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Antibiotics for MDR Pathogens
Case 1
A 53‐year‐old woman with a history of hemodialysis‐dependent end‐stage renal disease presents with left lower extremity pain and redness for the past 3 days. On physical examination, her temperature is 102.3F. Erythema, induration, and warmth are noted over her left lower leg and foot. Her history is remarkable for a line‐related bloodstream infection due to methicillin‐resistant Staphylococcus aureus (MRSA) 4 weeks ago. The infected line was removed and replaced with a right‐sided subclavian catheter. You note that the new line site is clean, not erythematous, and not tender. In the emergency department, the patient receives a dose of vancomycin for presumed MRSA cellulitis. Your patient wants to know if there are alternative agents for her infection so she does not require hospitalization.
Unfortunately, MRSA has become commonplace to the hospital setting. Among intensive care units in 2003, 64.4% of healthcare‐associated Staphylococcus aureus infections were caused by MRSA, compared with only 35.9% in 1992; a 3.1% increase per year.1, 2 Increased MRSA rates are not without consequence; a recent review suggests that MRSA infections kill nearly 19,000 hospitalized American patients annually.3 Of note, MRSA infection rates have also increased among previously healthy individuals. These community‐associated isolates (CA‐MRSA) often manifest as pyogenic skin and soft‐tissue infections (SSTIs). In a recent multicenter study, CA‐MRSA accounted for 59% of SSTIs among patients presenting to emergency rooms in the United States.4 In cases of SSTI, oral agents such as clindamycin, doxycycline, and trimethoprim‐sulfamethoxazole have proven successful. For invasive MRSA, vancomycin is still considered the standard treatment; however, several alternatives have emerged in recent years. The advantages and disadvantages of linezolid, daptomycin, tigecycline, and dalbavancin in the treatment of MRSA are described below.
Linezolid
Linezolid (Zyvox), an oxazolidinone approved in 2000, has been touted for its oral bioavailability, twice‐daily dosing, gram‐positive coverage, and unique mechanism of action. Like several other antimicrobials, linezolid inhibits bacterial protein synthesis. The drug binds to the 50S ribosomal subunit near its site of interaction with the 30S subunit, preventing formation of the 70S initiation complex.5 This site of action on the 50S subunit is unique to linezolid; as a result, cross‐resistance between linezolid and other antimicrobials that act at the 50S subunit (eg, chloramphenicol, macrolides, aminoglycosides, and tetracycline) does not occur.6
The oxazolidinones have excellent bacteriostatic activity against all pathogenic gram‐positive bacteria. The U.S. Food and Drug Administration (FDA) approved linezolid for the treatment of serious infections due to vancomycin‐resistant enterococci (VRE), including bacteremia, complicated skin and soft‐tissue infections (cSSTIs) due to Staphylococcus aureus (including MRSA), and nosocomial pneumonia due to Staphylococcus aureus (including MRSA) or penicillin‐susceptible Streptococcus pneumoniae (Table 1).
| Activity | Agent | FDA‐Approved Indications | Limitations in Use | Side Effects |
|---|---|---|---|---|
| ||||
| Gram‐positive | Daptomycin | cSSTIs; MSSA/MRSA bacteremia; MSSA/MRSA endocarditis | Not indicated for pneumonia (inhibited by pulmonary surfactant) | Reversible myopathy may be exacerbated by use with other medications |
| Quinupristin‐dalfopristin | Vancomycin‐resistant E. faecium; group A streptococci or MSSA cSSTIs | Myalgias and arthralgias; infusion site reaction;* thrombophlebitis;* liver enzyme elevation; inhibition of cytochrome p450 34a | ||
| Linezolid | Serious infections due to VRE; MSSA/MRSA cSSTIs; MSSA/MRSA nosocomial pneumonia; pneumonia due to penicillin‐sensitive S. pneumoniae | Not indicated for catheter‐related bloodstream infections or catheter site infections | Myelosuppression; serotonin syndrome; tyramine reaction; peripheral neuropathy; optic neuropathy | |
| Dalbavancin | Approval pending for cSSTIs | Not indicated for pneumonia bone and joint infection | Unknown | |
| Gram‐negative | Colistin | Gram‐negative bacteria that have demonstrated sensitivity to the drug | Not indicated for Proteus spp, Providencia spp, or Serratia spp | Acute tubular necrosis; neurotoxicity∥; bronchospasm |
| Gram‐positive and Gram‐negative | Ertapenem | Complicated intraabdominal infections#; cSSTIs; acute pelvic infections; complicated UTIs; community‐acquired pneumonia; prophylaxis of SSI following colorectal surgery in adult patients | Not indicated for Pseudomonas, Acinetobacter, S. maltophilia | Cross‐reactivity with penicillin; cross‐reactivity with cephalosporins; caution use if history of seizures |
| Doripenem | Complicated intraabdominal infections# and complicated UTIs, including pyelonephritis | Cross‐reactivity with penicillin; cross‐reactivity with cephalosporins; caution use if history of seizures | ||
| Tigecycline | cSSTIs (including those due to MRSA) complicated intraabdominal infections# | Nausea and vomiting; tooth discoloration in children | ||
In retrospective analyses of SSTIs due to MRSA, linezolid was as effective as vancomycin, resulting in higher clinical cure rates and shorter hospitalizations.7 As a result, linezolid has established a role in the treatment of community‐acquired MRSA SSTIs. Evidence limited to case reports and case series suggest that linezolid may also have a role in the treatment of bone and joint infections. In these cases, linezolid was often used because treatment with other agents had failed, the administration of other antibiotics was not indicated due to resistance patterns, the patient refused intravenous therapy, or the patient did not tolerate vancomycin. When such conditions exist, linezolid may be a consideration in cases of osteomyelitis or prosthetic joint infection.8
Potential side effects of linezolid may limit its use, especially for patients who require prolonged therapy (Table 1). Of note, as a reversible, relatively weak nonselective inhibitor of monoamine oxidase, linezolid may interact with adrenergic and serotonergic agents. Concomitant of a serotonin agent such as a selective serotonin‐reuptake inhibitor (SSRI) and linezolid should be approached with caution. Subsequent serotonin syndrome is characterized by autonomic dysfunction (eg, diaphoresis, tachycardia, hypertension) and neuromuscular hyperactivity (eg, muscle rigidity, clonus, hyperreflexia). Though infrequent, cases of reversible myelosuppression have been reported with linezolid use.9 Patients who will receive this drug for more than 2 weeks should be monitored for myelosuppression with a weekly complete blood count. Isolated reports suggest that the prolonged administration of linezolid (>28 days) may be associated with peripheral neuropathy and optic neuropathy. While prompt discontinuation of the drug often results in resolution of symptoms, peripheral or optic nerve injury can be permanent. The mechanism of injury is unclear, though mitochondrial toxicity is suspected.10
Daptomycin
Daptomycin (Cubicin), a cyclic lipopeptide, was discovered in the early 1980s, but skeletal muscle toxicity led to the discontinuation of early clinical trials. When a change from twice‐daily to once‐daily dosing in 2003 resulted in fewer adverse events, the FDA approved daptomycin to treat complicated skin and skin‐structure infections.11 Daptomycin binds to the cell membrane via a calcium‐dependent process, eventually disrupting the cell membrane potential. The bactericidal effect is limited to gram‐positive organisms.12
Daptomycin is effective against almost all gram‐positive organisms including methicillin‐susceptible Staphylococcus aureus (MSSA), MRSA, and VRE.12 As a result, it has FDA approval for the treatment of cSSTIs. While beta‐lactams remain the standard of care for MSSA bacteremia, daptomycin has FDA approval for bloodstream infections and right‐sided endocarditis due to MSSA or MRSA (Table 1).13 Daptomycin has poor penetration into alveolar fluid14 and is inhibited by pulmonary surfactants; as a consequence, it is not indicated for patients with pneumonia.15
Of note, daptomycin is mainly excreted via the kidneys and should be dose‐adjusted for patients with a creatinine clearance <30 mL/minute. A reversible myopathy may occur with daptomycin, requiring intermittent monitoring of creatinine kinase if prolonged use is anticipated. Caution should be used with the coadministration of medications that can also cause a myopathy, such as statins.
Tigecycline
Tigecycline (Tygacil) was approved for use by the FDA in 2005. The first in a class of new tetracycline analogs, the glycylcyclines, tigecycline is notable for its activity against several multidrug‐resistant (MDR) organisms, including MRSA, VRE, and Enterobacteriaceae carrying extended‐spectrum beta‐lactamases (ESBL). Tigecycline impairs bacterial protein synthesis by binding to the 30S ribosomal subunit. Due to steric hindrance from an N‐alkyl‐glycylamido group at position 9, tigecycline cannot be removed by most bacterial efflux mechanisms.16
Tigecycline has been approved for the therapy of cSSTIs, including those due to MSSA and MRSA. In a pooled analysis of 2 international, multicenter, phase III randomized, double‐blind trials, tigecycline was not inferior to vancomycin plus aztreonam in the treatment of cSSTIs. Of note, MRSA eradication rates were similar between patients treated with tigecycline and vancomycin plus aztreonam (78.1% and 75.8%, respectively).17
Dalbavancin
Dalbavancin (Zeven), a new, semisynthetic lipoglycopeptide, was approved by the FDA in late 2007; however, it has not been cleared for marketing. Though dalbavancin is derived from teicoplanin, its lipophilic anchor to the bacterial cell membrane makes the drug more potent than its predecessor. Dalbavancin interferes with bacterial cell wall synthesis by binding to the C‐terminal D‐alanyl‐D alanine of the growing peptidoglycan chains.18 Enhanced pharmacokinetic properties of dalbavancin (half‐life 149‐250 hours) allow it to be dosed once‐weekly, a novel concept in antimicrobial use.19
Like other glycopeptides, dalbavancin maintains in vitro activity against most gram‐positive aerobic organisms, including MRSA and penicillin‐susceptible and penicillin‐resistant strains of Streptococcus pneumoniae. Notably, when compared to vancomycin in vitro, the agent is more active against Enterococcus faecium and Enterococcus faecalis isolates. In a recent phase III double‐blind trial, dalbavancin was compared to linezolid for the treatment of cSSTIs. Dalbavancin was not inferior to linezolid (clinical success rate 90% vs. 92%). Of note, 51% of study patients with SSTI had infection due to MRSA. Microbiological response to dalbavancin paralleled the clinical success rate; MRSA eradication rates after dalbavancin and linezolid were 91% and 89%, respectively.20
Given its once‐weekly dosing, dalbavancin may be an attractive agent in the outpatient treatment of gram‐positive bacteremia. In a phase II study, dalbavancin administered as a single 1‐g dose, followed by a 500‐mg dose 1 week later, was comparable to 14 days of vancomycin for the treatment of catheter‐related bloodstream infections (CRBSI) due to coagulase‐negative staphylococci or S. aureus (including MRSA).21 Phase III studies are underway. At present, there is no evidence to support the use of dalbavancin for the treatment of pneumonia or bone and joint infections.
Despite the administration of vancomycin, the patient continues to experience fever and chills. Blood cultures drawn in the emergency department are now growing Enterococcus species. You review the patient's medical record and notice that she was colonized with VRE on a prior admission. You consider the antibiotic options for serious infections due to VRE.
Though rates of VRE have remained fairly stable in recent years,22 the pathogen continues to present a challenge to hospital epidemiologists. A national survey in 2004 suggested that nearly 30% of enterococci in U.S. intensive care units display vancomycin resistance.1 Additional U.S. surveillance data reveals that VRE accounts for 10% to 26% of enterococci hospital‐wide.23, 24 In 2005, a meta‐analysis noted that bloodstream infections due to VRE resulted in higher mortality rates than those due to vancomycin‐susceptible enterococci.25 This discrepancy is most evident among neutropenia patients.26 Unfortunately, the options for the treatment of serious infections due to VRE are limited. The advantages and disadvantages of linezolid, quinupristin‐dalfopristin, tigecycline, and daptomycin in the treatment for VRE are discussed below.
Linezolid
Currently, linezolid is the only oral drug that is FDA‐approved for the treatment of infections due to VRE, including bacteremia. Notably, linezolid therapy resulted in the cure of 77% of 22 cases of vancomycin‐resistant enterococcal endocarditis.27 Current guidelines by the Infectious Disease Society of America (IDSA) support the use of linezolid in cases of endocarditis due to ampicillin‐resistant and vancomycin‐resistant Enterococcus faecium.28 Unfortunately, recent reports highlight the emergence of linezolid‐resistant VRE,29 suggesting use of this drug should be limited to circumstances in which other alternatives do not exist.
Quinupristin‐Dalfopristin
Quinupristin‐dalfopristin (Synercid) was approved by the FDA in 1999. It is used in the treatment of infections caused by gram‐positive organisms and is a combination of 2 semisynthetic pristinamycin derivatives. They diffuse into bacteria and bind to different areas on the 50S ribosomal subunit, thereby inhibiting protein synthesis. Individually, quinupristin and dalfopristin are bacteriostatic but together they are bactericidal.30
Quinupristin‐dalfopristin has activity against Staphylococcus aureus (including MRSA), Streptococcus pneumoniae, gram‐positive anaerobes, and vancomycin‐sensitive and resistant Enterococcus faecium. It has little activity against Enterococcus faecalis.31 FDA‐approved uses of quinupristin‐dalfopristin are limited, but include the treatment of serious infections caused by vancomycin‐resistant E. faecium (VREF).32 In a study of 396 patients with VREF the clinical success rate of quinupristin‐dalfopristin was 73.6%.33 The drug also has FDA approval for the use in cSSTIs due to group A streptococci or MSSA.32 The use of this agent is limited due to its toxicity profile. In cases of serious VRE‐related infection, quinupristin‐dalfopristin is often only utilized if linezolid cannot be tolerated.
Daptomycin
In vitro studies suggest that daptomycin is active against enterococci, including vancomycin‐resistant isolates.34 However, clinical data on the use of this agent in the treatment of infections due to VRE are lacking. FDA approval for the use of daptomycin in cSSTI included the treatment of 45 patients infected with Enterococcus faecalis.13 In addition, several reports have detailed the successful treatment of VRE bloodstream infections with daptomycin,35, 36 including a case series of VRE endocarditis.37 To determine the role of this agent in the treatment of invasive infections due to VRE, further study is needed.
You decide to discontinue vancomycin and administer linezolid. The patient's vascular catheter is removed; catheter‐tip cultures grow >1000 colonies of VRE. Blood cultures the following day are negative and a new catheter is placed. You ask the patient to continue oral linezolid to complete a 2‐week course. A review of her medication list reveals that she is not taking SSRIs or monoamine oxidase inhibitors (MAOIs).
While linezolid has retained its FDA indication for VRE bacteremia, empiric use in suspected cases of CRBSI or catheter site infection is not advised. In an open‐label trial among seriously ill patients with intravascular catheter‐related infections, linezolid use was associated with a higher mortality when compared to vancomycin/oxacillin. Interestingly, mortality among linezolid‐treated patients included those with CRBSI due to gram‐negative pathogens, due to both gram‐negative and gram‐positive pathogens, or due to an identifiable pathogen; mortality rates did not differ among patients with gram‐positive infections only.38
Case 2
A 27‐year‐old male with a history of T10 paraplegia following a motor vehicle accident presents with abdominal pain, fever, and chills. He notes that he experiences these symptoms when he has a urinary tract infection (UTI), a frequent complication of his chronic indwelling suprapubic catheter. You review his medical record and notice that he has had prior UTIs with multiple gram‐negative rods over the past 2 years, including MDR Pseudomonas and Acinetobacter. When his urine culture grows >100,000 colonies of gram‐negative rods, you initiate meropenem and consider the options for treatment of these MDR pathogens.
According to national U.S. surveillance in 2001, 22% of Pseudomonas aeruginosa were resistant to imipenem, an increase of 32% from 1997.39 More alarming is the recent development of MDR P. aeruginosa, a pathogen resistant not only to the beta‐lactams (including the carbapenems) but to the fluoroquinolones and aminoglycosides as well.40 MDR P. aeruginosa is virulent, and has been associated with higher rates of mortality, longer hospital stays, and greater cost.41
Already equipped with intrinsic resistance to the aminopenicillins and first‐generation and second‐generation cephalosporins, A. baumannii has gained recent notoriety with acquired resistance to beta‐lactams, aminoglycosides, fluoroquinolones, and tetracyclines. Most notably, carbapenem‐resistant A. baumannii has emerged due to enzymes capable of hydrolyzing imipenem. Like MDR P. aeruginosa, MDR A. baumannii infection has led to longer hospital stays42 and increased patient mortality43 when compared to infections with more susceptible strains.
Therapeutic options for these MDR gram‐negative pathogens remain limited, but the advent of doripenem and the return of colistin may play a role in treatment. The use of these 2 agents and tigecycline in the treatment of MDR P. aeruginosa and/or A. baumannii are described below.
Doripenem
In October 2007, the FDA approved the use of doripenem (Doribax), a much‐anticipated carbapenem. In structure, doripenem resembles meropenem and does not require a renal dehydropeptidase I inhibitor (eg, cilastatin).44 Similar to other beta‐lactams, doripenem binds to penicillin‐binding proteins (PBPs), inhibiting PBP‐directed cell wall synthesis.
Like imipenem and meropenem, doripenem has broad‐spectrum antimicrobial activity. It demonstrates in vitro activity against most gram‐positive pathogens including MSSA and ampicillin‐sensitive enterococci. Doripenem also has in vitro activity against most gram‐negative pathogens (including ESBL‐producing Enterobacteriaceae) and most anaerobes, including Bacteriodes fragilis. Most notably, when compared to other carbapenems, doripenem has demonstrated better in vitro activity against Pseudomonas aeruginosa.45 However, clinical implications of this in vitro activity are unclear.
When compared to meropenem or levofloxacin for the treatment of complicated UTIs, doripenem is an effective alternative. Clinical response rates among affected patients were 95% to 96% with doripenem, 89% with meropenem, and 90% with levofloxacin.46, 47 Doripenem was not inferior to meropenem in patients with serious lower respiratory tract infections, and comparable to imipenem‐cilastin and pipercillin‐tazobactam for the treatment of nosocomial or ventilator‐associated pneumonia (VAP).48, 49 Finally, for the treatment of complicated intraabdominal infections, doripenem was not inferior to meropenem; both drugs achieved microbiologic cure rates of >84%.50
Currently, doripenem is FDA‐approved for the treatment of complicated intraabdominal infections (eg, appendicitis, pancreatitis, cholecystitis, peritonitis) and complicated lower UTIs or pyelonephritis (Table 1). Given its expanded spectrum of activity, use of doripenem should be limited to circumstances in which a MDR pathogen is highly suspected or confirmed.
Colistin
Colistin (Coly‐Mycin M) falls within the family of polymyxin antibiotics, which were discovered in 1947. Colistin has been available for almost 50 years for the treatment of infections caused by gram‐negative bacteria, including Pseudomonas spp. However, early use of colistin was associated with significant nephrotoxicity. Its use decreased markedly with the advent of new antibiotics that had the same antimicrobial spectrum and a better side effect profile. With the emergence of MDR gram‐negative bacteria, colistin has returned to limited clinical use.51 As a polymyxin, colistin is a cell membrane detergent. It disrupts the cell membrane, causing leakage of bacterial cell content and ultimately cell death.52
Colistin has bactericidal activity against most gram‐negative bacteria including Acinetobacter spp, and members of the family Enterobacteriaceae (eg, Klebsiella spp, Escherichia coli, Enterobacter spp), including those producing ESBLs.53 Colistin is not active against several predominant gram‐negative pathogens including Proteus spp, Providencia spp, or Serratia spp (Table 1).
In 2007, several studies suggested that colistin monotherapy was effective for patients with VAP due to MDR P. aeruginosa or A. baumannii isolate.54, 55 A third trial that year suggested that colistin may have a role in the treatment of MDR P. aeruginosa among neutropenic patients. In that study, infected patients receiving colistin monotherapy experienced higher rates of clinical and microbiologic response than those receiving other antipseudomonal agents (eg, beta‐lactams or fluoroquinolones if active against the isolate).56 While uncontrolled studies suggest that the use of colistin in combination with other antimicrobials (including carbapenems, ampicillin‐sulbactam, aminoglycosides, and rifampin) may have some success in the treatment of VAP due to MDR A. baumannii,57, 58 further trials are needed.
Currently, colistin has FDA approval only for the treatment of acute infections due to gram‐negative bacteria that have demonstrated susceptibility to the drug and is therefore administered on a case by case basis. Although it has been used via the inhalation route to treat infections in cystic fibrosis patients, colistin does not have FDA approval for this indication.
Tigecycline
Tigecycline is approved for the treatment of complicated intraabdominal infections based on the results of 2 international, multicenter, phase III, randomized, double‐blind trials. In this pooled analysis, tigecycline was as effective and as safe as imipenem/cilastatin. Notably, study patients were not severely ill (baseline APACHE II score of 6.0).59 FDA approval suggests tigecycline use be focused on intraabdominal infections due to members of the family Enterobacteriaceae (eg, Klebsiella spp, Escherichia coli, Enterobacter spp), including those producing ESBLs, vancomycin‐sensitive enterococci, and/or MSSA. Notably, tigecycline lacks significant in vitro activity against Pseudomonas spp, Proteus spp, or Providencia spp. It has demonstrated in vitro activity against MDR strains of Acinetobacter spp (Table 1).
Given its bacteriostatic activity, tigecycline's effectiveness in the treatment bacteremia is unclear.
In addition, as no published studies have addressed its activity among seriously ill patients, tigecycline is considered a second‐line or third‐line agent for SSTI and complicated intraabdominal infections. Evidence for use of tigecycline for the treatment of UTIs is lacking and, as a rule, its use should be limited to scenarios in which alternatives for the proven or suspected pathogens do not exist.
The urine isolate is identified as Escherichia coli. You review the susceptibility profile and determine that this isolate is an ESBL‐producing strain. In addition, the patient's isolate demonstrates resistance to the fluoroquinolones and trimethoprim‐sulfamethoxazole. You consider other options for treatment of this ESBL‐producing E. coli.
According to national surveillance data, more than 20% of Klebsiella isolates in U.S. intensive care units produced ESBLs in 2003, a 47% increase when compared to 1998.39 Bloodstream infections due to ESBL‐producing isolates have led to increased length of hospital stay,60, 61 increased hospital costs,4 improper antibiotic use,5 and, most notably, increased mortality.61‐63 Of concern, ESBLs have been demonstrated within community Enterobacteriaceae isolates, most notably due to CTX‐M beta‐lactamase production among E. coli. In addition to ESBL production, these community E. coli isolates tend to express fluoroquinolone and trimethoprim‐sulfamethoxazole resistance.64 Carbapenems remain the mainstay of therapy for serious infections due to ESBL‐producing organisms. The once‐daily dosing of ertapenem makes this agent an attractive alternative for outpatient management.
Ertapenem
Ertapenem (Invanz) obtained FDA approval for use in the United States in 2001 and in the European Union in 2002.65 Similar to doripenem, ertapenem blocks cell wall synthesis by binding to specific penicillin‐binding proteins (PBPs).
Ertapenem has activity against numerous gram‐positive and gram‐negative bacteria as well as some anaerobic microorganisms. The FDA‐approved indications include complicated intraabdominal infections, cSSTIs, acute pelvic infections, complicated UTIs, and community‐acquired pneumonias (Table 1).66 Of note, in contrast to other carabapenems, ertapenem does not have activity against Pseudomonas aeruginosa or Acinetobacter spp.67
Ertapenem is approved as a single daily dose of 1 g and can be administered intravenously or intramuscularly. Changes in dosing must also be considered for critically ill patients. When administered to patients with VAP, ertapenem achieved a lower maximum concentration and area under the curve.68 In such patients, it is recommended that the dosage interval be decreased or that a continuous infusion of ertapenem be administered.
The patient's symptoms improve on meropenem. A peripherally‐inserted central catheter is placed for the administration of intravenous antibiotics at home. You prescribe ertapenem (1 g/day) for the remainder of a 14‐day course.
Conclusions
MDR bacteria continue to present a clinical challenge to hospitalists. Proper treatment of patients infected with these organisms is necessary, as inappropriate antibiotic use for MDR bacterial infections has been associated with longer hospital stays, greater cost, and, in some cases, increased mortality. Unfortunately, antibiotic production and development has declined steadily in the past 25 years. To minimize the rate of antimicrobial resistance, physicians must take care to prescribe antibiotics appropriately. While these promising new agents for resistant gram‐positive and gram‐negative infections may aid in battling MDR infections, these antibiotics must be used judiciously to maintain their clinical utility. Hospitalists will continue to play an important role in ensuring that hospitalized patients receive the most effective antimicrobial therapy to both treat the infection and prevent the development of resistance.
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- ,,, et al.Emergence of antibiotic‐resistant Pseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents.Antimicrob Agents Chemother.1999;43(6):1379–1382.
- ,,, et al.Multidrug‐resistant Acinetobacter infection mortality rate and length of hospitalization.Emerg Infect Dis.2007;13:97–103.
- ,,, et al.Bloodstream infections due to Acinetobacter spp: epidemiology, risk factors, and impact of multi‐drug resistance.Eur J Clin Microbiol Infect Dis.2008;27(7):607–612.
- ,,,,.Doripenem (S‐4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluation.J Antimicrob Chemother.2004;54:144–154.
- ,,.Antimicrobial activity of doripenem (S‐4661): a global surveillance report.Clin Microbiol Infect.2005;11:974–984.
- ,,, et al.Intravenous therapy with. doripenem versus levofloxacin with an option for oral step‐down therapy in the treatment of complicated urinary tract infections and pyelonephritis. 17th European Congress of Clinical Microbiology and Infectious Diseases and the 25th International Congress of Chemotherapy. Munich, Germany. March 31‐April 3, 2007. Abstract no. 833 plus poster.
- .New uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin B, doxycyline, and minocycline revisited.Med Clin North Am.2006;90(6):1089–1107.
- ,,, et al.Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open‐label, multicenter study.Curr Med Res Opin.2008;24(7):2113–2126.
- ,,, et al.Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator‐associated pneumonia: a multicenter, randomized study.Crit Care Med.2008;36(4):1089–1096.
- ,,, et al.Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra‐abdominal infection: a phase III, prospective, multicenter, randomized, double‐blind, noninferiority study.Clin Ther.2008;30(5):868–883.
- ,,,,.Evaluation of colistin as an agent against multi‐resistant Gram‐negative bacteria.Int J Antimicrob Agents.2005;25(1):11–25.
- .New uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline revisited.Med Clin North Am.2006;90(6):1089–1107.
- ,.Colistin: the revival of polymyxins for the management of multidrug‐resistant gram‐negative bacterial infections.Clin Infect Dis.2005;40(9):1333–1341.
- ,,, et al.Ventilator‐associated pneumonia (VAP) due to susceptible only to colistin microorganisms.Eur Respir J.2007;30(2):307–313.
- ,,, et al.Safety and efficacy of colistin compared with imipenem in the treatment of ventilator‐associated pneumonia: a matched case‐control study.Intensive Care Med.2007;33(7):1162–1167.
- ,,, et al.Colistin is effective in treatment of infections caused by multidrug‐resistant Pseudomonas aeruginosa in cancer patients.Antimicrob Agents Chemother.2007;51(6):1905–1911.
- ,,,,,.Combination therapy with intravenous colistin for management of infections due to multidrug‐resistant gram‐negative bacteria in patients without cystic fibrosis.Antimicrob Agents Chemother.2005;49:3136–3146.
- ,,, et al.Combined colistin and rifampicin therapy for carbapenem‐resistant Acinetobacter baumannii infections: clinical outcome and adverse events.Clin Microbiol Infect.2005;11:682–683.
- ,,, et al.The efficacy and safety of tigecycline for the treatment of complicated intra‐abdominal infections: analysis of pooled clinical trial data.Clin Infect Dis.2005;41(suppl 5):S354–S367.
- ,,,,.Clinical implications of extended‐spectrum beta‐lactamase‐producing Klebsiella pneumoniae bacteraemia.J Hosp Infect.2002;52:99–106.
- ,,,,,.Clinical and economic impact of bacteremia with extended spectrum beta‐lactamase–producing Enterobacteriaceae.Antimicrob Agents Chemother.2006;50:1257–1262.
- ,,, et al.Ceftazidime‐resistant Klebsiella pneumoniae bloodstream infection in children with febrile neutropenia.Int J Infect Dis.2000;4:21–25.
- ,,, et al.Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended‐ spectrum beta‐lactamases.Clin Infect Dis.2004;39:31–37.
- ,.Extended‐spectrum beta‐lactamase‐producing Enterobacteriaceae: an emerging public‐health concern.Lancet Infect Dis.2008;8(3):159–166.
- ,.Ertapenem, the first of a new group of carbapenems.J Antimicrob Chemother.2003;52(4):538–542.
- Merck 2006.
- ,,.Ertapenem: the new carbapenem 5 years after first FDA licensing for clinical practice.Expert Opin Pharmacother.2007;8(2):237–256.
- ,,, et al.Ertapenem in critically ill patients with early‐onset ventilator‐associated pneumonia: pharmacokinetics with special consideration of free‐drug concentration.J Antimicrob Chemother.2007;59(2):277–284.
- ,.Quinupristin/dalfopristin: a therapeutic review.Clin Ther.2001;23(1):24–44.
Case 1
A 53‐year‐old woman with a history of hemodialysis‐dependent end‐stage renal disease presents with left lower extremity pain and redness for the past 3 days. On physical examination, her temperature is 102.3F. Erythema, induration, and warmth are noted over her left lower leg and foot. Her history is remarkable for a line‐related bloodstream infection due to methicillin‐resistant Staphylococcus aureus (MRSA) 4 weeks ago. The infected line was removed and replaced with a right‐sided subclavian catheter. You note that the new line site is clean, not erythematous, and not tender. In the emergency department, the patient receives a dose of vancomycin for presumed MRSA cellulitis. Your patient wants to know if there are alternative agents for her infection so she does not require hospitalization.
Unfortunately, MRSA has become commonplace to the hospital setting. Among intensive care units in 2003, 64.4% of healthcare‐associated Staphylococcus aureus infections were caused by MRSA, compared with only 35.9% in 1992; a 3.1% increase per year.1, 2 Increased MRSA rates are not without consequence; a recent review suggests that MRSA infections kill nearly 19,000 hospitalized American patients annually.3 Of note, MRSA infection rates have also increased among previously healthy individuals. These community‐associated isolates (CA‐MRSA) often manifest as pyogenic skin and soft‐tissue infections (SSTIs). In a recent multicenter study, CA‐MRSA accounted for 59% of SSTIs among patients presenting to emergency rooms in the United States.4 In cases of SSTI, oral agents such as clindamycin, doxycycline, and trimethoprim‐sulfamethoxazole have proven successful. For invasive MRSA, vancomycin is still considered the standard treatment; however, several alternatives have emerged in recent years. The advantages and disadvantages of linezolid, daptomycin, tigecycline, and dalbavancin in the treatment of MRSA are described below.
Linezolid
Linezolid (Zyvox), an oxazolidinone approved in 2000, has been touted for its oral bioavailability, twice‐daily dosing, gram‐positive coverage, and unique mechanism of action. Like several other antimicrobials, linezolid inhibits bacterial protein synthesis. The drug binds to the 50S ribosomal subunit near its site of interaction with the 30S subunit, preventing formation of the 70S initiation complex.5 This site of action on the 50S subunit is unique to linezolid; as a result, cross‐resistance between linezolid and other antimicrobials that act at the 50S subunit (eg, chloramphenicol, macrolides, aminoglycosides, and tetracycline) does not occur.6
The oxazolidinones have excellent bacteriostatic activity against all pathogenic gram‐positive bacteria. The U.S. Food and Drug Administration (FDA) approved linezolid for the treatment of serious infections due to vancomycin‐resistant enterococci (VRE), including bacteremia, complicated skin and soft‐tissue infections (cSSTIs) due to Staphylococcus aureus (including MRSA), and nosocomial pneumonia due to Staphylococcus aureus (including MRSA) or penicillin‐susceptible Streptococcus pneumoniae (Table 1).
| Activity | Agent | FDA‐Approved Indications | Limitations in Use | Side Effects |
|---|---|---|---|---|
| ||||
| Gram‐positive | Daptomycin | cSSTIs; MSSA/MRSA bacteremia; MSSA/MRSA endocarditis | Not indicated for pneumonia (inhibited by pulmonary surfactant) | Reversible myopathy may be exacerbated by use with other medications |
| Quinupristin‐dalfopristin | Vancomycin‐resistant E. faecium; group A streptococci or MSSA cSSTIs | Myalgias and arthralgias; infusion site reaction;* thrombophlebitis;* liver enzyme elevation; inhibition of cytochrome p450 34a | ||
| Linezolid | Serious infections due to VRE; MSSA/MRSA cSSTIs; MSSA/MRSA nosocomial pneumonia; pneumonia due to penicillin‐sensitive S. pneumoniae | Not indicated for catheter‐related bloodstream infections or catheter site infections | Myelosuppression; serotonin syndrome; tyramine reaction; peripheral neuropathy; optic neuropathy | |
| Dalbavancin | Approval pending for cSSTIs | Not indicated for pneumonia bone and joint infection | Unknown | |
| Gram‐negative | Colistin | Gram‐negative bacteria that have demonstrated sensitivity to the drug | Not indicated for Proteus spp, Providencia spp, or Serratia spp | Acute tubular necrosis; neurotoxicity∥; bronchospasm |
| Gram‐positive and Gram‐negative | Ertapenem | Complicated intraabdominal infections#; cSSTIs; acute pelvic infections; complicated UTIs; community‐acquired pneumonia; prophylaxis of SSI following colorectal surgery in adult patients | Not indicated for Pseudomonas, Acinetobacter, S. maltophilia | Cross‐reactivity with penicillin; cross‐reactivity with cephalosporins; caution use if history of seizures |
| Doripenem | Complicated intraabdominal infections# and complicated UTIs, including pyelonephritis | Cross‐reactivity with penicillin; cross‐reactivity with cephalosporins; caution use if history of seizures | ||
| Tigecycline | cSSTIs (including those due to MRSA) complicated intraabdominal infections# | Nausea and vomiting; tooth discoloration in children | ||
In retrospective analyses of SSTIs due to MRSA, linezolid was as effective as vancomycin, resulting in higher clinical cure rates and shorter hospitalizations.7 As a result, linezolid has established a role in the treatment of community‐acquired MRSA SSTIs. Evidence limited to case reports and case series suggest that linezolid may also have a role in the treatment of bone and joint infections. In these cases, linezolid was often used because treatment with other agents had failed, the administration of other antibiotics was not indicated due to resistance patterns, the patient refused intravenous therapy, or the patient did not tolerate vancomycin. When such conditions exist, linezolid may be a consideration in cases of osteomyelitis or prosthetic joint infection.8
Potential side effects of linezolid may limit its use, especially for patients who require prolonged therapy (Table 1). Of note, as a reversible, relatively weak nonselective inhibitor of monoamine oxidase, linezolid may interact with adrenergic and serotonergic agents. Concomitant of a serotonin agent such as a selective serotonin‐reuptake inhibitor (SSRI) and linezolid should be approached with caution. Subsequent serotonin syndrome is characterized by autonomic dysfunction (eg, diaphoresis, tachycardia, hypertension) and neuromuscular hyperactivity (eg, muscle rigidity, clonus, hyperreflexia). Though infrequent, cases of reversible myelosuppression have been reported with linezolid use.9 Patients who will receive this drug for more than 2 weeks should be monitored for myelosuppression with a weekly complete blood count. Isolated reports suggest that the prolonged administration of linezolid (>28 days) may be associated with peripheral neuropathy and optic neuropathy. While prompt discontinuation of the drug often results in resolution of symptoms, peripheral or optic nerve injury can be permanent. The mechanism of injury is unclear, though mitochondrial toxicity is suspected.10
Daptomycin
Daptomycin (Cubicin), a cyclic lipopeptide, was discovered in the early 1980s, but skeletal muscle toxicity led to the discontinuation of early clinical trials. When a change from twice‐daily to once‐daily dosing in 2003 resulted in fewer adverse events, the FDA approved daptomycin to treat complicated skin and skin‐structure infections.11 Daptomycin binds to the cell membrane via a calcium‐dependent process, eventually disrupting the cell membrane potential. The bactericidal effect is limited to gram‐positive organisms.12
Daptomycin is effective against almost all gram‐positive organisms including methicillin‐susceptible Staphylococcus aureus (MSSA), MRSA, and VRE.12 As a result, it has FDA approval for the treatment of cSSTIs. While beta‐lactams remain the standard of care for MSSA bacteremia, daptomycin has FDA approval for bloodstream infections and right‐sided endocarditis due to MSSA or MRSA (Table 1).13 Daptomycin has poor penetration into alveolar fluid14 and is inhibited by pulmonary surfactants; as a consequence, it is not indicated for patients with pneumonia.15
Of note, daptomycin is mainly excreted via the kidneys and should be dose‐adjusted for patients with a creatinine clearance <30 mL/minute. A reversible myopathy may occur with daptomycin, requiring intermittent monitoring of creatinine kinase if prolonged use is anticipated. Caution should be used with the coadministration of medications that can also cause a myopathy, such as statins.
Tigecycline
Tigecycline (Tygacil) was approved for use by the FDA in 2005. The first in a class of new tetracycline analogs, the glycylcyclines, tigecycline is notable for its activity against several multidrug‐resistant (MDR) organisms, including MRSA, VRE, and Enterobacteriaceae carrying extended‐spectrum beta‐lactamases (ESBL). Tigecycline impairs bacterial protein synthesis by binding to the 30S ribosomal subunit. Due to steric hindrance from an N‐alkyl‐glycylamido group at position 9, tigecycline cannot be removed by most bacterial efflux mechanisms.16
Tigecycline has been approved for the therapy of cSSTIs, including those due to MSSA and MRSA. In a pooled analysis of 2 international, multicenter, phase III randomized, double‐blind trials, tigecycline was not inferior to vancomycin plus aztreonam in the treatment of cSSTIs. Of note, MRSA eradication rates were similar between patients treated with tigecycline and vancomycin plus aztreonam (78.1% and 75.8%, respectively).17
Dalbavancin
Dalbavancin (Zeven), a new, semisynthetic lipoglycopeptide, was approved by the FDA in late 2007; however, it has not been cleared for marketing. Though dalbavancin is derived from teicoplanin, its lipophilic anchor to the bacterial cell membrane makes the drug more potent than its predecessor. Dalbavancin interferes with bacterial cell wall synthesis by binding to the C‐terminal D‐alanyl‐D alanine of the growing peptidoglycan chains.18 Enhanced pharmacokinetic properties of dalbavancin (half‐life 149‐250 hours) allow it to be dosed once‐weekly, a novel concept in antimicrobial use.19
Like other glycopeptides, dalbavancin maintains in vitro activity against most gram‐positive aerobic organisms, including MRSA and penicillin‐susceptible and penicillin‐resistant strains of Streptococcus pneumoniae. Notably, when compared to vancomycin in vitro, the agent is more active against Enterococcus faecium and Enterococcus faecalis isolates. In a recent phase III double‐blind trial, dalbavancin was compared to linezolid for the treatment of cSSTIs. Dalbavancin was not inferior to linezolid (clinical success rate 90% vs. 92%). Of note, 51% of study patients with SSTI had infection due to MRSA. Microbiological response to dalbavancin paralleled the clinical success rate; MRSA eradication rates after dalbavancin and linezolid were 91% and 89%, respectively.20
Given its once‐weekly dosing, dalbavancin may be an attractive agent in the outpatient treatment of gram‐positive bacteremia. In a phase II study, dalbavancin administered as a single 1‐g dose, followed by a 500‐mg dose 1 week later, was comparable to 14 days of vancomycin for the treatment of catheter‐related bloodstream infections (CRBSI) due to coagulase‐negative staphylococci or S. aureus (including MRSA).21 Phase III studies are underway. At present, there is no evidence to support the use of dalbavancin for the treatment of pneumonia or bone and joint infections.
Despite the administration of vancomycin, the patient continues to experience fever and chills. Blood cultures drawn in the emergency department are now growing Enterococcus species. You review the patient's medical record and notice that she was colonized with VRE on a prior admission. You consider the antibiotic options for serious infections due to VRE.
Though rates of VRE have remained fairly stable in recent years,22 the pathogen continues to present a challenge to hospital epidemiologists. A national survey in 2004 suggested that nearly 30% of enterococci in U.S. intensive care units display vancomycin resistance.1 Additional U.S. surveillance data reveals that VRE accounts for 10% to 26% of enterococci hospital‐wide.23, 24 In 2005, a meta‐analysis noted that bloodstream infections due to VRE resulted in higher mortality rates than those due to vancomycin‐susceptible enterococci.25 This discrepancy is most evident among neutropenia patients.26 Unfortunately, the options for the treatment of serious infections due to VRE are limited. The advantages and disadvantages of linezolid, quinupristin‐dalfopristin, tigecycline, and daptomycin in the treatment for VRE are discussed below.
Linezolid
Currently, linezolid is the only oral drug that is FDA‐approved for the treatment of infections due to VRE, including bacteremia. Notably, linezolid therapy resulted in the cure of 77% of 22 cases of vancomycin‐resistant enterococcal endocarditis.27 Current guidelines by the Infectious Disease Society of America (IDSA) support the use of linezolid in cases of endocarditis due to ampicillin‐resistant and vancomycin‐resistant Enterococcus faecium.28 Unfortunately, recent reports highlight the emergence of linezolid‐resistant VRE,29 suggesting use of this drug should be limited to circumstances in which other alternatives do not exist.
Quinupristin‐Dalfopristin
Quinupristin‐dalfopristin (Synercid) was approved by the FDA in 1999. It is used in the treatment of infections caused by gram‐positive organisms and is a combination of 2 semisynthetic pristinamycin derivatives. They diffuse into bacteria and bind to different areas on the 50S ribosomal subunit, thereby inhibiting protein synthesis. Individually, quinupristin and dalfopristin are bacteriostatic but together they are bactericidal.30
Quinupristin‐dalfopristin has activity against Staphylococcus aureus (including MRSA), Streptococcus pneumoniae, gram‐positive anaerobes, and vancomycin‐sensitive and resistant Enterococcus faecium. It has little activity against Enterococcus faecalis.31 FDA‐approved uses of quinupristin‐dalfopristin are limited, but include the treatment of serious infections caused by vancomycin‐resistant E. faecium (VREF).32 In a study of 396 patients with VREF the clinical success rate of quinupristin‐dalfopristin was 73.6%.33 The drug also has FDA approval for the use in cSSTIs due to group A streptococci or MSSA.32 The use of this agent is limited due to its toxicity profile. In cases of serious VRE‐related infection, quinupristin‐dalfopristin is often only utilized if linezolid cannot be tolerated.
Daptomycin
In vitro studies suggest that daptomycin is active against enterococci, including vancomycin‐resistant isolates.34 However, clinical data on the use of this agent in the treatment of infections due to VRE are lacking. FDA approval for the use of daptomycin in cSSTI included the treatment of 45 patients infected with Enterococcus faecalis.13 In addition, several reports have detailed the successful treatment of VRE bloodstream infections with daptomycin,35, 36 including a case series of VRE endocarditis.37 To determine the role of this agent in the treatment of invasive infections due to VRE, further study is needed.
You decide to discontinue vancomycin and administer linezolid. The patient's vascular catheter is removed; catheter‐tip cultures grow >1000 colonies of VRE. Blood cultures the following day are negative and a new catheter is placed. You ask the patient to continue oral linezolid to complete a 2‐week course. A review of her medication list reveals that she is not taking SSRIs or monoamine oxidase inhibitors (MAOIs).
While linezolid has retained its FDA indication for VRE bacteremia, empiric use in suspected cases of CRBSI or catheter site infection is not advised. In an open‐label trial among seriously ill patients with intravascular catheter‐related infections, linezolid use was associated with a higher mortality when compared to vancomycin/oxacillin. Interestingly, mortality among linezolid‐treated patients included those with CRBSI due to gram‐negative pathogens, due to both gram‐negative and gram‐positive pathogens, or due to an identifiable pathogen; mortality rates did not differ among patients with gram‐positive infections only.38
Case 2
A 27‐year‐old male with a history of T10 paraplegia following a motor vehicle accident presents with abdominal pain, fever, and chills. He notes that he experiences these symptoms when he has a urinary tract infection (UTI), a frequent complication of his chronic indwelling suprapubic catheter. You review his medical record and notice that he has had prior UTIs with multiple gram‐negative rods over the past 2 years, including MDR Pseudomonas and Acinetobacter. When his urine culture grows >100,000 colonies of gram‐negative rods, you initiate meropenem and consider the options for treatment of these MDR pathogens.
According to national U.S. surveillance in 2001, 22% of Pseudomonas aeruginosa were resistant to imipenem, an increase of 32% from 1997.39 More alarming is the recent development of MDR P. aeruginosa, a pathogen resistant not only to the beta‐lactams (including the carbapenems) but to the fluoroquinolones and aminoglycosides as well.40 MDR P. aeruginosa is virulent, and has been associated with higher rates of mortality, longer hospital stays, and greater cost.41
Already equipped with intrinsic resistance to the aminopenicillins and first‐generation and second‐generation cephalosporins, A. baumannii has gained recent notoriety with acquired resistance to beta‐lactams, aminoglycosides, fluoroquinolones, and tetracyclines. Most notably, carbapenem‐resistant A. baumannii has emerged due to enzymes capable of hydrolyzing imipenem. Like MDR P. aeruginosa, MDR A. baumannii infection has led to longer hospital stays42 and increased patient mortality43 when compared to infections with more susceptible strains.
Therapeutic options for these MDR gram‐negative pathogens remain limited, but the advent of doripenem and the return of colistin may play a role in treatment. The use of these 2 agents and tigecycline in the treatment of MDR P. aeruginosa and/or A. baumannii are described below.
Doripenem
In October 2007, the FDA approved the use of doripenem (Doribax), a much‐anticipated carbapenem. In structure, doripenem resembles meropenem and does not require a renal dehydropeptidase I inhibitor (eg, cilastatin).44 Similar to other beta‐lactams, doripenem binds to penicillin‐binding proteins (PBPs), inhibiting PBP‐directed cell wall synthesis.
Like imipenem and meropenem, doripenem has broad‐spectrum antimicrobial activity. It demonstrates in vitro activity against most gram‐positive pathogens including MSSA and ampicillin‐sensitive enterococci. Doripenem also has in vitro activity against most gram‐negative pathogens (including ESBL‐producing Enterobacteriaceae) and most anaerobes, including Bacteriodes fragilis. Most notably, when compared to other carbapenems, doripenem has demonstrated better in vitro activity against Pseudomonas aeruginosa.45 However, clinical implications of this in vitro activity are unclear.
When compared to meropenem or levofloxacin for the treatment of complicated UTIs, doripenem is an effective alternative. Clinical response rates among affected patients were 95% to 96% with doripenem, 89% with meropenem, and 90% with levofloxacin.46, 47 Doripenem was not inferior to meropenem in patients with serious lower respiratory tract infections, and comparable to imipenem‐cilastin and pipercillin‐tazobactam for the treatment of nosocomial or ventilator‐associated pneumonia (VAP).48, 49 Finally, for the treatment of complicated intraabdominal infections, doripenem was not inferior to meropenem; both drugs achieved microbiologic cure rates of >84%.50
Currently, doripenem is FDA‐approved for the treatment of complicated intraabdominal infections (eg, appendicitis, pancreatitis, cholecystitis, peritonitis) and complicated lower UTIs or pyelonephritis (Table 1). Given its expanded spectrum of activity, use of doripenem should be limited to circumstances in which a MDR pathogen is highly suspected or confirmed.
Colistin
Colistin (Coly‐Mycin M) falls within the family of polymyxin antibiotics, which were discovered in 1947. Colistin has been available for almost 50 years for the treatment of infections caused by gram‐negative bacteria, including Pseudomonas spp. However, early use of colistin was associated with significant nephrotoxicity. Its use decreased markedly with the advent of new antibiotics that had the same antimicrobial spectrum and a better side effect profile. With the emergence of MDR gram‐negative bacteria, colistin has returned to limited clinical use.51 As a polymyxin, colistin is a cell membrane detergent. It disrupts the cell membrane, causing leakage of bacterial cell content and ultimately cell death.52
Colistin has bactericidal activity against most gram‐negative bacteria including Acinetobacter spp, and members of the family Enterobacteriaceae (eg, Klebsiella spp, Escherichia coli, Enterobacter spp), including those producing ESBLs.53 Colistin is not active against several predominant gram‐negative pathogens including Proteus spp, Providencia spp, or Serratia spp (Table 1).
In 2007, several studies suggested that colistin monotherapy was effective for patients with VAP due to MDR P. aeruginosa or A. baumannii isolate.54, 55 A third trial that year suggested that colistin may have a role in the treatment of MDR P. aeruginosa among neutropenic patients. In that study, infected patients receiving colistin monotherapy experienced higher rates of clinical and microbiologic response than those receiving other antipseudomonal agents (eg, beta‐lactams or fluoroquinolones if active against the isolate).56 While uncontrolled studies suggest that the use of colistin in combination with other antimicrobials (including carbapenems, ampicillin‐sulbactam, aminoglycosides, and rifampin) may have some success in the treatment of VAP due to MDR A. baumannii,57, 58 further trials are needed.
Currently, colistin has FDA approval only for the treatment of acute infections due to gram‐negative bacteria that have demonstrated susceptibility to the drug and is therefore administered on a case by case basis. Although it has been used via the inhalation route to treat infections in cystic fibrosis patients, colistin does not have FDA approval for this indication.
Tigecycline
Tigecycline is approved for the treatment of complicated intraabdominal infections based on the results of 2 international, multicenter, phase III, randomized, double‐blind trials. In this pooled analysis, tigecycline was as effective and as safe as imipenem/cilastatin. Notably, study patients were not severely ill (baseline APACHE II score of 6.0).59 FDA approval suggests tigecycline use be focused on intraabdominal infections due to members of the family Enterobacteriaceae (eg, Klebsiella spp, Escherichia coli, Enterobacter spp), including those producing ESBLs, vancomycin‐sensitive enterococci, and/or MSSA. Notably, tigecycline lacks significant in vitro activity against Pseudomonas spp, Proteus spp, or Providencia spp. It has demonstrated in vitro activity against MDR strains of Acinetobacter spp (Table 1).
Given its bacteriostatic activity, tigecycline's effectiveness in the treatment bacteremia is unclear.
In addition, as no published studies have addressed its activity among seriously ill patients, tigecycline is considered a second‐line or third‐line agent for SSTI and complicated intraabdominal infections. Evidence for use of tigecycline for the treatment of UTIs is lacking and, as a rule, its use should be limited to scenarios in which alternatives for the proven or suspected pathogens do not exist.
The urine isolate is identified as Escherichia coli. You review the susceptibility profile and determine that this isolate is an ESBL‐producing strain. In addition, the patient's isolate demonstrates resistance to the fluoroquinolones and trimethoprim‐sulfamethoxazole. You consider other options for treatment of this ESBL‐producing E. coli.
According to national surveillance data, more than 20% of Klebsiella isolates in U.S. intensive care units produced ESBLs in 2003, a 47% increase when compared to 1998.39 Bloodstream infections due to ESBL‐producing isolates have led to increased length of hospital stay,60, 61 increased hospital costs,4 improper antibiotic use,5 and, most notably, increased mortality.61‐63 Of concern, ESBLs have been demonstrated within community Enterobacteriaceae isolates, most notably due to CTX‐M beta‐lactamase production among E. coli. In addition to ESBL production, these community E. coli isolates tend to express fluoroquinolone and trimethoprim‐sulfamethoxazole resistance.64 Carbapenems remain the mainstay of therapy for serious infections due to ESBL‐producing organisms. The once‐daily dosing of ertapenem makes this agent an attractive alternative for outpatient management.
Ertapenem
Ertapenem (Invanz) obtained FDA approval for use in the United States in 2001 and in the European Union in 2002.65 Similar to doripenem, ertapenem blocks cell wall synthesis by binding to specific penicillin‐binding proteins (PBPs).
Ertapenem has activity against numerous gram‐positive and gram‐negative bacteria as well as some anaerobic microorganisms. The FDA‐approved indications include complicated intraabdominal infections, cSSTIs, acute pelvic infections, complicated UTIs, and community‐acquired pneumonias (Table 1).66 Of note, in contrast to other carabapenems, ertapenem does not have activity against Pseudomonas aeruginosa or Acinetobacter spp.67
Ertapenem is approved as a single daily dose of 1 g and can be administered intravenously or intramuscularly. Changes in dosing must also be considered for critically ill patients. When administered to patients with VAP, ertapenem achieved a lower maximum concentration and area under the curve.68 In such patients, it is recommended that the dosage interval be decreased or that a continuous infusion of ertapenem be administered.
The patient's symptoms improve on meropenem. A peripherally‐inserted central catheter is placed for the administration of intravenous antibiotics at home. You prescribe ertapenem (1 g/day) for the remainder of a 14‐day course.
Conclusions
MDR bacteria continue to present a clinical challenge to hospitalists. Proper treatment of patients infected with these organisms is necessary, as inappropriate antibiotic use for MDR bacterial infections has been associated with longer hospital stays, greater cost, and, in some cases, increased mortality. Unfortunately, antibiotic production and development has declined steadily in the past 25 years. To minimize the rate of antimicrobial resistance, physicians must take care to prescribe antibiotics appropriately. While these promising new agents for resistant gram‐positive and gram‐negative infections may aid in battling MDR infections, these antibiotics must be used judiciously to maintain their clinical utility. Hospitalists will continue to play an important role in ensuring that hospitalized patients receive the most effective antimicrobial therapy to both treat the infection and prevent the development of resistance.
Case 1
A 53‐year‐old woman with a history of hemodialysis‐dependent end‐stage renal disease presents with left lower extremity pain and redness for the past 3 days. On physical examination, her temperature is 102.3F. Erythema, induration, and warmth are noted over her left lower leg and foot. Her history is remarkable for a line‐related bloodstream infection due to methicillin‐resistant Staphylococcus aureus (MRSA) 4 weeks ago. The infected line was removed and replaced with a right‐sided subclavian catheter. You note that the new line site is clean, not erythematous, and not tender. In the emergency department, the patient receives a dose of vancomycin for presumed MRSA cellulitis. Your patient wants to know if there are alternative agents for her infection so she does not require hospitalization.
Unfortunately, MRSA has become commonplace to the hospital setting. Among intensive care units in 2003, 64.4% of healthcare‐associated Staphylococcus aureus infections were caused by MRSA, compared with only 35.9% in 1992; a 3.1% increase per year.1, 2 Increased MRSA rates are not without consequence; a recent review suggests that MRSA infections kill nearly 19,000 hospitalized American patients annually.3 Of note, MRSA infection rates have also increased among previously healthy individuals. These community‐associated isolates (CA‐MRSA) often manifest as pyogenic skin and soft‐tissue infections (SSTIs). In a recent multicenter study, CA‐MRSA accounted for 59% of SSTIs among patients presenting to emergency rooms in the United States.4 In cases of SSTI, oral agents such as clindamycin, doxycycline, and trimethoprim‐sulfamethoxazole have proven successful. For invasive MRSA, vancomycin is still considered the standard treatment; however, several alternatives have emerged in recent years. The advantages and disadvantages of linezolid, daptomycin, tigecycline, and dalbavancin in the treatment of MRSA are described below.
Linezolid
Linezolid (Zyvox), an oxazolidinone approved in 2000, has been touted for its oral bioavailability, twice‐daily dosing, gram‐positive coverage, and unique mechanism of action. Like several other antimicrobials, linezolid inhibits bacterial protein synthesis. The drug binds to the 50S ribosomal subunit near its site of interaction with the 30S subunit, preventing formation of the 70S initiation complex.5 This site of action on the 50S subunit is unique to linezolid; as a result, cross‐resistance between linezolid and other antimicrobials that act at the 50S subunit (eg, chloramphenicol, macrolides, aminoglycosides, and tetracycline) does not occur.6
The oxazolidinones have excellent bacteriostatic activity against all pathogenic gram‐positive bacteria. The U.S. Food and Drug Administration (FDA) approved linezolid for the treatment of serious infections due to vancomycin‐resistant enterococci (VRE), including bacteremia, complicated skin and soft‐tissue infections (cSSTIs) due to Staphylococcus aureus (including MRSA), and nosocomial pneumonia due to Staphylococcus aureus (including MRSA) or penicillin‐susceptible Streptococcus pneumoniae (Table 1).
| Activity | Agent | FDA‐Approved Indications | Limitations in Use | Side Effects |
|---|---|---|---|---|
| ||||
| Gram‐positive | Daptomycin | cSSTIs; MSSA/MRSA bacteremia; MSSA/MRSA endocarditis | Not indicated for pneumonia (inhibited by pulmonary surfactant) | Reversible myopathy may be exacerbated by use with other medications |
| Quinupristin‐dalfopristin | Vancomycin‐resistant E. faecium; group A streptococci or MSSA cSSTIs | Myalgias and arthralgias; infusion site reaction;* thrombophlebitis;* liver enzyme elevation; inhibition of cytochrome p450 34a | ||
| Linezolid | Serious infections due to VRE; MSSA/MRSA cSSTIs; MSSA/MRSA nosocomial pneumonia; pneumonia due to penicillin‐sensitive S. pneumoniae | Not indicated for catheter‐related bloodstream infections or catheter site infections | Myelosuppression; serotonin syndrome; tyramine reaction; peripheral neuropathy; optic neuropathy | |
| Dalbavancin | Approval pending for cSSTIs | Not indicated for pneumonia bone and joint infection | Unknown | |
| Gram‐negative | Colistin | Gram‐negative bacteria that have demonstrated sensitivity to the drug | Not indicated for Proteus spp, Providencia spp, or Serratia spp | Acute tubular necrosis; neurotoxicity∥; bronchospasm |
| Gram‐positive and Gram‐negative | Ertapenem | Complicated intraabdominal infections#; cSSTIs; acute pelvic infections; complicated UTIs; community‐acquired pneumonia; prophylaxis of SSI following colorectal surgery in adult patients | Not indicated for Pseudomonas, Acinetobacter, S. maltophilia | Cross‐reactivity with penicillin; cross‐reactivity with cephalosporins; caution use if history of seizures |
| Doripenem | Complicated intraabdominal infections# and complicated UTIs, including pyelonephritis | Cross‐reactivity with penicillin; cross‐reactivity with cephalosporins; caution use if history of seizures | ||
| Tigecycline | cSSTIs (including those due to MRSA) complicated intraabdominal infections# | Nausea and vomiting; tooth discoloration in children | ||
In retrospective analyses of SSTIs due to MRSA, linezolid was as effective as vancomycin, resulting in higher clinical cure rates and shorter hospitalizations.7 As a result, linezolid has established a role in the treatment of community‐acquired MRSA SSTIs. Evidence limited to case reports and case series suggest that linezolid may also have a role in the treatment of bone and joint infections. In these cases, linezolid was often used because treatment with other agents had failed, the administration of other antibiotics was not indicated due to resistance patterns, the patient refused intravenous therapy, or the patient did not tolerate vancomycin. When such conditions exist, linezolid may be a consideration in cases of osteomyelitis or prosthetic joint infection.8
Potential side effects of linezolid may limit its use, especially for patients who require prolonged therapy (Table 1). Of note, as a reversible, relatively weak nonselective inhibitor of monoamine oxidase, linezolid may interact with adrenergic and serotonergic agents. Concomitant of a serotonin agent such as a selective serotonin‐reuptake inhibitor (SSRI) and linezolid should be approached with caution. Subsequent serotonin syndrome is characterized by autonomic dysfunction (eg, diaphoresis, tachycardia, hypertension) and neuromuscular hyperactivity (eg, muscle rigidity, clonus, hyperreflexia). Though infrequent, cases of reversible myelosuppression have been reported with linezolid use.9 Patients who will receive this drug for more than 2 weeks should be monitored for myelosuppression with a weekly complete blood count. Isolated reports suggest that the prolonged administration of linezolid (>28 days) may be associated with peripheral neuropathy and optic neuropathy. While prompt discontinuation of the drug often results in resolution of symptoms, peripheral or optic nerve injury can be permanent. The mechanism of injury is unclear, though mitochondrial toxicity is suspected.10
Daptomycin
Daptomycin (Cubicin), a cyclic lipopeptide, was discovered in the early 1980s, but skeletal muscle toxicity led to the discontinuation of early clinical trials. When a change from twice‐daily to once‐daily dosing in 2003 resulted in fewer adverse events, the FDA approved daptomycin to treat complicated skin and skin‐structure infections.11 Daptomycin binds to the cell membrane via a calcium‐dependent process, eventually disrupting the cell membrane potential. The bactericidal effect is limited to gram‐positive organisms.12
Daptomycin is effective against almost all gram‐positive organisms including methicillin‐susceptible Staphylococcus aureus (MSSA), MRSA, and VRE.12 As a result, it has FDA approval for the treatment of cSSTIs. While beta‐lactams remain the standard of care for MSSA bacteremia, daptomycin has FDA approval for bloodstream infections and right‐sided endocarditis due to MSSA or MRSA (Table 1).13 Daptomycin has poor penetration into alveolar fluid14 and is inhibited by pulmonary surfactants; as a consequence, it is not indicated for patients with pneumonia.15
Of note, daptomycin is mainly excreted via the kidneys and should be dose‐adjusted for patients with a creatinine clearance <30 mL/minute. A reversible myopathy may occur with daptomycin, requiring intermittent monitoring of creatinine kinase if prolonged use is anticipated. Caution should be used with the coadministration of medications that can also cause a myopathy, such as statins.
Tigecycline
Tigecycline (Tygacil) was approved for use by the FDA in 2005. The first in a class of new tetracycline analogs, the glycylcyclines, tigecycline is notable for its activity against several multidrug‐resistant (MDR) organisms, including MRSA, VRE, and Enterobacteriaceae carrying extended‐spectrum beta‐lactamases (ESBL). Tigecycline impairs bacterial protein synthesis by binding to the 30S ribosomal subunit. Due to steric hindrance from an N‐alkyl‐glycylamido group at position 9, tigecycline cannot be removed by most bacterial efflux mechanisms.16
Tigecycline has been approved for the therapy of cSSTIs, including those due to MSSA and MRSA. In a pooled analysis of 2 international, multicenter, phase III randomized, double‐blind trials, tigecycline was not inferior to vancomycin plus aztreonam in the treatment of cSSTIs. Of note, MRSA eradication rates were similar between patients treated with tigecycline and vancomycin plus aztreonam (78.1% and 75.8%, respectively).17
Dalbavancin
Dalbavancin (Zeven), a new, semisynthetic lipoglycopeptide, was approved by the FDA in late 2007; however, it has not been cleared for marketing. Though dalbavancin is derived from teicoplanin, its lipophilic anchor to the bacterial cell membrane makes the drug more potent than its predecessor. Dalbavancin interferes with bacterial cell wall synthesis by binding to the C‐terminal D‐alanyl‐D alanine of the growing peptidoglycan chains.18 Enhanced pharmacokinetic properties of dalbavancin (half‐life 149‐250 hours) allow it to be dosed once‐weekly, a novel concept in antimicrobial use.19
Like other glycopeptides, dalbavancin maintains in vitro activity against most gram‐positive aerobic organisms, including MRSA and penicillin‐susceptible and penicillin‐resistant strains of Streptococcus pneumoniae. Notably, when compared to vancomycin in vitro, the agent is more active against Enterococcus faecium and Enterococcus faecalis isolates. In a recent phase III double‐blind trial, dalbavancin was compared to linezolid for the treatment of cSSTIs. Dalbavancin was not inferior to linezolid (clinical success rate 90% vs. 92%). Of note, 51% of study patients with SSTI had infection due to MRSA. Microbiological response to dalbavancin paralleled the clinical success rate; MRSA eradication rates after dalbavancin and linezolid were 91% and 89%, respectively.20
Given its once‐weekly dosing, dalbavancin may be an attractive agent in the outpatient treatment of gram‐positive bacteremia. In a phase II study, dalbavancin administered as a single 1‐g dose, followed by a 500‐mg dose 1 week later, was comparable to 14 days of vancomycin for the treatment of catheter‐related bloodstream infections (CRBSI) due to coagulase‐negative staphylococci or S. aureus (including MRSA).21 Phase III studies are underway. At present, there is no evidence to support the use of dalbavancin for the treatment of pneumonia or bone and joint infections.
Despite the administration of vancomycin, the patient continues to experience fever and chills. Blood cultures drawn in the emergency department are now growing Enterococcus species. You review the patient's medical record and notice that she was colonized with VRE on a prior admission. You consider the antibiotic options for serious infections due to VRE.
Though rates of VRE have remained fairly stable in recent years,22 the pathogen continues to present a challenge to hospital epidemiologists. A national survey in 2004 suggested that nearly 30% of enterococci in U.S. intensive care units display vancomycin resistance.1 Additional U.S. surveillance data reveals that VRE accounts for 10% to 26% of enterococci hospital‐wide.23, 24 In 2005, a meta‐analysis noted that bloodstream infections due to VRE resulted in higher mortality rates than those due to vancomycin‐susceptible enterococci.25 This discrepancy is most evident among neutropenia patients.26 Unfortunately, the options for the treatment of serious infections due to VRE are limited. The advantages and disadvantages of linezolid, quinupristin‐dalfopristin, tigecycline, and daptomycin in the treatment for VRE are discussed below.
Linezolid
Currently, linezolid is the only oral drug that is FDA‐approved for the treatment of infections due to VRE, including bacteremia. Notably, linezolid therapy resulted in the cure of 77% of 22 cases of vancomycin‐resistant enterococcal endocarditis.27 Current guidelines by the Infectious Disease Society of America (IDSA) support the use of linezolid in cases of endocarditis due to ampicillin‐resistant and vancomycin‐resistant Enterococcus faecium.28 Unfortunately, recent reports highlight the emergence of linezolid‐resistant VRE,29 suggesting use of this drug should be limited to circumstances in which other alternatives do not exist.
Quinupristin‐Dalfopristin
Quinupristin‐dalfopristin (Synercid) was approved by the FDA in 1999. It is used in the treatment of infections caused by gram‐positive organisms and is a combination of 2 semisynthetic pristinamycin derivatives. They diffuse into bacteria and bind to different areas on the 50S ribosomal subunit, thereby inhibiting protein synthesis. Individually, quinupristin and dalfopristin are bacteriostatic but together they are bactericidal.30
Quinupristin‐dalfopristin has activity against Staphylococcus aureus (including MRSA), Streptococcus pneumoniae, gram‐positive anaerobes, and vancomycin‐sensitive and resistant Enterococcus faecium. It has little activity against Enterococcus faecalis.31 FDA‐approved uses of quinupristin‐dalfopristin are limited, but include the treatment of serious infections caused by vancomycin‐resistant E. faecium (VREF).32 In a study of 396 patients with VREF the clinical success rate of quinupristin‐dalfopristin was 73.6%.33 The drug also has FDA approval for the use in cSSTIs due to group A streptococci or MSSA.32 The use of this agent is limited due to its toxicity profile. In cases of serious VRE‐related infection, quinupristin‐dalfopristin is often only utilized if linezolid cannot be tolerated.
Daptomycin
In vitro studies suggest that daptomycin is active against enterococci, including vancomycin‐resistant isolates.34 However, clinical data on the use of this agent in the treatment of infections due to VRE are lacking. FDA approval for the use of daptomycin in cSSTI included the treatment of 45 patients infected with Enterococcus faecalis.13 In addition, several reports have detailed the successful treatment of VRE bloodstream infections with daptomycin,35, 36 including a case series of VRE endocarditis.37 To determine the role of this agent in the treatment of invasive infections due to VRE, further study is needed.
You decide to discontinue vancomycin and administer linezolid. The patient's vascular catheter is removed; catheter‐tip cultures grow >1000 colonies of VRE. Blood cultures the following day are negative and a new catheter is placed. You ask the patient to continue oral linezolid to complete a 2‐week course. A review of her medication list reveals that she is not taking SSRIs or monoamine oxidase inhibitors (MAOIs).
While linezolid has retained its FDA indication for VRE bacteremia, empiric use in suspected cases of CRBSI or catheter site infection is not advised. In an open‐label trial among seriously ill patients with intravascular catheter‐related infections, linezolid use was associated with a higher mortality when compared to vancomycin/oxacillin. Interestingly, mortality among linezolid‐treated patients included those with CRBSI due to gram‐negative pathogens, due to both gram‐negative and gram‐positive pathogens, or due to an identifiable pathogen; mortality rates did not differ among patients with gram‐positive infections only.38
Case 2
A 27‐year‐old male with a history of T10 paraplegia following a motor vehicle accident presents with abdominal pain, fever, and chills. He notes that he experiences these symptoms when he has a urinary tract infection (UTI), a frequent complication of his chronic indwelling suprapubic catheter. You review his medical record and notice that he has had prior UTIs with multiple gram‐negative rods over the past 2 years, including MDR Pseudomonas and Acinetobacter. When his urine culture grows >100,000 colonies of gram‐negative rods, you initiate meropenem and consider the options for treatment of these MDR pathogens.
According to national U.S. surveillance in 2001, 22% of Pseudomonas aeruginosa were resistant to imipenem, an increase of 32% from 1997.39 More alarming is the recent development of MDR P. aeruginosa, a pathogen resistant not only to the beta‐lactams (including the carbapenems) but to the fluoroquinolones and aminoglycosides as well.40 MDR P. aeruginosa is virulent, and has been associated with higher rates of mortality, longer hospital stays, and greater cost.41
Already equipped with intrinsic resistance to the aminopenicillins and first‐generation and second‐generation cephalosporins, A. baumannii has gained recent notoriety with acquired resistance to beta‐lactams, aminoglycosides, fluoroquinolones, and tetracyclines. Most notably, carbapenem‐resistant A. baumannii has emerged due to enzymes capable of hydrolyzing imipenem. Like MDR P. aeruginosa, MDR A. baumannii infection has led to longer hospital stays42 and increased patient mortality43 when compared to infections with more susceptible strains.
Therapeutic options for these MDR gram‐negative pathogens remain limited, but the advent of doripenem and the return of colistin may play a role in treatment. The use of these 2 agents and tigecycline in the treatment of MDR P. aeruginosa and/or A. baumannii are described below.
Doripenem
In October 2007, the FDA approved the use of doripenem (Doribax), a much‐anticipated carbapenem. In structure, doripenem resembles meropenem and does not require a renal dehydropeptidase I inhibitor (eg, cilastatin).44 Similar to other beta‐lactams, doripenem binds to penicillin‐binding proteins (PBPs), inhibiting PBP‐directed cell wall synthesis.
Like imipenem and meropenem, doripenem has broad‐spectrum antimicrobial activity. It demonstrates in vitro activity against most gram‐positive pathogens including MSSA and ampicillin‐sensitive enterococci. Doripenem also has in vitro activity against most gram‐negative pathogens (including ESBL‐producing Enterobacteriaceae) and most anaerobes, including Bacteriodes fragilis. Most notably, when compared to other carbapenems, doripenem has demonstrated better in vitro activity against Pseudomonas aeruginosa.45 However, clinical implications of this in vitro activity are unclear.
When compared to meropenem or levofloxacin for the treatment of complicated UTIs, doripenem is an effective alternative. Clinical response rates among affected patients were 95% to 96% with doripenem, 89% with meropenem, and 90% with levofloxacin.46, 47 Doripenem was not inferior to meropenem in patients with serious lower respiratory tract infections, and comparable to imipenem‐cilastin and pipercillin‐tazobactam for the treatment of nosocomial or ventilator‐associated pneumonia (VAP).48, 49 Finally, for the treatment of complicated intraabdominal infections, doripenem was not inferior to meropenem; both drugs achieved microbiologic cure rates of >84%.50
Currently, doripenem is FDA‐approved for the treatment of complicated intraabdominal infections (eg, appendicitis, pancreatitis, cholecystitis, peritonitis) and complicated lower UTIs or pyelonephritis (Table 1). Given its expanded spectrum of activity, use of doripenem should be limited to circumstances in which a MDR pathogen is highly suspected or confirmed.
Colistin
Colistin (Coly‐Mycin M) falls within the family of polymyxin antibiotics, which were discovered in 1947. Colistin has been available for almost 50 years for the treatment of infections caused by gram‐negative bacteria, including Pseudomonas spp. However, early use of colistin was associated with significant nephrotoxicity. Its use decreased markedly with the advent of new antibiotics that had the same antimicrobial spectrum and a better side effect profile. With the emergence of MDR gram‐negative bacteria, colistin has returned to limited clinical use.51 As a polymyxin, colistin is a cell membrane detergent. It disrupts the cell membrane, causing leakage of bacterial cell content and ultimately cell death.52
Colistin has bactericidal activity against most gram‐negative bacteria including Acinetobacter spp, and members of the family Enterobacteriaceae (eg, Klebsiella spp, Escherichia coli, Enterobacter spp), including those producing ESBLs.53 Colistin is not active against several predominant gram‐negative pathogens including Proteus spp, Providencia spp, or Serratia spp (Table 1).
In 2007, several studies suggested that colistin monotherapy was effective for patients with VAP due to MDR P. aeruginosa or A. baumannii isolate.54, 55 A third trial that year suggested that colistin may have a role in the treatment of MDR P. aeruginosa among neutropenic patients. In that study, infected patients receiving colistin monotherapy experienced higher rates of clinical and microbiologic response than those receiving other antipseudomonal agents (eg, beta‐lactams or fluoroquinolones if active against the isolate).56 While uncontrolled studies suggest that the use of colistin in combination with other antimicrobials (including carbapenems, ampicillin‐sulbactam, aminoglycosides, and rifampin) may have some success in the treatment of VAP due to MDR A. baumannii,57, 58 further trials are needed.
Currently, colistin has FDA approval only for the treatment of acute infections due to gram‐negative bacteria that have demonstrated susceptibility to the drug and is therefore administered on a case by case basis. Although it has been used via the inhalation route to treat infections in cystic fibrosis patients, colistin does not have FDA approval for this indication.
Tigecycline
Tigecycline is approved for the treatment of complicated intraabdominal infections based on the results of 2 international, multicenter, phase III, randomized, double‐blind trials. In this pooled analysis, tigecycline was as effective and as safe as imipenem/cilastatin. Notably, study patients were not severely ill (baseline APACHE II score of 6.0).59 FDA approval suggests tigecycline use be focused on intraabdominal infections due to members of the family Enterobacteriaceae (eg, Klebsiella spp, Escherichia coli, Enterobacter spp), including those producing ESBLs, vancomycin‐sensitive enterococci, and/or MSSA. Notably, tigecycline lacks significant in vitro activity against Pseudomonas spp, Proteus spp, or Providencia spp. It has demonstrated in vitro activity against MDR strains of Acinetobacter spp (Table 1).
Given its bacteriostatic activity, tigecycline's effectiveness in the treatment bacteremia is unclear.
In addition, as no published studies have addressed its activity among seriously ill patients, tigecycline is considered a second‐line or third‐line agent for SSTI and complicated intraabdominal infections. Evidence for use of tigecycline for the treatment of UTIs is lacking and, as a rule, its use should be limited to scenarios in which alternatives for the proven or suspected pathogens do not exist.
The urine isolate is identified as Escherichia coli. You review the susceptibility profile and determine that this isolate is an ESBL‐producing strain. In addition, the patient's isolate demonstrates resistance to the fluoroquinolones and trimethoprim‐sulfamethoxazole. You consider other options for treatment of this ESBL‐producing E. coli.
According to national surveillance data, more than 20% of Klebsiella isolates in U.S. intensive care units produced ESBLs in 2003, a 47% increase when compared to 1998.39 Bloodstream infections due to ESBL‐producing isolates have led to increased length of hospital stay,60, 61 increased hospital costs,4 improper antibiotic use,5 and, most notably, increased mortality.61‐63 Of concern, ESBLs have been demonstrated within community Enterobacteriaceae isolates, most notably due to CTX‐M beta‐lactamase production among E. coli. In addition to ESBL production, these community E. coli isolates tend to express fluoroquinolone and trimethoprim‐sulfamethoxazole resistance.64 Carbapenems remain the mainstay of therapy for serious infections due to ESBL‐producing organisms. The once‐daily dosing of ertapenem makes this agent an attractive alternative for outpatient management.
Ertapenem
Ertapenem (Invanz) obtained FDA approval for use in the United States in 2001 and in the European Union in 2002.65 Similar to doripenem, ertapenem blocks cell wall synthesis by binding to specific penicillin‐binding proteins (PBPs).
Ertapenem has activity against numerous gram‐positive and gram‐negative bacteria as well as some anaerobic microorganisms. The FDA‐approved indications include complicated intraabdominal infections, cSSTIs, acute pelvic infections, complicated UTIs, and community‐acquired pneumonias (Table 1).66 Of note, in contrast to other carabapenems, ertapenem does not have activity against Pseudomonas aeruginosa or Acinetobacter spp.67
Ertapenem is approved as a single daily dose of 1 g and can be administered intravenously or intramuscularly. Changes in dosing must also be considered for critically ill patients. When administered to patients with VAP, ertapenem achieved a lower maximum concentration and area under the curve.68 In such patients, it is recommended that the dosage interval be decreased or that a continuous infusion of ertapenem be administered.
The patient's symptoms improve on meropenem. A peripherally‐inserted central catheter is placed for the administration of intravenous antibiotics at home. You prescribe ertapenem (1 g/day) for the remainder of a 14‐day course.
Conclusions
MDR bacteria continue to present a clinical challenge to hospitalists. Proper treatment of patients infected with these organisms is necessary, as inappropriate antibiotic use for MDR bacterial infections has been associated with longer hospital stays, greater cost, and, in some cases, increased mortality. Unfortunately, antibiotic production and development has declined steadily in the past 25 years. To minimize the rate of antimicrobial resistance, physicians must take care to prescribe antibiotics appropriately. While these promising new agents for resistant gram‐positive and gram‐negative infections may aid in battling MDR infections, these antibiotics must be used judiciously to maintain their clinical utility. Hospitalists will continue to play an important role in ensuring that hospitalized patients receive the most effective antimicrobial therapy to both treat the infection and prevent the development of resistance.
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- ,,,,,.Clinical and economic impact of bacteremia with extended spectrum beta‐lactamase–producing Enterobacteriaceae.Antimicrob Agents Chemother.2006;50:1257–1262.
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