Infections Due to Other Members of the Enterobacteriaceae, Including Management of Multidrug-Resistant Strains

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CHAPTER 313  MANAGEMENT OF MULTIDRUG-RESISTANT STRAINS  

TABLE 313-1 MEDICALLY IMPORTANT MEMBERS OF THE ENTEROBACTERIACEAE FAMILY

313  INFECTIONS DUE TO OTHER MEMBERS OF THE ENTEROBACTERIACEAE, INCLUDING MANAGEMENT OF MULTIDRUG-RESISTANT STRAINS DAVID L. PATERSON

DEFINITION

The Pathogens

The Enterobacteriaceae is a family of gram-negative bacilli that are responsible for a broad range of infections in humans and animals. They may be motile or nonmotile, depending on the species. They are aerobic or facultatively anaerobic in growth and have a predilection for inhabiting the gastrointestinal tract. Only extra-gastrointestinal manifestations of disease are discussed in this chapter. Enteric infections caused by Escherichia coli are discussed in Chapter 312. From a microbiologic perspective, members of the Enterobacteriaceae ferment sugars. They grow on a variety of solid media and are usually readily identified by clinical microbiology laboratories. A number of subtleties can arise in the detection of antibiotic resistance mechanisms, however, sometimes affecting the reporting of antibiotic susceptibilities. There is a worldwide trend toward the development of multidrug resistance in all gramnegative bacilli, including the Enterobacteriaceae. This chapter emphasizes the treatment and prevention of these multidrug-resistant strains. Medically important members of the Enterobacteriaceae are listed in Table 313-1. Infections due to Salmonella, Shigella, and Yersinia are discussed in Chapters 316, 317, and 320, respectively.

EPIDEMIOLOGY

Members of the Enterobacteriaceae are among the most common pathogens that infect humans worldwide. They are responsible for community-acquired, hospital-acquired, and health care–associated infections. Examples of the last category include infections acquired in nursing homes and those associated with outpatient management of cancers or hematologic malignancies. It is also important to note that, as resident components of the gastrointestinal tract flora, isolates of Enterobacteriaceae may represent colonization rather than true infection. This applies to isolates from rectal swabs, urine, or respiratory secretions. Although most infections due to the Enterobacteriaceae arise sporadically, outbreaks of infection may occur. This is most common in hospitals or nursing homes with Klebsiella species. Less commonly, outbreaks may be due to E. coli, Enterobacter species, or Serratia marcescens. Typically, outbreaks are due to multiply resistant strains, compounding the difficulties of infection control.

GENUS Enterobacter

IMPORTANT SPECIES E. cloacae

Escherichia

E. coli

Klebsiella

K. pneumoniae, K. oxytoca

Morganella

M. morganii

Plesiomonas

P. shigelloides

Proteus

P. mirabilis, P. vulgaris

Providencia

P. stuartii

Salmonella

S. enterica

Serratia

S. marcescens

Shigella

S. sonnei

Yersinia

Y. pestis, Y. enterocolitica

E. coli is the most common cause of urinary tract infection (UTI), accounting for more than 80% of isolates from urine in most clinical situations. Any of the remaining members of the Enterobacteriaceae can cause this infection, with Klebsiella species and Proteus mirabilis being other common causes of UTI. Providencia stuartii is a notable cause of UTI among chronically catheterized patients. The Enterobacteriaceae can cause uncomplicated UTI in healthy women, acute pyelonephritis, and UTI complicating renal tract abnormalities or catheterization. As previously mentioned, the Enterobacteriaceae may colonize the urine or be found in contaminated, improperly collected samples. Antibiotic-resistant, uropathogenic E. coli may spread clonally. In other words, E. coli isolates from multiple people with UTIs may be identical or closely related at a genetic level. Trimethoprim/sulfamethoxazole–resistant E. coli is notable for its spread in a clonal fashion in the United States (e.g., “clonal group A” and E. coli O15:K52:H1). A widely spread E. coli clone, defined serologically as O25:H4 and by multilocus sequence typing as sequence type (ST) 131, is associated with the production of extendedspectrum β-lactamases (ESBLs). This clone is typically associated with community-acquired UTI. It has been detected in every inhabited continent and is particularly prominent in the United Kingdom, Canada, and India. In evaluations from New Zealand and Canada, the isolation of ESBL-producing ST131 E. coli has been associated with travel to India, Bangladesh, or Pakistan. The presence of ST131 E. coli has been confirmed in the United States. Given the niche of most Enterobacteriaceae in the gastrointestinal tract, it is not surprising that these bacteria are prominent as causes of peritonitis. E. coli is the most common cause of both spontaneous bacterial peritonitis (occurring in cirrhotic patients) and bacterial peritonitis arising from visceral perforation. Pyogenic liver abscess and intra-abdominal abscess may be due to E. coli as well. Other members of the Enterobacteriaceae may also cause these intra-abdominal infections, especially in patients with “tertiary” peritonitis occurring after prior surgery for intra-abdominal pathology. Enterobacteriaceae members may also be the causative pathogens of pneumonia. They are more frequently the cause of hospital-acquired and health care–associated pneumonia than community-acquired pneumonia. Klebsiella pneumoniae was once a renowned cause of community-acquired pneumonia in alcoholics, but it has declined in significance over the past few decades. One exception is the finding of pneumonia, liver abscess, or meningitis in Asia due to highly mucoid strains of K. pneumoniae. Hospital-acquired pneumonia due to the Enterobacteriaceae may be ventilator associated. Enterobacteriaceae members rank as some of the most common causes of ventilator-associated pneumonia, after Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii. The Enterobacteriaceae may also cause hospital-acquired pneumonia in non–mechanically ventilated patients, such as those with neurologic impairment from head injury or cerebrovascular accident. Outbreaks of antibiotic-resistant K. pneumoniae infection in hospitals have been prominent for more than 3 decades. In the hospital setting, K. pneumoniae is usually the cause of peritonitis, pneumonia, or complicated UTI. Blood stream infection arising from these sites of infection, from vascular catheters, or associated with neutropenia may also occur. In the 1970s, outbreaks occurred due to gentamicin-resistant strains. In the 1980s and 1990s,

CHAPTER 313  MANAGEMENT OF MULTIDRUG-RESISTANT STRAINS  

hospital outbreaks of ESBL-producing K. pneumoniae became commonplace. Finally, in the past decade, K. pneumoniae carbapenemase (KPC)–producing K. pneumoniae became a substantial infection control issue. The KPCproducing organisms are discussed in detail later in this chapter.

PATHOBIOLOGY

The virulence factors associated with E. coli causing enteric infections are discussed in detail in Chapter 312. At least 40 different virulence genes have been described in E. coli causing extraintestinal infections. Among the virulence properties of these strains is the renowned ability of E. coli to adhere to uroepithelial cells. It is noteworthy that the ST131 E. coli clone is typically highly virulent. It belongs to phylogenetic group B2, which is known for extraintestinal pathogenic infections. In an evaluation of the ST131 clone, 46 extraintestinal virulence genes were assessed, and 35% of these genes were found in at least one isolate. Five virulence genes were uniformly present in ST131 E. coli. A recently published clinical case documented the occurrence of severe recurrent pyelonephritis with multiple renal abscesses in a man whose daughter was infected with the same ST131-positive E. coli strain. The daughter developed emphysematous pyelonephritis with bacteremia and septic shock. Enterobacteriaceae other than E. coli also possess a number of virulence mechanisms. As previously noted, many members of Enterobacteriaceae are now multidrug resistant. Their resistance to aminoglycosides is usually mediated by the production of aminoglycoside-modifying enzymes. However, 16S ribosomal RNA methylation is a more recently described mechanism that results in resistance to gentamicin, tobramycin, and amikacin. Resistance of the Enterobacteriaceae to fluoroquinolones is a growing problem. In most areas, more than 20% of E. coli strains are resistant to fluoroquinolones. Resistance is usually mediated by mutation at target sites. However, other mechanisms, such as efflux pump overexpression or expression of the plasmid-mediated qnr genes, may play a role. The mechanisms of resistance of the Enterobacteriaceae to β-lactam antibiotics are worthy of detailed description (Table 313-2).

Narrow-Spectrum β-Lactamases

Ampicillin was introduced into clinical practice in the early 1960s. Enterobacteriaceae, with genes encoding β-lactamases inherent to their chromosome, were found to be intrinsically resistant to this antibiotic. Examples include the production of the SHV-1 β-lactamase by K. pneumoniae or the AmpC β-lactamase by Enterobacter cloacae. Other Enterobacteriaceae (e.g., E. coli, P. mirabilis, Salmonella) did not produce substantial amounts of chromosomally encoded β-lactamase. However, within months of the release of ampicillin, a plasmid-mediated β-lactamase, leading to E. coli’s resistance to the antibiotic, was discovered. This β-lactamase was called the TEM β-lactamase, in honor of the patient (Temoneira) from whom it was first isolated. Plasmids encoding resistance to ampicillin have now become

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widespread, with at least 40% of E. coli in most parts of the world being TEM β-lactamase producers.

Extended-Spectrum β-Lactamases

Third-generation cephalosporins (e.g., ceftriaxone) were active against Enterobacteriaceae producing narrow-spectrum β-lactamases. However, mutant genes encoding β-lactamases capable of inactivating third-generation cephalosporins were discovered in the 1980s. The genes encoding these β-lactamases were identical to TEM or SHV, except for point mutations that led to an altered amino acid sequence. The subsequent structural change led to an ability to hydrolyze and thus inactivate third-generation cephalosporins. In view of the extended antibiotic-hydrolyzing abilities compared with the parent TEM and SHV enzymes, these β-lactamases were called extended-spectrum β-lactamases. In addition to the TEM- and SHV-type ESBLs, many new ones have now been described, most notably the CTXM–type ESBL. Typically, the ST131 E. coli clone mentioned earlier produces a CTX-M– type ESBL (especially CTX-M-15). Although ESBLs are typically susceptible to β-lactamase inhibitors (e.g., clavulanic acid), many ST131 E. coli isolates produce an additional β-lactamase (OXA-1) that confers resistance to β-lactamase inhibitors. The antibiotic resistance phenotype of the ST131positive E. coli means that the organisms are typically resistant to ceftriaxone, cefotaxime, fluoroquinolones, trimethoprim, trimethoprim/sulfamethoxazole, penicillin/β-lactamase inhibitor combinations, and tetracyclines. Resistance to aminoglycosides is variable. The clone confers multidrug resistance by the presence of multiple antibiotic resistance genes. These are usually encoded on plasmids.

AmpC β-Lactamases

A number of genera within the Enterobacteriaceae have a chromosomally encoded β-lactamase capable of producing resistance to all penicillins and all cephalosporins except cefepime. Additionally, these β-lactamases are not affected by β-lactamase inhibitors such as clavulanic acid or tazobactam. These β-lactamases are known as AmpC β-lactamases. They are not derived from narrower spectrum parent β-lactamases, so it is not correct to call them ESBLs. These AmpC β-lactamases may be overproduced in the presence of certain antibiotics (i.e., the genes encoding the AmpC β-lactamases are “inducible”). Enterobacter species, Citrobacter freundii, S. marcescens, and Morganella morganii have inducible, chromosomally encoded AmpC β-lactamases. The genes encoding these β-lactamases have now been found on plasmids in E. coli, Salmonella, and other gram-negative bacteria.

Klebsiella pneumoniae Carbapenemase and Other Carbapenemases

AmpC AmpC

Found universally Occasional plasmidmediated strains

In 2001, a novel carbapenem-hydrolyzing β-lactamase from a carbapenemresistant strain of K. pneumoniae was first described: KPC. KPC-producing organisms are typically resistant to penicillins, cephalosporins, and carbapenems and are not inhibited by clavulanic acid or other commonly used β-lactamase inhibitors such as sulbactam and tazobactam. KPC production has been documented in E. coli and in many genera of the Enterobacteriaceae, such as Enterobacter, Citrobacter, Proteus, and Salmonella. The epicenter of KPC-producing K. pneumoniae has been New York City. By 2004, approximately one quarter of K. pneumoniae isolates in a surveillance study in Brooklyn, New York, were KPC producing. The Centers for Disease Control and Prevention has reported KPC-producing organisms in numerous cities across the United States. International spread of KPC-producing organisms has been well described, with outbreaks in Israel and Greece being particularly problematic. Individual patients with KPC-producing organisms in France and the United Kingdom had traveled in the United States, Israel, or Greece. Investigators in China and South America have also reported KPC-producing organisms. Other β-lactamase types have been linked to resistance of the Enterobacteriaceae to carbapenems. The most significant have been metallo-βlactamases. These also result in resistance to penicillins and cephalosporins. A new metallo-β-lactamase (termed the New Delhi metallo-β-lactamase, or NDM) in K. pneumoniae from India, with subsequent spread to the United Kingdom, Sweden, and Australia, is particularly concerning.

K. pneumoniae

KPC

K. pneumoniae

NDM

Hospital outbreaks in the United States Hospital outbreaks in India

The clinical manifestations of UTI, peritonitis, pneumonia, and blood stream infection due to the Enterobacteriaceae are described in other chapters devoted to specific microbial pathogens.

TABLE 313-2 ANTIBIOTIC RESISTANCE ISSUES IN ENTEROBACTERIACEAE ORGANISM

β-LACTAMASE

COMMENTS

NARROW-SPECTRUM β-LACTAMASES Escherichia coli

TEM-1

Klebsiella pneumoniae

SHV-1

Present in at least 40% of strains globally Found universally

EXTENDED-SPECTRUM β-LACTAMASES E. coli

CTX-M-15

K. pneumoniae

SHV, TEM, CTX-M

International clone causing community-acquired urinary tract infection Hospital outbreaks

AmpC β-LACTAMASES Enterobacter cloacae E. coli CARBAPENEMASES

CLINICAL MANIFESTATIONS

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DIAGNOSIS

Infection with Enterobacteriaceae is readily diagnosed in clinical microbiology laboratories after the collection of appropriate specimens. Examination of the Gram stain enables the rapid differentiation of gram-negative bacilli from other pathogens. However, it is frequently difficult to differentiate infection with the Enterobacteriaceae from infection with other gram-negative bacilli, such as P. aeruginosa, based on clinical findings and Gram stain results. Once a member of the Enterobacteriaceae has been identified, it is important to perform appropriate antibiotic susceptibility testing. In some instances, specialized tests need to be performed by the clinical microbiology laboratory to detect ESBL or KPC production. Molecular epidemiologic assessment may be required to determine whether an isolate belongs to an outbreak strain.

TREATMENT  Treatment depends on the site of infection and the extent of antibiotic resistance. Empirical antibiotic choices for orally administered therapy for UTI due to E. coli and the other Enterobacteriaceae may include fluoroquinolones, trimethoprim/sulfamethoxazole, amoxicillin/clavulanate, or nitrofurantoin. It is noteworthy that P. mirabilis is resistant to nitrofurantoin. Empirical parenteral choices may include third-generation cephalosporins, penicillin/β-lactamase inhibitor combinations, aminoglycosides, fluoroquinolones, or carbapenems. The advent of antibiotic resistance in the Enterobacteriaceae may have a huge impact on the treatment of common infections. UTI is a pertinent example. Orally administered drugs such as fluoroquinolones, trimethoprim/ sulfamethoxazole, and amoxicillin/clavulanate are typically inactive against the ST131 E. coli strain. Because of this resistance, some patients may need to be admitted for parenteral antibiotics. Worse still, some patients with hospitalacquired infections may need “last-line” antibiotics such as colistin or polymyxin B. Specific treatment choices for antibiotic-resistant Enterobacteriaceae are given in the following paragraphs and in Table 313-3.

Treatment of ESBL-Producing Organisms

In vitro, the carbapenems (including imipenem, meropenem, doripenem, and ertapenem) have the most potent activity against ESBL-producing organisms. This is not surprising, given that these antibiotics are not inactivated by ESBLs. Carbapenems should be regarded as the drugs of choice for serious infections with ESBL-producing organisms, based on extensive positive clinical experience. No randomized trials have been performed comparing carbapenems with other antibiotic classes against ESBL producers. Prospective, observational studies have shown a significantly lower mortality from carbapenem-treated blood stream infections due to ESBL-producing K. pneumoniae compared with other antibiotic classes. Although synergy has occasionally been exhibited between carbapenems and other antibiotic classes, there is no evidence that combination therapy is superior to the use of a carbapenem alone. The choice among the different carbapenems for serious infections with ESBL producers is difficult. In general, minimal inhibitory concentrations (MICs) are slightly lower for meropenem and doripenem than for imipenem and ertapenem, although the clinical significance of this in vitro difference is not clear. The ability to administer ertapenem once daily makes it potentially useful for serious infections due to ESBL producers in nursing home residents or patients continuing parenteral therapy outside the hospital. However, some ESBL-producing strains are resistant to ertapenem. The advent of KPC, NDM, and other carbapenemases threatens the future utility of the carbapenems. Tigecycline and colistin are active against most ESBL-producing strains and, as non-β-lactams, are not inactivated by β-lactamases. Clinical experience with tigecycline or colistin to treat ESBL producers is sparse. Fluoroquinolones and aminoglycosides are obviously not

TABLE 313-3 TREATMENT OPTIONS FOR MULTIPLY RESISTANT ENTEROBACTERIACEAE ESBL PRODUCERS Carbapenems (first choice, serious infections) Piperacillin/tazobactam, cefepime (second choice, serious infections) Nitrofurantoin, fosfomycin (first choice, UTI) Ciprofloxacin, amoxicillin/clavulanate (second choice, UTI) KPC PRODUCERS Colistin, polymyxin B, tigecycline ESBL = extended-spectrum β-lactamase; KPC = Klebsiella pneumoniae carbapenemase; UTI = urinary tract infection.

affected by β-lactamases either, but the coexistence of resistance mechanisms affecting these antibiotics and ESBLs is frequent. Three observational clinical studies have assessed the relative merits of quinolones and carbapenems for serious infections due to ESBL-producing organisms. Two of these studies found that carbapenems were superior to quinolones, and one study found that they were equally effective. It is possible that suboptimal dosing of quinolones in the presence of strains with elevated quinolone MICs (yet remaining in the “susceptible” range) accounts for these differences. Nitrofurantoin is an option for the oral treatment of cystitis due to ESBLproducing E. coli or Klebsiella species. It is important to note that nitrofurantoin is not useful in patients with upper tract infections or with moderate to severe renal impairment. Oral pivmecillinam and fosfomycin are available in some countries for the treatment of cystitis due to ESBL producers.

Treatment of KPC Producers

Treatment of KPC-producing organisms is difficult because they may lack susceptibility to all β-lactam antibiotics, fluoroquinolones, and aminoglycosides. KPC-producing organisms sometimes appear to be susceptible to carbapenems such as meropenem and imipenem (although they are always recognized as resistant to ertapenem), but these antibiotics should not be used against KPC producers. Susceptibility to polymyxins (colistin, polymyxin B) and tigecycline is typically present. However, neither of these drug classes is a perfect solution. The pharmacokinetics of the polymyxins is not well understood, especially in critically ill or renally impaired patients. Nephrotoxicity and neurotoxicity are potential adverse effects of the polymyxins, although they are less common than they were 30 to 50 years ago, when the polymyxins first came into widespread use. Of concern is that increased polymyxin MICs have been observed during the treatment of KPC producers. Tigecycline attains low serum, urine, and cerebrospinal fluid concentrations relative to MICs of the drug with KPC producers. For this reason, tigecycline should be used with great caution in blood stream infection, UTI, and meningitis. Antibiotics that may not be widely available, such as fosfomycin and temocillin, may have activity against KPC producers. Clinical experience with these antibiotics against KPC-producing organisms is limited. Combination therapy (e.g., colistin plus a carbapenem or rifampin) is an option, but it has not been evaluated in randomized controlled trials. Novel inhibitors of KPC may hold some promise, but their clinical availability is years away.

PREVENTION

Prevention of hospital-acquired outbreaks caused by ESBL or KPC producers rests on a number of basic infection control principles (Chapter 290). First, if a focus of infection exists in the hospital environment, it should be removed. Examples include contamination of ultrasonography coupling gel or bronchoscopes. Outbreaks have been dramatically curtailed when these sources of contamination have been properly cleaned or removed. Evidence suggests that transient carriage on the hands of health care workers is the most important means of transferring ESBL- or KPCproducing Enterobacteriaceae from patient to patient. The hands of health care workers are presumably colonized by contact with the colonized skin of patients or by contact with a contaminated environment around the patient. It is important to recognize that many patients may have asymptomatic colonization with ESBL- or KPC-producing organisms and thus exhibit no signs of overt infection. These patients represent an important reservoir of organisms. In some hospital wards with ongoing issues related to ESBL or KPC producers, more than 30% of patients have gastrointestinal tract colonization with these organisms at any given time. These patients should be subject to contact precautions. Hand carriage by health care workers is usually eliminated by hand hygiene with alcohol-based agents. Compliance with contact isolation precautions and hand hygiene must be high to maximize the effectiveness of these interventions. Changes in antibiotic policy may play a role in controlling outbreaks attributed to ESBL and KPC producers, but this concept remains controversial. In one reported outbreak of ESBL producers, no effort was made to change infection control procedures. Instead, ceftazidime use decreased, and piperacillin-tazobactam was introduced to the hospital’s formulary. This coincided with curtailment of the outbreak. In another institution, the entire class of cephalosporins was removed to gain control over endemic ESBL producers. The difficulty with this approach is that the replacement of one antibiotic class with another may result in the replacement of one antibiotic resistance issue with another. No study has demonstrated that removing carbapenems from a hospital formulary leads to the elimination of KPC producers. This is not surprising, because no study has shown an independent association between prior carbapenem use and the isolation of KPC producers. These

organisms are resistant to multiple antibiotic classes, and it is more common for patients to receive β-lactam/β-lactamase inhibitor combinations and fluoroquinolones than carbapenems prior to colonization or infection with KPC producers. Prudent use of all antibiotic classes, with an emphasis on reducing the duration of antibiotic use, may be more useful than the restriction of individual antibiotic classes.

PROGNOSIS

The prognosis of infection with the Enterobacteriaceae depends on multiple factors, including site of infection, presence of underlying diseases, and adequacy of empirical antibiotic therapy. At one extreme, inadequate orally administered antibiotic therapy for uncomplicated UTI due to an ESBL producer may have no impact on mortality, although it may have an impact on the duration of symptoms and the need for parenteral therapy due to treatment failure. At the other extreme, patients in the intensive care unit with serious infections due to KPC producers may have an in-hospital mortality rate exceeding 70%. In contrast, comparable patients without infection due to a KPC producer have in-hospital mortality rates of 20 to 30%. SUGGESTED READINGS Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1-12. Underscores the relative importance of antibiotic resistance issues among the Enterobacteriaceae and the paucity of new agents being developed to meet this threat. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum β-lactamase-producting Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc. 2011:86:250-259. Review of the current approach to infections with resistant organisms. Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med. 2010;362:1804-1813. Comprehensive review of resistance mechanisms, clinical manifestations, and limited management options. Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother. 2009;53:5046-5054. First report of the NDM β-lactamase, which threatens patients in India and poses a major antibiotic resistance issue.