Page 966 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 75: Urinary Tract Infections 697

TABLE 75-1 Molecular Epidemiology of Resistance in Enterobacteriaceae
Enzyme Molecular Epidemiology Distribution and Dominant Species Cross-resistance Susceptibility and Therapy
ESBL Group-1 CTX-M enzymes, mainly Global, hospital and community Resistant to cephalosporins, extended-spectrum Imipenem, meropenem,
CTX-M-15, O25:H4-ST131 K pneumoniae and E coli penicillins, aztreonam, fluoroquinolones, ertapenem, doripenem
aminoglycosides. Susceptible to carbapenems
AmpC and porin mutation Chromosomal Global, but uncommon As above, but resistant to carbapenems Colistin, tigecycline, fosfo-
a
IMP Mainly plasmid Global but uncommon As above, but resistant to carbapenems mycin, extended-infusion
carbapenem, combinations
b
VIM Plasmid more than clonal Global, endemic in Greece As above, but resistant to carbapenems of the above
spread Nosocomial. K pneumoniae
KPC Mainly clonal spread; limited USA, mainly NYC and NE states; endemic As above, but resistant to carbapenems
plasmid spread in Greece and Israel. Outbreaks in Europe
Nosocomial. K pneumoniae
OXA-48 Plasmid and clonal spread Turkey, Mid-East, and N Africa. K pneumoniae As above, but resistant to carbapenems
Limited importation to Europe Nosocomial
NDM Interspecies plasmid spread Widespread India and Pakistan Spreading As above, but resistant to carbapenems
occurs readily and is more globally. K pneumoniae and E coli
important than clonal spread Potential for widespread fecal
colonization in the community
a Inadequate blood levels and renal excretion cannot be relied upon alone for bacteremia or UTI.
b Awaiting studies.
■ EMERGING ANTIMICROBIAL RESISTANCE IN ENTEROBACTERIACEAE resultant increased resistance in third- and fourth-generation cepha-

In the 21st century, the prevalence of antimicrobial resistance in gram- losporins and aztreonam is mainly due to Group-1 CTX-M enzymes,
negative bacilli has increased dramatically worldwide so that many previ- principally CTX-M-15. In addition, these strains are usually resistant to
ously effective antimicrobial regimens are no longer reliable for UTI. In fluoroquinolones, aminoglycosides, and all ß-lactams except carbapen-
particular both extended-spectrum-ß-lactamase (ESBL)–producing and ems. This multidrug resistance is due to a linkage on the plasmid of the
†
carbapenem-resistant Enterobacteriaceae (CRE) have emerged as major CTX-M-15 gene* to a gene for aminoglycoside resistance that also deac-
‡
challenges. The genes for both ESBLs and CRE are on plasmids, which tivates fluoroquinolones and to a gene encoding an inhibitor-resistant
also commonly carry genes for resistance against most non-ß-lactam penicillinase. Klebsiella pneumoniae organisms with ESBLs have caused
antimicrobial agents. Some are prone to interspecies transfer, resulting in common source ICU outbreaks, including UTI. Of greater concern,
widespread dissemination. Globalization has facilitated spread, especially E coli isolates with ESBLs have become increasingly common worldwide
for Enterobacteriaceae, which constitute such a huge proportion of the causing infection in both the hospital and community, including pyelo-
normal colonic flora. The absence of new agents for gram-negative bacilli nephritis. One-third of recent E coli urinary isolates in the Asia-Pacific
18
in development raises the prospect of increased mortality for patients region had ESBLs, including 60% of isolates from India. An ICU in
China reported that 80% of E coli isolates between 2003 and 2007 were
with urosepsis in the second decade of the 21st century. However, in 21
2011, there is great geographic variation in resistance and in many resistant to third-generation cephalosporins. In the United Kingdom
and Ireland, the proportion of E coli bacteremia resistant to third-
regions community-acquired urinary pathogens still remain susceptible
to standard antimicrobial regimens (Table 75-1). generation cephalosporins began to increase steadily from 2% in 2001 to
12% by 2007. Many of these were of urinary origin in the community
22
Prior to 2000, resistance to fluoroquinolones in gram-negative bacilli
was rare in the community and was only significant in P aeruginosa due to spread of CTM-15, often due to the international O25 : H4-ST131
clone, which is commonly fluoroquinolone resistant. It had also been
23
in the ICU. Fluoroquinolones were ideal urinary agents, with a broad
spectrum of activity against urinary pathogens, excellent bioavailability reported in many other countries by 2010, including France, Switzerland,
Spain, Portugal, Turkey, Lebanon, Korea, Canada, and USA.
The
24,25
facilitating oral switch, and high volume of distribution favoring tissue
penetration. Predominantly renal excretion results in high urinary levels need to cover ESBLs has driven a more extensive use of carbapenems for
empiric therapy, sometimes even for pyelonephritis, eroding the reserve
of ciprofloxacin, ofloxacin, and levofloxacin, but not of moxifloxacin
or gemifloxacin; the latter two agents are not recommended for UTI. role of carbapenems.
16
With the emergence of widespread resistance, fluoroquinolones can no Carbapenem-resistant Enterobacteriaceae consist mainly of strains
longer be relied upon empirically as monotherapy for severe urosepsis. producing carbapenemases, which are subdivided into metallo-
The prevalence of resistance to ciprofloxacin in gram-negative bacilli, β-lactamases (IMP, VIM, NDM) or nonmetallo enzymes (KPC,
including P aeruginosa, increased from 14% in 1994 to 24% in 2000, in OXA-48). Additionally, a small minority of carbapenem resistance in
the ICUs of large US hospitals. This corelated with a 2.5-fold increase Enterobacteriaceae is due to a chromosomal mutation leading to a
in national fluoroquinolone use. By 2011, nearly half of all E coli porin loss in combination with hyperexpression of an ESBL or AmpC
17
urinary isolates were resistant to fluoroquinolones in the Asia-Pacific enzyme. Most CRE strains are resistant to all other β-lactams and often
region. By contrast in 2007 to 2009, the rate of such resistance in have multiple aminoglycoside-modifying enzymes; those with NDM-1
18
urinary pathogens in Canadian ICUs was 19% and in the community carbapenemase typically also have 16S rRNA methylases, conferring
19
was 6%. Resistance to third- and fourth-generation cephalosporins in high-level resistance to all aminoglycosides. The vast majority are also
20
Enterobacteriaceae was previously rare but abruptly increased in the first
decade of this century and is now common worldwide. By 2010, in excess
of 650 molecular varieties of ESBLs had been described, which had *bla CTX-M-15
evolved from older narrower spectrum ß-lactamases, such as TEM-1, † aac6 -1b-cr encoding an amikacin acetyltransferase
1
TEM-2, and SHV-1, by one to four amino acid substitutions. The ‡ bla
OXA-1
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