generalized tonic-clonic (n=37), with the rest divided time during which drug concentration exceeds the MIC of the between focal seizures and myoclonus. Imipenem dosages in organism. Lodise and colleagues evaluated an extended-infu- excess of manufacturer recommendations were associated with sion dosing scheme for piperacillin-tazobactam therapy, using increased risk of seizures.36 A possible clinical concern is that a Monte Carlo simulation, to improve clinical outcomes in criti- physicians may use suboptimal doses in an effort to avoid pos- cally ill patients with P. aeruginosa infections. Among patients sible seizures with imipenem, thereby complicating overall treat- with APACHE-II scores of 17 or greater, the 14-day mortality rate ment outcomes. was significantly lower among patients who received extended- A medical chart review of 75 patients receiving imipenem in infusion therapy (4 hours) than among patients who received a municipal hospital during a 6-month interval was conducted intermittent-infusion therapy (30 minutes), and the median by Koppel and colleagues. Findings from this study demon- duration of hospital stay was significantly shorter.31 strated that imipenem use is safe and is not associated with 8 Why wait? Access this program and post-test @ CMEZone.com

100 Doripenem 90 83.3% 83.0% Meropenem 80 74.5% 75.7% 70

40 Clinical Cure (%) 30

10 135/162127/153 149/200 140/185 0 Microbiologically Evaluable Microbiological Modified ITT 95% CI, -8.6 –+9.2 95% CI, -10.3 –+8.0

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

CI, confidence interval; cIAI, complicated intra-abdominal infection; ITT, intent to treat Adapted from reference 30. increased risk of seizure. Of the 75 charts reviewed, only 4 Summary patients had seizures during imipenem treatment and 8 patients had seizures before or after imipenem use. Although The carbapenem class of antimicrobials is characterized by the incidence of seizure was greater among critically ill excellent in vitro activity and broad-spectrum antimicrobial activ- patients, it did not differ with use of imipenem. Determining ity. These agents are considered to be the therapy of choice for the proper dose of imipenem at initiation of therapy and infection with ESBL-producing pathogens. Doripenem repre- avoiding dosing at more than 2 g per day appears to mitigate sents a novel, broad-spectrum carbapenem with impressive non- the risk for seizures related to imipenem.34 clinical activity and documented success in clinical trials. The In an animal model study, doripenem showed no convul- unique characteristics of doripenem, including greater activity sive activity when administered via I.V. or intracerebroventric- against Gram-negative MDR pathogens and a favorable toxicol- ular route. Furthermore, this agent did not potentiate seizures ogy profile, offer clinicians a practical treatment to combat these in the pentylenetetrazol (PTZ)-induced convulsive model, had pathogens in critically ill patients. Use of polymyxins has resur- a low affinity for GABA receptors compared with other β-lac- faced for those patients infected with A. baumannii, P. aerugi- tams, did not induce seizure discharges when used concomi- nosa, or other isolates that are resistant to virtually all available tantly with valproic acid in the PTZ- or bicuculine-induced antimicrobial agents. However, heteroresistance to colistin has seizure model, and caused no changes in electroencephalo- recently been documented; thus, overuse or misuse of these gram (EEG) or behavior in any animal studied. These findings agents can rapidly lead to development of resistance and nega- suggest that doripenem neurotoxicity may be negligible in tive outcomes. Adherence to clinical practice guidelines for the clinical use settings. Conversely, imipenem produced seizure treatment of nosocomially acquired Gram-negative pathogens discharges on EEG and/or convulsive activity in rats, mice, ensures appropriate antimicrobial selection and judicious use of and dogs; and meropenem caused shaking behavior in rats available agents for MDR pathogens, and can reduce emer- and spikes or seizure discharges in dogs.37 gence of resistance.

References 1. Landman D, Bratu S, Alam M, Quale J. Citywide emergence of Pseudomonas ety of America and Society for Healthcare Epidemiology of America. Infec- aeruginosa strains with reduced susceptibility to polymyxin B. J Antimicrob tious Diseases Society of America and the Society for Healthcare Epidemiol- Chemother. 2005;55:954-957. ogy of America guidelines for developing an institutional program to enhance 2. Fournier PE, Vallenet D, Barbe V, et al. Comparative genomics in multidrug antimicrobial stewardship. Clin Infect Dis. 2007;44:159-177. resistance in Acinetobacter baumannii. PLoS Genet. 2006;2:e7. 7. Li J, Rayner CR, Nation RL, et al. Heteroresistance to colistin in multidrug- 3. National Nosocomial Infections Surveillance System. National Nosocomial resistant Acinetobacter baumannii. Antimicrob Agents Chemother. Infections Surveillance (NNIS) System Report, data summary from January 2006;50:2946-2950. 1992 through June 2004, issued October 2004. Am J Infect Control. 8. Dodek P, Keenan S, Cook D, et al, and the Canadian Critical Care Society. Evi- 2004;32:470-485. dence-based clinical practice guideline for the prevention of ventilator-associ- 4. Garnacho-Montero J, Ortiz-Leyba C, Fernandez-Hinojosa E, et al. Acinetobac- ated pneumonia. Ann Intern Med. 2004;141:305-313. ter baumannii ventilator-associated pneumonia: epidemiological and clinical 9. Solomkin JS, Mazuski JE, Baron EJ, et al, and the Infectious Diseases Soci- findings. Intensive Care Med. 2005;31:649-655. ety of America. Guidelines for the selection of anti-infective agents for compli- 5. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical cated intra-abdominal infections. Clin Infect Dis. 2003;37:997-1005. update. Clin Microbiol Rev. 2005;18:657-686. 10. Bonfiglio G, Russo G, Nicoletti G. Recent developments in carbapenems. 6. Dellit TH, Owens RC, McGowan JE Jr, et al, and the Infectious Diseases Soci- Expert Opin Investig Drugs. 2002;11:529-544. 9 11. Jones RN, Huynh HK, Biedenbach DJ, Fritsche TR, Sader HS. Doripenem (S- 26. Jones RN, Sader HS, Fritsche TR. Comparative activity of doripenem and 4661), a novel carbapenem: comparative activity against contemporary three other carbapenems tested against Gram-negative bacilli with various pathogens including bactericidal action and preliminary in vitro methods eval- beta-lactamase resistance mechanisms. Diagn Microbiol Infect Dis. uations. J Antimicrob Chemother. 2004;54:144-154. 2005;52:71-74. 12. Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem. 27. Sakyo S, Tomita H, Tanimoto K, Fujimoto S, Ike Y. Potency of carbapenems J Antimicrob Chemother. 2003;52:331-344. for the prevention of carbapenem-resistant mutants of Pseudomonas aerugi- 13. Rodloff AC, Goldstein EJ, Torres A. Two decades of imipenem therapy. J nosa: the high potency of a new carbapenem doripenem. J Antibiot (Tokyo). Antimicrob Chemother. 2006;58:916-929. 2006;59:220-228. 14. Hurst M, Lamb HM. Meropenem: a review of its use in patients in intensive 28. Huynh HK, Biedenbach DJ, Jones RN. Delayed resistance selection for care. Drugs. 2000;59:653-680. doripenem when passaging Pseudomonas aeruginosa isolates with doripenem plus an aminoglycoside. Diagn Microbiol Infect Dis. 2006;55:241-243. 15. American Thoracic Society; Infectious Diseases Society of America. Guide- lines for the management of adults with hospital-acquired, ventilator-associat- 29. Mushtaq S, Ge Y, Livermore DM. Doripenem versus Pseudomonas aerugi- ed, and healthcare-associated pneumonia. Am J Respir Crit Care Med. nosa in vitro: activity against characterized isolates, mutants, and transconju- 2005;171:388-416. gants and resistance selection potential. Antimicrob Agents Chemother. 2004;48:3086-3092. 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- 30. Malafaia O, Umeh O, Jiang J. Doripenem versus meropenem for the treat- lines on antimicrobial therapy for intra-abdominal infections: evidence for the ment of complicated intra-abdominal infections. Poster presented at: 46th recommendations. Surg Infect (Larchmt). 2002;3:175-233. Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 27-30, 2006; San Francisco, Calif. Poster L-1564b. 17. Tellado JM, Wilson SE. Empiric treatment of nosocomial intra-abdominal infections: a focus on the carbapenems. Surg Infect (Larchmt). 2005;6:329-343. 31. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infu- 18. Du B, Long Y, Liu H, et al. Extended-spectrum beta-lactamase-producing sion dosing strategy. Clin Infect Dis. 2007;44:357-363. Escherichia coli and Klebsiella pneumoniae bloodstream infection: risk factors and clinical outcome. Intensive Care Med. 2002;28:1718-1723. 32. Jaruratanasirikul S, Raungsri N, Punyo J, Sriwiriyajan S. Pharmacokinetics of imipenem in healthy volunteers following administration by 2 h or 0.5 h infu- 19. Verwaest C, on behalf of the Belgian Multicenter Study Group. Meropenem sion. J Antimicrob Chemother. 2005;56:1163-1165. versus imipenem/cilastatin as empirical monotherapy for serious bacterial infections in the intensive care unit. Clin Microbiol Infect. 2000;6:294-302. 33. Tam VH, Schilling AN, Neshat S, Poole K, Melnick DA, Coyle EA. Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resis- 20. Falagas ME, Kasiakou SK, Tsiodras S, Michalopoulos A. The use of intra- tance of Pseudomonas aeruginosa. Antimicrob Agents Chemother. venous and aerosolized polymyxins for the treatment of infections in critically 2005;49:4920-4927. ill patients: a review of the recent literature. Clin Med Res. 2006;4:138-146. 34. Koppel BS, Hauser WA, Politis C, van Duin D, Daras M. Seizures in the criti- 21. Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S, Falagas ME. Col- cally ill: the role of imipenem. Epilepsia. 2001;42:1590-1593. istin treatment in patients with ICU-acquired infections caused by multiresis- tant gram-negative bacteria: the renaissance of an old antibiotic. Clin 35. Wong VK, Wright HT Jr, Ross LA, Mason WH, Inderlied CB, Kim KS. Imipen- Microbiol Infect. 2005;11:115-121. em/cilastatin treatment of bacterial meningitis in children. Pediatr Infect Dis J. 1991;10:122-125. 22. Holloway KP, Rouphael NG, Wells JB, King MD, Blumberg HM. Polymyxin B and doxycycline use in patients with multidrug-resistant Acinetobacter baumannii 36. Calandra G, Lydick E, Carrigan J, Weiss L, Guess H. Factors predisposing to infections in the intensive care unit. Ann Pharmacother. 2006;40:1939-1945. seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin. Am J Med. 1988;84:911-918. 23. Reina R, Estenssoro E, Sáenz G, et al. Safety and efficacy of colistin in Acine- tobacter and Pseudomonas infections: a prospective cohort study. Intensive 37. Horiuchi M, Kimura M, Tokumura M, Hasebe N, Arai T, Abe K. Absence of Care Med. 2005;31:1058-1065. convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics. Toxicology. 2006;222:114-124. 24. Linden PK, Paterson DL. Parenteral and inhaled colistin for treatment of ventilator-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.

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

1. β-lactam antimicrobials, the most commonly 3. In an animal model study, which agent(s) caused NO prescribed antimicrobial agents because of their seizure discharges or shaking behavior in rats, mice, efficacy and tolerability, comprise _____. or dogs? a. 10% to 25% of all antimicrobial therapies a. Meropenem and doripenem b. <15% of all antimicrobial therapies b. Meropenem and imipenem c. >50% of all antimicrobial therapies c. Meropenem only d. >80% of all antimicrobial therapies d. Doripenem only

2. Which of the following statements does not explain 4. In the case of HAP, VAP, or HCAP, when MDR Gram- why carbapenems demonstrate excellent in vitro negative infection is suspected, guidelines recom- activity? mend _____. a. Carbapenems efficiently penetrate bacteria. a. Isolation of patients to prevent the spread of bacteria b. Carbapenems offer narrow-spectrum antimicrobial b. Monotherapy up front with an antimicrobial that targets activity. specific bacteria c. Carbapenems have a high affinity for essential PBPs of c. Empiric therapy with doripenem, followed by imipenem Gram-negative bacteria. d. Empiric therapy with an antipseudomonal carbapenem d. Carbapenems offer stability to hydrolysis by nearly all or β-lactam/β-lactamase inhibitor plus an anti- clinically important serine β-lactamases. pseudomonal fluoroquinolone or an aminoglycoside

10 Why wait? Access this program and post-test @ CMEZone.com

5. For adult patients with HAP, ATS and IDSA bacteriologically efficacious than imipenem/cilastatin recommend _____. for the empirical monotherapy of serious bacterial a. broad-spectrum therapy for patients at risk for MDR infections in ICU patients pathogens b. the clinical response rate of meropenem surpassed the b. combination antimicrobial therapy clinical response rate of imipenem-cilastatin c. aggressive monotherapy treatment that targets c. meropenem was at least as clinically and bacteriologi- P. aeruginosa cally efficacious as imipenem/cilastatin for the d. ceftriaxone/metronidazole for the treatment of mild to empirical monotherapy of serious bacterial infections in moderate infections ICU patients d. imipenem/cilastatin was significantly more efficacious 6. Which of the following statements is true based on than meropenem when used as empirical monotherapy the ATS/IDSA guidelines for the management of HAP? for serious bacterial infections in ICU patients a. Antimicrobial de-escalation should be conducted based solely on the patient’s clinical response. 11. Based on a retrospective chart review of 37 ICU b. An empiric therapy regimen should include agents from patients with MDR A. baumannii who received different antimicrobial classes than the patient has polymyxin B ______. recently received. a. neurotoxicity was more common than nephrotoxicity c. A shorter duration of therapy is pertinent in patients b. generalizability of findings may be limited by older age with complicated HAP who have received initially of patients appropriate therapy and have experienced a good c. crude mortality for these patients was 17% clinical response. d. clinical cure rate for these patients was 76% d. Combination antimicrobial therapy is required in all patients with HAP. 12. In an in vitro study by Jones and colleagues, which of the following demonstrated activity against wild-type 7. Which of the following statements is true based A. baumannii isolates? on the IDSA and SIS guidelines for the management a. Imipenem and meropenem of cIAIs? b. Meropenem and doripenem a. Antimicrobial therapy should commence once cIAI is c. Doripenem confirmed. d. Doripenem, imipenem, and meropenem b. Broad-spectrum penicillins are the only recommended monotherapy for cIAIs because their spectrum of 13. Sakyo and colleagues examined the potency of activity effectively covers aerobes and anaerobes. 3 antimicrobials and their ability to prevent the c. Multidrug regimens are not indicated for the treatment emergence of carbapenem-resistant P. aeruginosa of cIAIs. mutants. Based on their findings, these investigators d. Only carbapenems and broad-spectrum penicillins are determined that ______. recommended monotherapy for the treatment of cIAIs a. doripenem and meropenem had equal ability to prevent since their spectrum of activities effectively cover the emergence of mutants aerobes and anaerobes. b. doripenem had the greatest ability to prevent emergence of mutants 8. Based on SIS guidelines, it is recommended that a c. imipenem had the greatest ability to prevent emergence patient at lower risk for cIAI be treated with ______. of mutants a. ciprofloxacin monotherapy d. meropenem had the greatest ability to prevent b. aztreonam monotherapy emergence of mutants c. meropenem monotherapy d. clindamycin monotherapy 14. Clinically, the efficacy of doripenem for treatment of cIAIs is comparable with that of ______. 9. In a prospective, observational study of patients a. meropenem with K. pneumoniae bacteremia, multivariate b. ertapenem analysis and other predictors of mortality demon- c. faropenem strated that use of a carbapenem during the 5-day d. imipenem period after onset of bacteremia resulting from an ESBL-producing organism was independently 15. In an animal model study evaluating the effects of associated with ______. doripenem on CNS activity, which of the following a. neither treatment success nor improved patient were evident? outcome a. Doripenem, compared with other β-lactams, had a high b. lower mortality affinity for GABA receptors. c. a 30% mortality rate b. Doripenem potentiated seizures in the PTZ-induced d. lower morbidity and mortality convulsive model. c. Doripenem caused no changes in EEG or behavior in 10. The Belgian Multicenter Study Group compared the any animal studied. efficacy and tolerability of meropenem and d. Doripenem demonstrated convulsive activity only in rats. imipenem/cilastatin as empirical monotherapy in 212 ICU patients with serious bacterial infections. Results demonstrated that ______. a. meropenem was significantly more clinically and

11 ✃

ANSWER SHEET & EVALUATION FORM 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

Directions: A score of 70% or higher on the post-test awards physicians up to 1.5 AMA PRA Category 1 Credits™. To claim continuing education credit, individuals must complete the self-study activity, post-test, and evaluation. Please submit your answers only once through one of the methods listed below. Participate online at: or mail to: Attn: Distance Education Test Code: CMEZone.com Continuing Education Office MEN07159-02 Enter “SR07012” in the keyword field. Colleges of Pharmacy and Medicine University of Kentucky One Quality Street, 6th Floor Lexington, KY 40507-1428 or fax to: (859) 323-2920 Must be postmarked by August 31, 2008 Participant Information: (please print) Name: Soc. Sec. No.: Address: City: State: ZIP: Daytime Phone: Fax: E-mail: State of Licensure: License No.: I certify that I completed this activity personally based on the material presented. The actual time I spent on this activity was: Hours: Minutes: Signature: Date:

Post-test Answers: Evaluation: 1. abcd 9. a b c d Ratings: 1=Poor 3=Satisfactory 5=Excellent 2. abcd 10. abcd 1. Extent to which the objectives were achieved: 1 2 3 4 5 3. abcd 11. abcd 2. Potential effect on your practice: 1 2 3 4 5 4. abcd 12. abcd 3. Detail of information presented: 1 2 3 4 5 5. abcd 13. abcd 6. abcd 14. abcd 4. Overall evaluation of this CME activity: 1 2 3 4 5 7. abcd 15. abcd 5. Suggestions for future CME topics: 8. abcd SR07012