Serratia marcescens

Authors: Celine Herra, M.Sc., Frederick R Falkiner, B.A., Ph.D, FTCD.

Monograph
Tables
What's New
Reviews
History

MICROBIOLOGY

Once considered a harmless saprophyte, Serratia marcescens is now recognized as an important opportunistic pathogen combining a propensity for healthcare-associated infection and antimicrobial resistance.

Serratia marcescens is a member of the genus Serratia, which is a part of the family Enterobacteriaceae. Currently 14 species ofSerratia are recognized within the genus, eight of which are associated with human infection (67). Of the eight species implicated in clinical infection S. marcescens, S. liquefaciens and S. odorifera are best known (31, 67). Of all Serratia species, S. marcescens is the most common clinical isolate and the most important human pathogen.

S. marcescens is credited with a long fanatical history dating back to antiquity, when, because of its ability to produce a red pigment it was described as having ‘masqueraded’ as blood (36). Early in this century, this distinctive red pigmentation of S. marcescens, combined with an apparent low level of virulence, led to its use as a biological marker of infection. Consequently, S. marcescens was used in a number of classic bacterial transmission experiments, which led to improved understanding of the epidemiology of infection (124). Under more controversial settings, S. marcescens was also used by the US military in a series of biological warfare test experiments conducted on the general population (124). From 1960 onwards, however, non-pigmented isolates of S. marcescenspredominated over pigmented strains in the clinical setting and were increasingly implicated in healthcare-associated infection (24,30) particularly among compromised patients.

As members of the Enterobacteriaceae family, Serratia spp are motile, non-endospore forming Gram-negative rods. In the laboratorySerratia are routinely isolated from bloodstream and wound sites using blood agar culture or from respiratory and urinary sites using selective culture methods. Common selective agar cultures include MacConkey agar which categorizes Serratia isolates with the other non-lactose fermenting Enterobacteriaceae or chromogenic agars, which classifies them into a broad Klebsiella, Enterobacter,Serratia and Citrobacter (KESC) grouping (13, 17).

Phenotypically Serratia is one of the easiest genera to differentiate within the Enterobacteriaceae family. Unlike other enterobacteria, strains of Serratia usually produce extracellular deoxyribonuclease (DNase), gelatinase and lipase and are resistant to the antibiotics colistin and cephalothin. Traditionally, Serratia spp were identified using the Analytical Profile Index (API) 20E (bio-Merieux) phenotypic microbial identification system (40). With the widespread introduction of automated identification systems, laboratory identification of Serratia spp. is now routinely performed using systems including Vitek 2 (bio-Merieux), Microscan Walk-Away (Dade-Behring, Siemens), or BD Phoenix (BD Diagnostics, Sparks) (71). More recently, species level identification of Serratia isolates has been successfully achieved using rapid, automated MALDI-TOF MS (matrix-assisted laser desorbtion/ionization time-of-flight mass spectrometry) identification systems (86, 95).

EPIDEMIOLOGY

Serratia marcescens is an opportunistic pathogen whose clinical significance has been appreciated only in the last four decades. While S. marcescens is a rare cause of community-acquired infections, it has emerged as an important nosocomial healthcare-associated pathogen and a frequent source of outbreaks of hospital infection (72), in both adult (122) and paediatric patients (115). Results from a recent surveillance programme in the US and Europe, indicate that Serratia spp., accounts for an average of 6.5% of all Gram negative infection in Intensive Care Units (ranked 5th amongst Gram negative organisms in ICU) and an average of 3.5% in non-ICU patients (91). Currently Serratia is the seventh most common cause of pneumonia with an incidence of 4.1% in the US, 3.2% in Europe and 2.4% in Latin America (51), and the tenth most common cause of bloodstream infection with an incidence of 2.0% amongst hospitalized patients (2).

S. marcescens is rarely associated with primary invasive infection. It operates as a true opportunist producing infection whenever it gains access to a suitably compromised host. Patients most at risk include those with debilitating or immunocompromising disorders, those treated with broad-spectrum antibiotics and patients in ICU who are subjected to invasive instrumentation. The indwelling urinary catheter is a major risk factor for infection. The risk of a catheterized patient becoming infected with S. marcescens has been directly related to the proximity of other catheterized patients colonized or infected with the organism (68). The respiratory tract is also recognized as a major portal of entry with S. marcescens being isolated from the respiratory tract of up to 80% of post-operative patients developing S. marcescens bacteremia (125). Not surprisingly, common infections include urinary tract infection in patients with indwelling catheters, respiratory tract infection in intubated patients and bloodstream infection in post-surgical patients, especially in those with intravenous catheters.

CLINICAL MANIFESTATIONS

S. marcescens is implicated in a wide range of serious infections including pneumonia (51), lower respiratory tract infection (112), urinary tract infection (53), bloodstream infection, wound infection and meningitis (72, 74). The organism has also been described as an important cause of ocular infection with high incidence in contact lens-related keratitis (4, 21, 92).

S. marcescens is also a rare cause of endocarditis. In the 1970s, S. marcescens was the most frequent cause of Gram-negative endocarditis among intravenous drug addicts in San Francisco (73). The frequency has since subsided, although sporadic cases ofSerratia endocarditis still occasionally occur with two of the highest risk groups including intravenous drug users and patients undergoing prosthetic valve surgery. Skin and soft tissue infections are also unusual although rare cases of invasive cellulitis and necrotizing fasciitis have been reported (60). Septic arthritis has also been reported following diagnostic and therapeutic intra-articular injections (76).

Over the years, S. marcescens infection has been attributed to many different sources. Outbreaks of infection have been traced to medical equipment including nebulisers (87), bronchoscopes (82), electrocardiogram leads (100), laryngoscopes (20) and contaminated solutions such as inhalation medications (112), prefilled heparin syringes (8, 103), saline solutions (105), parenteral nutrition (3) and antiseptics (76). Many diverse environmental sources such as air conditioning units (82), urine-collecting basins (122), bed-pan macerators (42), liquid soap dispensers (104) and even tap water (46) have also been implicated.

Outside of environmental sources, hospital patients have also been recognized as a reservoir for infection. The gastrointestinal tract is recognized as the predominant site of colonization for S. marcescens, as is the case for most members of the Enterobacteriaceaefamily. Studies have shown, however, that rates of S. marcescens gastrointestinal carriage are largely dependent on the population screened (11). In the healthy host and non-infected immunocompetent patient, carriage rates remain low (<1% and 3%, respectively). However, in affected wards carriage rates of 21% have been reported in non-infected patients, whilst over 30% of patients infected with S. marcescens carry the organism in the gut (11, 123). Once established, carriage is persistent and patients are likely to carry the organism at multiple sites, with the throat and nose identified as common sites in 59% and 31% of colonized patients, respectively (11).

Regardless of the source or reservoir, the predominant mode of spread of S. marcescens is thought to be hand-to-hand transmission by hospital personnel (23, 68). The recovery of epidemic strains of S. marcescens from hand cultures of hospital staff has been reported consistently in epidemiologic studies (39, 49). In one hospital, almost 50% of hand cultures from staff were positive at the end of their working shift (113). Factors such as debilitating clinical condition, lengthy ward-stay and frequent exposure to medical interventions, most likely act by necessitating increased frequency and intensity of direct contact with staff hands (111).

PATHOGENESIS

In keeping with its role as an agent of opportunistic infection, S. marcescens was traditionally associated with low intrinsic pathogenicity. Whilst almost all isolates produce extracellular products such as DNase, chitinase, lecithinase, lipase, gelatinase and siderophores, it appears that in S. marcescens, these products do not act as potent virulence factors (5). Nevertheless, ongoing studies indicate that S. marcescens may produce other invasive factors. Almost all isolates of S. marcescens secrete a pore-forming haemolysin, ShIA, that is associated with cell cytotoxicity and the release of inflammatory mediators. This cytotoxin is thought to assist in tissue penetration (43) and may be linked to the expression of an extensive host invasive pathogenic pathway involving bacterial swarming and quorum sensing (58, 61). S. marcescens isolates have also been shown to engage in cell signaling mechanisms involved in biofilm production (97). If future studies confirm the pathogenic role of biofilm in S. marcescens, this may correlate with other characteristics of this opportunistic pathogen including adherence, colonization and antimicrobial resistance.

SUSCEPTIBILITY IN VITRO AND IN VIVO

In the last two decades Enterobacteriaceae have demonstrated an exceptional ability to acquire, transfer, and modify the expression of multiple antimicrobial resistance genes (64). As a typical member of the Enterobacteriaceae family and complementary to its capacity for survival, S. marcescens characteristically demonstrates a propensity to express antimicrobial resistance. S. marcescensare uniformly resistant to a wide range of antibiotics including narrow-spectrum-penicillins and cephalosporins, cefuroxime, cephamycins, macrolides, tetracycline, nitrofurantoin and colistin (101). In addition, clinical isolates display a selective advantage through their readiness to acquire and express many other antimicrobial resistance determinants. In the past, agents such aminoglycosides, fluoroquinolones and third-generation cephalosporins comprised the mainstay of treatment of S. marcescensinfection. However, many clinical isolates of S. marcescens now demonstrate multiple antimicrobial resistance to these agents (72,121). The pattern of resistance displayed by clinical isolates of S. marcescens invariably reflects patterns of antimicrobial use.

In the 1960s isolates of S. marcescens were invariably susceptible to aminoglycosides. Early studies reported that more than 97% of isolates were susceptible to gentamicin at 1 µg/ml or less (119). In the 1970s, however, gentamicin resistance was observed inSerratia. Yu (126) noted that 24% of 140 healthcare-associated infections caused by S. marcescens identified from 1974 through 1977 were gentamicin resistant and that the emergence of this resistance paralleled the overall increased use of gentamicin in the hospital. Over the next decade, aminoglycoside resistance was widely reportedbeing present in up to 50% of clinical isolates. In more recent years, the increased use of other agents such as third-generation cephalosporins and fluoroquinolones has led to a reduction in the use of aminoglycosides. Consequently, the rate of aminoglycoside resistance amongst S. marcescens isolates has decreased to an average of 6%, with rates varying from 5% in respiratory isolates, 7% in bloodstream isolates and 9% in urinary tract isolates (65). Nevertheless, over the years, clinically significant outbreaks of aminoglycoside-resistant S. marcescens infection continue to be reported in the healthcare environment, with strains demonstrating resistance to one or more of the aminoglycosides and cross resistance to other antibiotic families including the beta-lactams and fluoroquinolones (49, 74).

In S. marcescens aminoglycoside resistance is most frequently attributed to the presence of plasmid-mediated aminoglycoside-modifying enzymes, which confer high levels of resistance to one or more aminoglycosides (99). In S. marcescens the most frequently occurring aminoglycoside-modifying enzymes include N-acetyltransferases AAC(6')-I and AAC(3)-I and O-adenyltransferase ANT(2'')-I. The geographic distribution of different aminoglycoside-modifying enzymes varies considerably depending on regional aminoglycoside usage. AAC(6')-I, which mediates resistance to tobramycin, netilmicin, amikacin and dibekacin, and ANT(2'')-I which confers resistance to gentamicin, tobramycin and dibekacin, are frequently found in the US and the Far East (98). Outside of enzyme inactivation, aminoglycoside resistance may also result from diminished uptake or efflux, which confer low-level resistance to all aminoglycosides. More recently aminoglycoside resistance has also been attributed to a rare mechanism involving 16S rRNA methylase-mediated ribosomal protection. Novel plasmid-mediated 16S rRNA methylase enzymes including RmtB, ArmA, RmtA, and RmtC have been identified in S. marcescens. These enzymes have been shown to mediate high-level resistance to several aminoglycosides, including kanamycin, tobramycin, amikacin, gentamicin, streptomycin and arbekacin (25, 52). Regardless of the mechanism involved, aminoglycoside resistance is readily detected in S. marcescens using routine disc diffusion or microbroth dilution susceptibility testing.

In the early 1990s fluoroquinolones were shown to demonstrate considerable activity against S. marcescens with ciprofloxacin and levofloxacin expressing minimum inhibitory concentrations (MICs) of 0.5 µg/ml (34, 44). In the following years, however, the marked increase in the use of fluoroquinolones in hospital patients was reflected by a corresponding increase in the numbers of fluoroquinolone-resistant S. marcescens isolates. Reports indicate that over a twelve year period from 1984 to 1995, the percentage of fluoroquinolone-resistant S. marcescens isolates rose from 14% to 70% compared with increases from 5% to 15% for other healthcare-associated enterobacteria such as Enterobacter cloacae and Citrobacter freundii (1). In more recent years the overall rate of fluoroquinolone resistance has decreased, presumably reflecting increased reliance on beta-lactam therapy. The SENTRY antimicrobial resistance survey, 2009-2011, recorded reduced resistance rates to ciprofloxacin (15%) and levofloaxacin (11%) in S. marcescens isolates from ICU patients in US and European hospitals(91). Nevertheless, as would be expected with an organism with the adaptive capacity of S. marcescens, highly divergent rates of fluoroquinolone resistance still exist between institutions. In one study conducted in a military base from 2008 to 2010, 95% of all S. marcescens were fluoroquinolone sensitive (67) whilst other studies investigating healthcare-associated infection continue to report resistance rates of up to 60% in S. marcescens (122).

As with other members of the Enterobacteriaceae family, fluoroquinolone resistance in S. marcescens is attributable to a number of mechanisms. The main mechanism for resistance involves mutations in the gyrA gene which codes for the A subunit of the target enzyme, DNA gyrase (35, 117). In addition to target modification, fluoroquinolone resistance may result from alterations in membrane proteins, primarily Omp1 (90), and chromosomally-mediated resistance-nodulation-cell-division (NRD) efflux pumps, SdeAB, SdeCDE and SdeXY (7). In more recent years reports of a diverse range of plasmid-mediated quinolone resistance determinants including quinolone resistance proteins (qnr), aac(6’)-Ib-cr, QepA efﬂux and OqxAB, have also been detected in high level quinolone-resistantS. marcescens isolates (120, 121). Similar to the aminoglycosides, fluoroquinolone-resistant S. marcescens isolates are also detected using routine antimicrobial susceptibility testing.

With the widespread reliance on beta-lactam antibiotics, the frequency of resistance to these common agents has risen steadily among Gram negative bacilli (66). Enterobacteriaceae, have not only evolved to allow for increased production of existing beta-lactamases but also for the production of modified enzymes with extended substrate profiles and decreased susceptibility to beta-lactamase inhibitors (29, 70). As expected, one of the most striking examples of the potential of Enterobacteriaceae to demonstrate extended beta-lactam resistance is S. marcescens. This organism demonstrates most, if not all, common modes of beta-lactam resistance.

S. marcescens are inherently resistant to a range of narrow-spectrum penicillins including ampicillin, amoxicillin, amoxicillin-clavulanate, ampicillin-sulbactam and several narrow-spectrum cephalosporins (101) (Table 1). This resistance is attributed to the presence of a chromosomal AmpC beta-lactamase enzyme. Similar to other Enterobacteriaceae, S. marcescens express class C, inducible AmpC beta-lactamase (50). Expression of AmpC is linked to perturbation in cell wall synthesis and the interplay of several gene products associated with cell wall recycling (50). In wild-type isolates (uninduced state) transcription of the structural ampCbeta-lactamase gene is repressed, thus only trace amounts of AmpC beta-lactamase enzyme are produced and resistance is restricted to narrow spectrum beta-lactam agents. In the presence of beta-lactam agents expression of AmpC is inducible and bacteria produce a transient increase in beta-lactamase production which returns to low-level when the inducer is removed (63). Induction per se is thus not associated with clinically significant resistance. The ampC gene is, however, also capable of undergoing mutation to produce a state of stable derepression or constitutive beta-lactamase over-production (78). These stably-derepressed or hyperproducing mutants segregate spontaneously within the normal inducible population (62). Since this constitutive high-level beta-lactamase production occurs independent of the presence of inducers, derepressed mutants demonstrate clinically significant cross-resistance to most beta-lactam agents including the beta-lactamase-stable broad-spectrum cephalosporins, monobactams and the beta-lactam/beta-lactamase inhibitor combinations.

Individual beta-lactam drugs differ in their ability to induce AmpC activity. Broad-spectrum cephalosporins such as cefotaxime, ceftazidime, ceftriaxone and cefepime are weak inducers of the enzyme and thus remain stable against AmpC-inducible bacteria (50). However, this activity against inducible cells renders the drugs highly selective for the pre-existing resistant derepressed mutants that can survive and overgrow. Consequently, the clinical importance of inducible beta-lactamases and derepressed mutants has increased dramatically since the introduction of third-generation cephalosporins. Since the selective process occurs within days of treatment with these broad-spectrum agents, it is associated with a high rate of therapeutic failure (37). Once selected, these ampCmutants are stable, can be transferred from patient to patient and may in time, constitute a major proportion of the isolates of that species in a hospital. Similar to other AmpC-inducible enterobacteria, the selection of derepressed isolates in S. marcescens has been associated with high-level cephalosporin cross-resistance (6, 38, 84). Nevertheless, in contrast to other enterobacteria, where high-frequency selection of AmpC-derepresed mutants results in equally high rates of clinical failure, this has not been the case for S. marcescens (16). Studies investigating S. marcescens AmpC production have revealed that selection is a rare event and is associated with beta-lactamase levels 10-fold below derepressed Enterobacter and Citrobacter spp (63).

Currently there is no standardized laboratory method for AmpC detection (50). Cefoxtin resistance can used as a marker for AmpC production, however, this test is non-specific as several class A beta-lactamases and some carbapenemases can mediate this resistance. A three dimensional cefoxitin disc diffusion test can be used for AmpC detection, but this method is laborious for routine use and results are inoculum-dependent (96). Cephomycin Etest strips (AB Biodisk), in the presence and absence of cloxacillin (AmpC inhibitor), have also been evaluated for AmpC detection, but in this case, poor sensitivity (88%) is reported (50). Despite the absence of a simple, reliable detection method, the level of resistance associated with constitutive AmpC over-production, even in S. marcescens, is such that routine susceptibility test methods are generally considered adequate for the detection of AmpC-mediated resistance. Moreover, since AmpC expression is chromosomally-mediated, all isolates of S. marcescens are capable of producing the enzyme. Hence, it is generally agreed that identification of this organism is sufficient to alert the clinician that the isolate has the potential to develop AmpC-mediated cephalosporin resistance (94).

Outside of the expression of chromosomal AmpCbeta-lactamase, S. marcescens is also associated with the acquisition of class A plasmid-encoded beta-lactamases. In common with all Enterobacteriaceae, S. marcescens express classic, plasmid-encoded class A beta-lactamases such as TEM1 and SHV1, which hydrolyse penicillins and early generation cephalosporins. However, in addition to these narrow-spectrum enzymes, S. marcescens have also acquired a range of plasmid-mediated extended spectrum beta-lactamases (ESBLs) (9). ESBLs are derived from mutation of classical plasmid-encoded beta-lactamases, which extend the hydrolytic spectrum of the enzymes to include broad-spectrum agents such as cefotaxime, ceftazidime and cefepime (66). Over the thirty years since ESBLs first emerged their production has predominated in Klebsiella pneumoniae and Escherichia coli, with geographic ESBL prevalence rates varying from 5.3% and 2.8% in the US to 8.8% and 6.4% in Europe, respectively (89). Nevertheless, ESBLs continue to be reported in other enterobacteria including S. marcescens (69, 74).

Over the years, ESBL-producing S. marcescens have been reported in both single episodes and healthcare-associated outbreaks of infection. In recent reports ESBL-producing S. marcescens have been implicated in serious outbreaks of infection involving neonatal and adult ICU departments and transplantation units (19, 49). Whilst the prevalence of ESBLs varies, high rates of expression have been observed in a number of regions including Thailand, South Korea and India where ESBLs have been found in 24% (56), 30% (55) and 33% (88) of S. marcescens isolates, respectively. In keeping with the intercontinental and regional spread of non-TEM, non-SHV-derived ESBLs (66), S. marcescens is most frequently associated with the acquisition of CTX-M ESBLs, with studies reporting frequent production of CTX-M-3 (15, 69). Nonetheless, other reports of S marcescens carrying TEM- and SHV- type ESBLs and a novel ESBL derivative, BES-1, are also evident (67). It also worth noting that similar to other ESBL-producing Enterobacteriaceaewhich often incorporate transferable resistance elements that confer multi-drug resistance (MDR), ESBL-producing S. marcescensisolates often demonstrate cross resistance to other antibiotic classes including aminoglycosides and fluoroquinolones (49). Clonal spread of MDR-ESBL-producing S. marcescens may severely limit therapeutic options.

Unlike AmpC production where high levels of beta lactamase correlate with in vitro demonstration of resistance, ESBLs tend to demonstrate lower beta-lactam hydrolytic efficiency. ESBL-producing organisms may thus produce in vivo resistance and therapeutic failure and yet appear to demonstrate in vitro ‘susceptibility’ to many cephalosporins (14). Since ESBL-mediated resistance is not readily detected, clinical laboratories are required to adopt specialized screening methods (107). Early inhibitor-based detection methods using the clavulanic-double disc synergy test, where the clavulanic inhibitor was used to potentiate the activity of the indicator drug against an ESBL-producing isolate by enhancing the zone of inhibition, have been found to be unreliable (28). Current ESBL detection methods rely on standardized susceptibility testing using a range of indicator cephalosporins. In isolates with evidence of reduced susceptibility, ESBL production is then confirmed using combination tests where cephalosporin susceptibility is repeated, in the presence and absence of clavulanic acid (ESBL inhibitor) (18). To date, results of the various commercial ESBL-confirmatory combination tests including the combination disc test (Oxoid), MIC-ESBL strips (AB Biodisk) and Vitek 2 ESBL panels (bio-Mérieux), indicate improved sensitivity (99%) for ESBL detection in isolates such as K. pneumoniae and E. coli (28, 80). Nevertheless, the application of these combination susceptibility methods remains limited in isolates such as S. marcescens where co-production of inducible AmpC beta-lactamase (that is resistant to clavulanic acid) masks ESBL detection (106). The recent introduction of ESBL screening agars, such as EbSA (AlphaOmega) which combine cephalosporin indicator antibiotics and AmpC beta lactamase inhibitors may thus prove more successful for ESBL detection in AmpC-producing Enterobacteriaceae such as S. marcescens (80).

Broad spectrum carbapenem beta-lactam antibiotics, such as imipenem and meropenem, resist inactivation by chromosomal AmpC and plasmid-mediated ESBL beta-lactamases. In general, both these carbapenems have MIC90 values for S. marcescens of 2 µg/ml or less and would thus be expected to be very effective against Serratia infection (Table 1). Nevertheless, in keeping with the alarming spread of carbapenem resistance amongst Enterobacteriaceae, a small number of S. marcescens isolates has also been found to express an alarming diversity of carbapenem inactivating enzymes. SME-1, a class A chromosomal beta-lactamase with activity against narrow spectrum cephalosporins, carbapenems and monobactams, was first described in a clinical isolate of S. marcescens in London in 1982 (75). Since then two other class A chromosomal carbapenemases, SME-2 and SME-3, have been described in S. marcescens. In these sporadic infections, isolates were recovered from different regions in the US, suggesting that convergent evolution of these enzymes may have occurred following selection with increased clinical use of imipenem (22, 83).

The increased use of carbapenems has also been associated with the acquisition of plasmid-mediated carbapenemases in S. marcescens. Class B plasmid-encoded metallo-carbapenemases first appeared in S. marcescens in Japan in 1991 (48, 79). These IMP carbapenemases, mediate high-level cross-resistance to cephalosporins and carbapenems but, to date, have only been implicated in infrequent outbreaks of S. marcescens infection (41). A further plasmid-mediated carbapenemase, GES-1, has also been described in an isolated outbreak of S. marcescens in a Dutch hospital. Whilst this class A enzyme mediates resistance to broad spectrum cephalosporins, the carbapenemase activity is low level (23). Of more concern, S. marcescens have also been associated with the expression of the more readily-disseminated, plasmid-mediated KPC class carbapenemases. KPCs were first described in S. marcescens in an outbreak in China in 2006 (12). Thus far, these enzymes have only been described in isolated episodes of S. marcescens infections (22, 108), nevertheless, the appearance KPCs in S. marcescens in different regions is alarming, especially since these transmissible enzymes can mediate high level resistance to all beta-lactam agents.

Prompt detection of carbapenemase-producing Enterobacteriaceae is necessary to limit their spread. Current detection methods rely on standardized susceptibility testing with meropenem or ertapenem (18). Recommended confirmatory methods include the modified Hodge test (18, 59). This confirmatory methods is simple to perform, but interpretation of results has proven difficult (27, 116). Inhibitor-based tests involving the EDTA double disc synergy test and Etest MBL strips (AB Biodisk) have also been employed, however, these approaches have proven unreliable, especially in isolates with low-level carbapenem resistance (116). Whilst the results of chromogenic carbapenemase detection media are variable, some screening agars, such as Brilliance CRE (Oxoid), have proved sensitive (33). Current reports indicate that more rapid methods such as the chromogenic Carba NP test (CNP) could be useful alternative tools for carbapenemase detection (114).

Outside of the expression of a diverse array of beta-lactamase enzymes, beta-lactam resistance in S. marcescens may also result from a decrease in the permeability of the outer membrane via porin mutations (77). Reports indicate that reduced permeability may be combined with AmpC beta-lactamase and carbapenemase production to achieve high-level cephalosporin and carbapenem resistance in S. marcescens (102, 118).

ANTIMICROBIAL THERAPY

During the last forty years, S. marcescens has emerged as a serious healthcare-associated pathogen renowned for its ability to exhibit multiple antimicrobial resistance. Evidence has indicated, however, that healthcare institutions vary greatly in their experience with S. marcescens. Many hospitals have few, if any, problems and see very small numbers of isolates in a given time period. When isolates are recovered they are invariably susceptible to commonly used antibiotics and are readily treated. In other hospitals, however, the reverse is true. As a result of cross-infection, many isolates of the same strain are recovered. The strains become endemic within the healthcare population and usually develop multiple antimicrobial resistance. Outbreaks of infection are likely to coincide with any breakdown in infection control procedures. Then as the pathogen continues to become established within the hospital, antibiotic usage continues to select for the antibiotic-resistant population. Thus in hospitals where serious S. marcescensinfection is likely, the wide range of natural and acquired antibiotic resistance determinants associated with this pathogen render antimicrobial therapy limited.

Until gentamicin resistance began to emerge in the mid-1970s, aminoglycosides were considered the drugs of choice for treatment of infections caused by S. marcescens. In the past three decades, the increased use of agents such as third-generation cephalosporins has led to a reduction in the use of aminoglycosides. Coincident with this decline, current figures for the rate of aminoglycoside resistance amongst S. marcescens isolates has decreased to 6% (65). Nevertheless, given the potential of aminoglycosides for nephrotoxicity and ototoxicity, these agents have failed to regain their previous role as the single drugs of choice against S. marcescens and are largely used in combination with other antibiotics (Table 2).

The divergent rates of fluoroquinolone resistance in S. marcescens has limited the use of these agents in the treatment of serious infection. Consequently, fluoroquinolone use has become restricted to the treatment of uncomplicated infection at clinical sites where effective antibiotic concentrations are attainable and thus reduce the likelihood of the development of resistance.

In the recent past third-generation cephalosporins such as cefotaxime and ceftazidime comprised the mainstay of treatment of S. marcescens infection. The recognition that this pathogen cannot only engage in constitutive over-production of broad spectrum AmpC beta-lactamase but can also acquire and express a range of ESBLs, has eroded the use of these third generation cephalosporins as empiric agents. Whilst the demonstration of ESBL-production in S. marcescens clearly precludes the use of all cephalosporins, the utilization of these agents in isolates with evidence of AmpC derepression is debatable. High-frequency selection of AmpC derepresed mutants is not routinely associated with S. marcescens (16). However, as with all AmpC-inducible enterobacteria, the likelihood of selection ultimately depends on the infection site, the bacterial population density, the level of available drug at the site of infection and the clinical condition of the patient. Hence, in the urinary tract where the level of available antibiotic is adequate and the likelihood of selection is reduced, the drugs of choice for the treatment of ESBL-negative S. marcescens infection remain third-generation cephalosporins, used alone or in combination with aminoglycosides (gentamicin,amikacin) (Table 2) (63). However, in clinical settings where antibiotic bioavailability is reduced and resistance is likely to develop e.g. respiratory tract, bloodstream infection and deep-sited wound infections, or where the host is immunocompromised and thus dependent on the antibiotic alone for bacterial eradication, it is prudent to avoid the use of third-generation cephalosporins (63).

In the past, therapeutic approaches to the treatment of enterobacteria with the capacity for high-level ampC expression have used a beta-lactam drug in combination with a second non-beta-lactam agent such as an aminoglycoside. However, there are many reports of the failure of these combinations to prevent the emergence of resistance (93). Where AmpC derepression is a possibility and ESBLs are undetected, treatment options for S. marcescens include fourth-generation cephalosporins which retain beta-lactamase stability, or piperacillin/ tazoabactam where the risk of emergent resistance and clinical failure is minimal (37).

In recent years, tigecycline, a derivative of minocycline, has been used as an alternative treatment option for MDR enterobacteria. This first-in-class glycylcycline has been shown to retain activity against ESBL-positive and AmpC- producing isolates (45, 127) with MIC90 values of ≤ 2µg/ml for all Enterobacteriaceae including S. marcescens (Table 1) (32). Nevertheless, the use of this broad spectrum agent is limited in S. marcescens where up-regulation of the SdeXY-HasF efflux pump is associated with reduced susceptibility (47). Furthermore, tigecycline is also inadvisable for use in S. marcescens urinary tract infection, as the drug has largely biliary excretion with low urinary recovery (81).

More often, the drug of choice for S. marcescens isolates with evidence of AmpC derepression and/or ESBL production has become the carbapenems (37). Carbapenems remain active against bacteria expressing high levels of AmpC and ESBLS. Nevertheless, the emergence of carbapenemase-mediated resistance in S. marcescens suggests that judicious use of these agents must also be advised (12). To date, reports of chromosomal and plasmid-mediated carbapenemase production in S. marcescens have been restricted to sporadic episodes or isolated outbreaks of infection and, as such, carbapenem treatment has remained the preserve of serious S. marcescens infection. In the future, should the pattern of spread of multi-resistant carbapenemases in this pathogen, reflect the widespread dissemination seen in other enterobacteria, then the therapeutic options for S. marcescens will be greatly limited.

If S. marcescens is isolated from a normally sterile site such as blood or urine, the organism is clearly clinically significant and appropriate antimicrobial therapy must be administered. Given the epidemiologic profile of the organism intravenous catheters and indwelling urinary catheters must be considered possible portals of entry. If indwelling vascular lines are suspected they should be removed. If urinary catheters are implicated appropriate treatment may only be started just prior to catheter removal, as it is not possible to treat bacteriuria successfully while the urethral catheter remains in situ. Alternatively, if S. marcescens is isolated from a nonsterile site such as sputum then interpretation of the significance of this isolate is difficult, because colonization of the respiratory tract occurs readily (10). Since a major precipitating factor in the emergence of S. marcescens and its increasing association with antibiotic resistance is the over-use of broad-spectrum antibiotics, care must be taken to distinguish between active infection where prompt administration of therapy is necessary and colonization where the use of antibiotics is clearly contraindicated.

PREVENTION

Infection Control Measures

With continuing evidence of S. marcescens healthcare-associated infection it is apparent that opportunities for infection control not only depend on the prudent use of antimicrobials but also on the implementation of effective infection control policies (54). If an increase in the incidence of S. marcescens infections is evident, the infection-control team should become involved to prevent spread within the hospital, particularly when multi-resistant strains are isolated (57). As in all aspects of infection control hand hygiene is the most important component, and when S. marcescens is encountered, this should be re-emphasized to all healthcare personnel. Cohorting patients in specified rooms or units to minimise contact between personnel and non-infected patients with consideration of isolation measures may also be indicated.

CONCLUSION

Over the last four decades, S. marcescens has emerged as an important healthcare-associated pathogen. Infection with this organism represents a tangible cost in terms of patient morbidity and antibiotic usage. In the light of the multiple antimicrobial resistance demonstrated by S. marcescens, it is essential that the clinician evaluates the antimicrobial susceptibility of clinical isolates on the basis of data supplied by the microbiology laboratory and on the clinical setting of the infection, prior to the selection of appropriate therapy.

REFERENCES

1. Acar JF,Goldstein FW. Trends in bacterial resistance to fluoroquinolones. Clin Infect Dis 1997; 24 (Suppl.1): S67-73. [PubMed]

2. Anonymous. Annual epidemiological report 2012: Reporting on 2010 surveillance data and 2011 epidemic intelligence data. European Centre for Disease Prevention and Control, Stockholm, Sweden.

3. Arslan U, Erayman I, Kirdar S, Yuksekkaya S, Cimen O, Tuncer I, Bozdogan B. . Serratia marcescens sepsis outbreak in a neonatal intensive care unit. Pediatr Int 2010; 52: 208-212. [PubMed]

4. Atlee W, Burns R, Oden M. Serratia marcescens keratoconjunctivitis. Am J Ophthalmol 1970; 70: 31-33. [PubMed]

5. Aucken HM, Pitt TL. Antibiotic resistance and putative virulence factors of Serratia marcescens with respect to O and K serotypes. J Med Microbiol 1998; 47: 1105-1113. [PubMed]

6. Bagattini M, Crispino M, Gentile F, Barretta E, Schiavone D, Boccia MC, Triassi M, Zarrilli R. A nosocomial outbreak of Serratia marcescens producing inducible Amp C-type beta-lactamase enzyme and carrying antimicrobial resistance genes within a class 1 integron. J Hosp Infect 2004; 56: 29-36. [PubMed]

7. Begic S, Worobec EA. The role of the Serratia marcescens SdeAB multidrug efflux pump and TolC homologue in fluoroquinolone resistance studied via gene-knockout mutagenesis. Microbiology 2008; 154: 454-461. [PubMed]

8. Blossom D, Noble-Wang J, Su J, Pur S, Chemaly R, Shams A, Jensen B, Pascoe N, Gullion J, Casey E, Hayden M, Arduino M, Budnitz DS, Raad I, Trenholme G, Srinivasan A; Serratia in Prefilled Syringes Investigation Team Group. Multistate outbreak ofSerratia marcescens bloodstream infections caused by contamination of prefilled heparin and isotonic sodium chloride solution syringes. Arch Intern Med. 2009; 169: 1705-1711. [PubMed]

9. Bush K. Bench-to-bedside review: The role of beta-lactamases in antibiotic-resistant Gram-negative infections. Crit Care 2010; 14: 224-232. [PubMed]

10. Byrne AH, Boyle B, Herra CM, Hone R, Keane CT. Serratia marcescens causing hospital-acquired lower respiratory tract infection. J Hosp Infect 2000; 45: 242-244. [PubMed]

11. Byrne AH, Herra CM, Aucken H, Keane CT. Rate of carriage of Serratia marcescens in patients with and without evidence of infection. Scand J Infect Dis 2001; 33: 822-826. [PubMed]

12. Cai JC, Zhou HW, Zhang R, Chen GX. Emergence of Serratia marcescens, Klebsiella pneumoniae, and Escherichia coliisolates possessing the plasmid-mediated carbapenem-hydrolyzing beta-lactamase KPC-2 in intensive care units of a Chinese hospital. Antimicrob Agents Chemother 2008; 52: 2014-2018. [PubMed]

13. Carricajo A, Boiste S, Thore J, Aubert G, Gille Y, Freydière AM. Comparative evaluation of five chromogenic media for detection, enumeration and identification of urinary tract pathogens. Eur J Clin Microbiol Infect Dis 1999; 18: 796-803. [PubMed]

14. Carter MW, Oakton KJ, Warner M, Livermore DM. Detection of extended-spectrum b-lactamases in klebsiellae with the Oxoid combination disk method. J Clin Microbiol 2000; 38: 4228-4232. [PubMed]

15. Cheng KC, Chuang YC, Wu LT, Huang GC, Yu WL. Clinical experiences of the infections caused by extended-spectrum beta-lactamase-producing Serratia marcescens at a medical center in Taiwan. Jpn J Infect Dis 2006; 59: 147-152. [PubMed]

16. Choi SH, Lee JE, Park SJ, Choi SH, Lee SO, Jeong JY, Kim MN, Woo JH, Kim YS. Emergence of antibiotic resistance during therapy for infections caused by Enterobacteriaceae producing AmpC beta-lactamase: implications for antibiotic use. Antimicrob Agents Chemother 2008; 52: 995-1000. [PubMed]

17. Ciragil P, Gul M, Aral M, Ekerbicer H. Evaluation of a new chromogenic medium for isolation and identification of common urinary tract pathogens. Eur J Clin Microbiol Infect Dis 2006; 25: 108-111. [PubMed]

18. CLSI, Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility tests: Approved Standard-20th Edition M100-S20. 2010:CLSI, Wayne, PA.

19. Crivaro V, Bagattini M, Salza MF, Raimondi F, Rossano F, Triassi M, Zarrilli R. Risk factors for extended-spectrum beta-lactamase-producing Serratia marcescens and Klebsiella pneumoniae acquisition in a neonatal intensive care unit. J Hosp Infect 2007; 67: 135-141. [PubMed]

20. Cullen MM, Trail A, Robinson M, Keaney M, Chadwick PR. Serratia marcescens outbreak in a neonatal intensive care unit prompting review of decontamination of laryngoscopes. J Hosp Infect 2005; 59: 68-70. [PubMed]

21. Das S, Sheorey H, Taylor HR, Vajpayee RB. Association between cultures of contact lens and corneal scraping in contact lens related microbial keratitis. Arch Ophthalmol 2007; 125: 1182-1185. [PubMed]

22. Deshpande LM, Rhomberg PR, Sader HS, Jones RN. Emergence of serine carbapenemases (KPC and SME) among clinical strains of Enterobacteriaceae isolated in the United States Medical Centers: report from the MYSTIC Program (1999-2005). Diagn Microbiol Infect Dis 2006; 56: 367-372. [PubMed]

23. de Vries JJ, Baas WH, van der Ploeg K, Heesink A, Degener JE, Arends JP. Outbreak of Serratia marcescens colonization and infection traced to a healthcare worker with long-term carriage on the hands. Infect Control Hosp Epidemiol 2006; 27: 1153-1158 [PubMed]

24. Dodson WH. Serratia marcescens septicemia. Arch Intern Med 1968; 121: 145-150. [PubMed]

25. Doi Y, Yokoyama K, Yamane K, Wachino J, Shibata N, Yagi T, Shibayama K, Kato H, Arakawa Y. Plasmid-mediated 16S rRNA methylase in Serratia marcescens conferring high-level resistance to aminoglycosides. Antimicrob Agents Chemother 2004;48: 49-496. [PubMed]

26. Dowzicky MJ, Park CH. Update on antimicrobial susceptibility rates among gram-negative and gram-positive organisms in the United States: results from the Tigecycline Evaluation and Surveillance Trial (TEST) 2005 to 2007. Clin Ther 2008;30:2040-2050. [PubMed]

27. Doyle D, Peirano G, Lascols C, Lloyd T, Church DL, Pitout JD. Laboratory detection of Enterobacteriaceae that produce carbapenemases. J Clin Microbiol 2012; 50: 3877-3880. [PubMed]

28. Ejaz H, UI-Haq I, Mahmood S, Zafar A, Mohsin Javed M. Detection of extended-spectrum β-lactamases in Klebsiella pneumoniae: comparison of phenotypic characterization methods. Pak J Med Sci 2013; 29: 768-772 [PubMed]

29. El Salabi A, Walsh TR, Chouchani C. Extended spectrum β-lactamases, carbapenemases and mobile genetic elements responsible for antibiotics resistance in Gram-negative bacteria. Crit Rev Microbiol 2013; 39: 113-122. [PubMed]

30. Elston HR, Magnuson CW. Lung abscess caused by nonchromogenic Serratia marcescens. Amer Rev Resp Dis 1965; 92: 624-631. [PubMed]

31. Farmer JJ III. Enterobacteriaceae: Introduction and Identification. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of Clinical Microbiology. Washington, DC: American Society for Microbiology Press, 1995: 438-449.

32. Fernández-Canigia L, Dowzicky MJ. Susceptibility of important Gram-negative pathogens to tigecycline and other antibiotics in Latin America between 2004 and 2010. Ann Clin Microbiol Antimicrob 2012;11:1-9. [PubMed]

33. Frawley J, Mangan L, Boo TW. Comparison of four laboratory methods in the detection of carbapenemase-producingEnterobacteriaceae. J Med Microbiol 2013; 62: 1094-1096. [PubMed]

34. Fu KP, Lafredo SC, Foleno B, Isaacson DM, Barrett JF, Tobia AJ, Rosenthale ME. In vitro and in vivo antibacterial activities of levofloxacin (l-ofloxacin), an optically active ofloxacin. Antimicrob Agents Chemother 1992; 36: 860-866. [PubMed]

35. Fujimaki K, Fujii T, Aoyama H, Sato K, Inoue Y, Inoue M, Mitsuhashi S. Quinolone resistance in clinical isolates of Serratia marcescens. Antimicrob Agents Chemother 1989; 33: 785-787. [PubMed]

36. Gaughran ER. From superstition to science: the history of a bacterium. Trans NY Acad Sci1969;31: 3-24. [PubMed]

37. Harris PN, Ferguson JK. Antibiotic therapy for inducible AmpC beta-lactamase-producing Gram-negative bacilli: what are the alternatives to carbapenems, quinolones and aminoglycosides? Int J Antimicrob Agents 2012; 40: 297-305. [PubMed]

38. Hechler U, Van Den Weghe M, Martin HH, Frere JM. Overproduced b-lactamase and the outer-membrane barrier as resistance actors in Serratia marcescens highly resistant to b-lactamase-stable b-lactam antibiotics. Journal of General Microbiology 1989; 135: 1275-1290. [PubMed]

39. Hejazi A, Aucken HM, Falkiner FR. Epidemiology and susceptibility of Serratia marcescens in a large general hospital over an 8-year period. J Hosp Infect 2000;45:42-46. [PubMed]

40. Hejazi A, Falkiner FR. Serratia marcescens. J Med Microbiol 1997; 46: 903-912. [PubMed]

41. Herbert S, Halvorsen DS, Leong T, Franklin C, Harrington G, Spelman D. Large outbreak of infection and colonization with gram-negative pathogens carrying the metallo- beta-lactamase gene blaIMP-4 at a 320-bed tertiary hospital in Australia. Infect Control Hosp Epidemiol 2007;28:98-101. [PubMed]

42. Herra CM, Knowles SJ, Kaufmann ME, Mulvihill E, McGrath B, Keane CT. An outbreak of an unusual strain of Serratia marcescens in two Dublin hospitals. J Hosp Infect 1998; 38: 135-141. [PubMed]

43. Hertle R. The family of Serratia type pore forming toxins. Curr Protein Pept Sci 2005; 6: 313-325. [PubMed]

44. Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Engl J Med 1991; 324: 384-394. [PubMed]

45. Hope R, Warner M, Potz NA, Fagan EJ, James D, Livermore DM. Activity of tigecycline against ESBL-producing and AmpC-hyperproducing Enterobacteriaceae from south-east England. J Antimicrob Chemother 2006; 58: 1312-1314. [PubMed]

46. Horcajada JP, Martínez JA, Alcón A, Marco F, De Lazzari E, de Matos A, Zaragoza M, Sallés M, Zavala E, Mensa J. Acquisition of multidrug-resistant Serratia marcescens by critically ill patients who consumed tap water during receipt of oral medication. Infect Control Hosp Epidemiol 2006; 27: 774-777. [PubMed]

47. Hornsey M, Ellington MJ, Doumith M, Hudson S, Livermore DM, Woodford N. Tigecycline resistance in Serratia marcescensassociated with up-regulation of the SdeXY-HasF efflux system also active against ciprofloxacin and cefpirome. J Antimicrob Chemother 2010; 65: 479-482. [PubMed]

48. Ito H, Arakawa Y, Ohsuka S, Wacharotayankun R, Kato N, Ohta M. Plasmid-mediated dissemination of the metallo-b-lactamase gene blaIMP among clinically isolated strains of Serratia marcescens. Antimicrob Agents Chemother 1995; 39: 824-829. [PubMed]

49. Ivanova D, Markovska R, Hadjieva N, Schneider I, Mitov I, Bauernfeind A. Extended-spectrum beta-lactamase-producing Serratia marcescens outbreak in a Bulgarian hospital. J Hosp Infect 2008;70:60-65. [PubMed]

50. Jacoby GA. AmpC beta-lactamases. Clin Microbiol Rev 2009; 22: 161-182. [PubMed]

51. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis. 2010;51 (Suppl1):S81-87. [PubMed]

52. Kang HY, Kim KY, Kim J, Lee JC, Lee YC, Cho DT, Seol SY. Distribution of conjugative-plasmid-mediated 16S rRNA methylase genes among amikacin-resistant Enterobacteriaceae isolates collected in 1995 to 1998 and 2001 to 2006 at a university hospital in South Korea and identification of conjugative plasmids mediating dissemination of 16S rRNA methylase. J Clin Microbiol 2008;46:700-706. [PubMed]

53. Kawecki D, Kwiatkowski A, Sawicka-Grzelak A, Durlik M, Paczek L, Chmura A, Mlynarczyk G, Rowinski W, Luczak M. Urinary tract infections in the early posttransplant period after kidney transplantation: etiologic agents and their susceptibility. Transplant Proc 2011;43:2991-2993. [PubMed]

54. Khan AS, Dancer SJ, Humphreys H. Priorities in the prevention and control of multidrug-resistant Enterobacteriaceae in hospitals. J Hosp Infect 2012; 82: 85-93. [PubMed]

55. Kim J, Lim YM. Prevalence of derepressed ampC mutants and extended-spectrum beta-lactamase producers among clinical isolates of Citrobacter freundii, Enterobacter spp., and Serratia marcescens in Korea: dissemination of CTX-M-3, TEM-52, and SHV-12. J Clin Microbiol 2005; 43: 2452-2455. [PubMed]

56. Kiratisin P, Henprasert A. Resistance phenotype-genotype correlation and molecular epidemiology of Citrobacter, Enterobacter, Proteus, Providencia, Salmonella and Serratia that carry extended-spectrum β-lactamases with or without plasmid-mediated AmpC β-lactamase genes in Thailand. Trans R Soc Trop Med Hyg 2011; 105: 46-51. [PubMed]

57. Knowles S, Herra C, Devitt E, O'Brien A, Mulvihill E, McCann SR, Browne P, Kennedy MJ, Keane CT. An outbreak of multiply resistant Serratia marcescens: the importance of persistent carriage. Bone Marrow Transplant 2000; 25: 873-877. [PubMed]

58. Lai HC, Soo PC, Wei JR, Yi WC, Liaw SJ, Horng YT, Lin SM, Ho SW, Swift S, Williams P. The RssAB two-component signal transduction system iSerratia marcescens regulates swarming motility and cell envelope architecture in response to exogenous saturated fatty acids. J Bacteriol 2005; 187: 3407-3414. [PubMed]

59. Lee W, Chung HS, Lee Y, Yong D, Jeong SH, Lee K, Chong Y. Comparison of matrix-assisted laser desorption ionization-time-of-flight mass spectrometry assay with conventional methods for detection of IMP-6, VIM-2, NDM-1, SIM-1, KPC-1, OXA-23, and OXA-51 carbapenemase-producing Acinetobacter spp., Pseudomonas aeruginosa, and Klebsiella pneumoniae. Diagn Microbiol Infect Dis 2013; 77: 227-230. [PubMed]

60. Liangpunsakul, Pursell K. Community-acquired necrotising fasciitis caused by Serratia marcescens: case report and review. Eur J Clin Microbiol Infect Dis 2001; 20: 509-521. [PubMed]

61. Lin CS, Horng JT, Yang CH, Tsai YH, Su LH, Wei CF, Chen CC, Hsieh SC, Lu CC, Lai HC. RssAB-FlhDC-ShlBA as a major pathogenesis pathway in Serratia marcescens. Infect Immun 2010; 7: 4870-4881. [PubMed]

62. Livermore DM. Clinical significance of beta-lactamase induction and stable derepression in Gram-negative rods. Eur J Clin Microbiol 1987; 6: 439-445. [PubMed]

63. Livermore DM. b-lactamases in laboratory and clinical resistance. Clin Microbiol Rev 1995; 8: 557-584. [PubMed]

64. Livermore DM. b-Lactamase-mediated resistance and opportunities for its control. J Antimicrob Chemother 1998; 41(Suppl. D): 25-41. [PubMed]

65. Lockhart SR, Abramson MA, Beekmann SE, Gallagher G, Riedel S, Diekema DJ, Quinn JP, Doern GV. Antimicrobial resistance among Gram-negative bacilli causing infections in intensive care unit patients in the United States between 1993 and 2004. J Clin Microbiol 2007; 45: 3352-3359. [PubMed]

66. Lynch JP, Clark NM, Zhanel GG. Evolution of antimicrobial resistance among Enterobacteriaceae (focus on extended spectrum b-lactamases and carbapenemases). Expert Opin Pharmacother 2013; 14: 199-210. [PubMed]

67. Mahlen SD. Serratia Infections: from Military Experiments to Current Practice. Clin Microbiol Review 2011; 24: 755-791.[PubMed]

68. Maki DG, Hennekens CG, Phillips CW, Shaw WV, Bennett JV. Nosocomial urinary tract infection with Serratia marcescens: an epidemiologic study. J Infect Dis 1973; 128: 579-587. [PubMed]

69. Markovska RD, Stoeva TJ, Bojkova KD, Mitov IG. Epidemiology and Molecular Characterization of Extended-Spectrum Beta-Lactamase-Producing Enterobacter spp., Pantoea agglomerans, and Serratia marcescens Isolates from a Bulgarian Hospital. Microb Drug Resist 2014; 20: 131-137. [PubMed]

70. Matsumura N, Minami S, Mitsuhashi S. Sequences of homologous b-lactamases from clinical isolates of Serratia marcescens with different substrate specificities. Antimicrob Agents Chemother 1998; 42: 176-179. [PubMed]

71. Menozzi MG, Eigner U, Covan S, Rossi S, Somenzi P, Dettori G, Chezzi C, Fahr AM. Two-center collaborative evaluation of performance of the BD phoenix automated microbiology system for identification and antimicrobial susceptibility testing of gram-negative bacteria. J Clin Microbiol 2006; 44; 4085-4094. [PubMed]

72. Merkier AK, Rodríguez MC, Togneri A, Brengi S, Osuna C, Pichel M, Cassini MH; Serratia marcescens Argentinean Collaborative Group, Centrón D. Outbreak of a cluster with epidemic behavior due to Serratia marcescens after colistin administration in a hospital setting. J Clin Microbiol 2013; 51: 2295-2302. [PubMed]

73. Mills J, Drew D. Serratia marcescens endocarditis: a regional illness associated with intravenous drug abuse. Ann Intern Med 1976; 84: 29-35. [PubMed]

74. Młynarczyk A, Młynarczyk G, Pupek J, Bilewska A, Kawecki D, Łuczak M, Gozdowska J, Durlik M, Paczek L, Chmura A, Rowińnski W. Serratia marcescens isolated in 2005 from clinical specimens from patients with diminished immunity. Transplant Proc 2007; 39: 2879-2882. [PubMed]

75. Naas T, Livermore DM, Nordmann P. Characterization of an LysR family protein, SmeR from Serratia marcescens S6, its effect on expression of the carbapenem-hydrolyzing b-lactamase Sme-1, and comparison of this regulator with other b- lactamase regulators. Antimicrob Agents Chemother 1995; 39: 629-637. [PubMed]

76. Nakashima AK, McCarthy MA, Martone WJ, Anderson RL. Epidemic septic arthritis caused by Serratia marcescens and associated with a benzalkonium chloride antiseptic. J Clin Microbiol 1987; 25: 1014-1018. [PubMed]

77. Nikaido H. Outer membrane barrier as a mechanism of antimicrobial resistance. Antimicrob Agents Chemother 1989; 33: 1831-1836. [PubMed]

78. Nomura K, Yoshida T. Nucleotide sequence of the Serratia marcescens SR50 chromosomal ampC b-lactamase gene. FEMS Microbiol Lett 1990; 70: 295-299. [PubMed]

79. Osano E, Arakawa Y, Wacharotayankun R, Ohta M, Horii T, Ito H, Yoshimura F, Kato N. Molecular characterization of an enterobacterial metallo beta-lactamase found in a clinical isolate of Serratia marcescens that shows imipenem resistance. Antimicrob Agents Chemother 1994; 38: 71-78. [PubMed]

80. Overdevest IT, Willemsen I, Elberts S, Verhulst C, Kluytmans JA. Laboratory detection of extended-spectrum-beta-lactamase-producing Enterobacteriaceae: evaluation of two screening agar plates and two confirmation techniques. J Clin Microbiol 2011; 49:519-522. [PubMed]

81. Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med 2010; 362: 1804-1813. [PubMed]

82. Peltroche-Llacsahuanga H, Lütticken R, Haase G. Temporally overlapping nosocomial outbreaks of Serratia marcescensinfections: an unexpected result revealed by pulsed-field gel electrophoresis. Infect Control Hosp Epidemiol 1999; 20: 387-388.[PubMed]

83. Queenan AM, Torres-Viera C, Gold HS, Carmeli Y, Eliopoulos GM, Moellering RC, Jr., Quinn JP, Hindler J, Medeiros AA, Bush K. SME-type carbapenem-hydrolyzing class A b-lactamases from geographically diverse Serratia marcescens strains. Antimicrob Agents Chemother 2000; 44: 3035-3039. [PubMed]

84. Raimondi A, Sisto F, Nikaido H. Mutation in Serratia marcescens AmpC b-lactamase producing high-level resistance to ceftazidime and cefpirome. Antimicrob Agents Chemother 2001; 45: 2331-2339. [PubMed]

85. Rhomberg PR, Jones RN. Summary trends for the Meropenem Yearly Susceptibility Test Information Collection Program: a 10-year experience in the United States (1999-2008). Diagn Microbiol Infect Dis 2009;65:414-426. [PubMed]

86. Richter SS, Sercia L, Branda JA, Burnham CA, Bythrow M, Ferraro MJ, Garner OB, Ginocchio CC, Jennemann R, Lewinski MA, Manji R, Mochon AB, Rychert JA, Westblade LF, Procop GW. Identification of Enterobacteriaceae by matrix-assisted laser desorption/ionization time-of flight mass spectrometry using the VITEK MS system. Eur J Clin Microbiol Infect Dis 2013; 32: 1571-1578. [PubMed]

87. Ringrose RE, McKown B, Felton FG, Barclay BO, Muchmore HG, Rhoades ER. A hospital outbreak of Serratia marcescensassociated with ultrasonic nebulizers. Ann Intern Med 1968; 69: 719-729. [PubMed]

88. Rizvi M, Fatima N, Rashid M, Shukla I, Malik A, Usman A, Siddiqui S. Extended spectrum AmpC and metallo-beta-lactamases inSerratia and Citrobacter spp. in a disc approximation assay. J Infect Dev Ctries 2009; 3: 285-294. [PubMed]

89. Rossi F, Baquero F, Hsueh PR, Paterson DL, Bochicchio GV, Snyder TA, Satishchandran V, McCarroll K, DiNubile MJ, Chow JW. In vitro susceptibilities of aerobic and facultatively anaerobic Gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: 2004 results from SMART (Study for Monitoring Antimicrobial Resistance Trends). J Antimicrobe Chemother 2006;58:205-210. [PubMed]

90. Ruiz N, Montero T, Hernandez-Borrell J, Viñas M. The role of Serratia marcescens porins in antibiotic resistance. Microb Drug Resist 2003;9:257-264. [PubMed]

91. Sader HS, Farrell DJ, Flamm RK, Jones RN. Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalized in intensive care units in United States and European hospitals (2009-2011). Diagn Microbiol Infect Dis 2014;78: 443-448. [PubMed]

92. Samonis G, Vouloumanou EK, Christofaki M, Dimopoulou D, Maraki S, Triantafyllou E, Kofteridis DP, Falagas ME. Serratia infections in a general hospital: characteristics and outcomes. Eur J Clin Microbiol Infect Dis 2011;30:653-660. [PubMed]

93. Sanders CC, Sanders WE, Jr. Beta-Lactam resistance in Gram-negative bacteria: global trends and clinical impact. Clin Infect Dis 1992;15:824-839. [PubMed]

94. Sanders WE Jr, Sanders CC. Inducible b-lactamases: clinical and epidemiologic implications for use of newer cephalosporins. Rev Infect Dis 1988;10:830-838. [PubMed]

95. Schaumann R, Knoop N, Genzel GH, Losensky K, Rosenkranz C, Stîngu CS, Schellenberger W, Rodloff AC, Eschrich K. Discrimination of Enterobacteriaceae and Non-fermenting Gram Negative Bacilli by MALDI-TOF Mass Spectrometry. Open Microbiol J 2013; 7: 118-122. [PubMed]

96. Shahid M, Malik A, Agrawal M, Singhal S. Phenotypic detection of extended-spectrum and AmpC beta-lactamases by a new spot-inoculation method and modified three-dimensional extract test: comparison with the conventional three-dimensional extract test. J Antimicrob Chemother 2004; 54: 684-687. [PubMed]

97. Shanks RM, Stella NA, Kalivoda EJ, Doe MR, O'Dee DM, Lathrop KL, Guo FL, Nau GJ. A Serratia marcescens OxyR homolog mediates surface attachment and biofilm formation. J Bacteriol 2007; 189: 7262-7272. [PubMed]

98. Shimizu K, Kumada T, Hsieh WC, Chung HY, Chong Y, Hare RS, Miller GH, Sabatelli FJ, Howard J. Comparison of aminoglycoside resistance patterns in Japan, Formosa, and Korea, Chile, and the United States. Antimicrob Agents Chemother 1985; 28: 282-288. [PubMed]

99. Sleigh JD. Antibiotic resistance in Serratia marcescens. BMJ 1983; 287: 1651-1653. [PubMed]

100. Sokalski SJ, Jewell MA, Asmus-Shillington AC, Mulcahy J, Segreti J. An outbreak of Serratia marcescens in 14 adult cardiac surgical patients associated with 12-lead electrocardiogram bulbs. Arch Intern Med 1992;152:841-844. [PubMed]

101. Stock I, Grueger T, Wiedemann B. Natural antibiotic susceptibility of strains of Serratia marcescens and the S. liquefaciens complex: S. liquefaciens sensu stricto, S. proteamaculans and S. grimesii. Int J Antimicrob Agents 2003; 22: 35-47. [PubMed]

102. Suh B, Bae IK, Kim J, Jeong SH, Yong D, Lee K. Outbreak of meropenem-resistant Serratia marcescens comediated by chromosomal AmpC beta-lactamase overproduction and outer membrane protein loss. Antimicrob Agents Chemother 2010; 54: 5057-5061. [PubMed]

103. Sunenshine RH, Tan ET, Terashita DM, Jensen BJ, Kacica MA, Sickbert-Bennett EE, Noble-Wang JA, Palmieri MJ, Bopp DJ, Jernigan DB, Kazakova S, Bresnitz EA, Tan CG, McDonald LC. A multistate outbreak of Serratia marcescens bloodstream infection associated with contaminated intravenous magnesium sulfate from a compounding pharmacy. Clin Infect Dis 2007; 45: 527-533. [PubMed]

104. Takahashi H, Kramer MH, Yasui Y, Fujii H, Nakase K, Ikeda K, Imai T, Okazawa A, Tanaka T, Ohyama T, Okabe N. Nosocomial Serratia marcescens outbreak in Osaka, Japan, from 1999 to 2000. Infect Control Hosp Epidemiol 2004; 25: 156-161. [PubMed]

105. Tanaka T, Takahashi H, Kobayashi JM, Ohyama T, Okabe N. A nosocomial outbreak of febrile bloodstream infection caused by heparinized-saline contaminated with Serratia marcescens, Tokyo, 2002. Jpn J Infect Dis 2004; 57: 189-192. [PubMed]

106. Thomson KS, Sanders CC. Detection of extended-spectrum b-lactamases in members of the family Enterobacteriaceae: comparison of the double-disk and three-dimensional tests. Antimicrob Agents Chemother 1992; 36: 1877-1882. [PubMed]

107. Thomson KS, Sanders CC. A simple and reliable method to screen isolates of Escherichia coli and Klebsiella pneumonia for the production of TEM- and SHV-derived extended-spectrum b-lactamases. Clin Microbiol Infect 1997; 3:549-554. [PubMed]

108. Tsakris A, Voulgari E, Poulou A, Kimouli M, Pournaras S, Ranellou K, Kosmopoulou O, Petropoulou D. In vivo acquisition of a plasmid-mediated bla (KPC-2) gene among clonal isolates of Serratia marcescens. J Clin Microbiol 2010;48:2546-2549. [PubMed]

109. Turner PJ. MYSTIC Europe 2007: activity of meropenem and other broad-spectrum agents against nosocomial isolates. Diagn Microbiol Infect Dis 2009;63:217-222. [PubMed]

110. Tygacil® Product Insert. http://www.pfizerpro.com/hcp/tygacil

111. van der Sar-van der Brugge S, Arend SM, Bernards AT, Berbee GA, Westendorp RG, Feuth JD, van den Broek PJ. Risk factors for acquisition of Serratia marcescens in a surgical intensive care unit. J Hosp Infect 1999; 41:291-299. [PubMed]

112. van der Vorm ER, Woldring-Zwaan C. Source, carriers, and management of a Serratia marcescens outbreak on a pulmonary unit. J Hosp Infect 2002;52:263-267. [PubMed]

113. van Ogtrop ML, van Zoeren-Grobben D, Verbakel-Salomons EM, van Boven CP. Serratia marcescens infections in neonatal departments: description of an outbreak and review of the literature. J Hosp Infect 1997; 36: 95-103. [PubMed]

114. Vasoo S, Cunningham SA, Kohner PC, Simner PJ, Mandrekar JN, Lolans K, Hayden MK, Patel R. Comparison of a novel, rapid chromogenic biochemical assay, the Carba NP test, with the modified Hodge test for detection of carbapenemase-producing Gram-negative bacilli. J Clin Microbiol 2013; 51: 3097-3101. [PubMed]

115. Voelz A, Müller A, Gillen J, Le C, Dresbach T, Engelhart S, Exner M, Bates CJ, Simon A. Outbreaks of Serratia marcescens in neonatal and pediatric intensive care units: clinical aspects, risk factors and management. Int J Hyg Environ Health 2010; 213: 79-87.

116. Voulgari E, Poulou A, Koumaki V, Tsakris A. Carbapenemase-producing Enterobacteriaceae: now that the storm is finally here, how will timely detection help us fight back? Future Microbiol 2013;8:27-39. [PubMed]

117. Weigel LM, Steward CD, Tenover FC. gyrA mutations associated with fluoroquinolone resistance in eight species ofEnterobacteriaceae. Antimicrob Agents Chemother 1998;42:2661-2667. [PubMed]

118. Weindorf H, Schmidt H, Martin HH. Contribution of overproduced chromosomal b-lactamase and defective outer membrane porins to resistance to extended-spectrum b-lactam antibiotics in Serratia marcescens. J Antimicrob Chemother 1998; 41: 189-195. [PubMed]

119. Wilkowske CJ, Washington JA 2nd, Martin WJ, Ritts RE Jr. Serratia marcescens. Biochemical characteristics, antibiotic susceptibility patterns, and clinical significance. JAMA 1970; 214: 2157-2162. [PubMed]

120. Yang HF, Cheng J, Hu LF, Ye Y, Li JB. Identification of a Serratia marcescens clinical isolate with multiple quinolone resistance mechanisms from China. Antimicrob Agents Chemother 2012;56:5426-5427. [PubMed]

121. Yang HF, Cheng J, Hu LF, Ye Y, Li JB. Plasmid-mediated quinolone resistance in extended-spectrum-β-lactamase- and AmpC β-lactamase-producing Serratia marcescens in China. Antimicrob Agents Chemother 2012;56:4529-4531. [PubMed]

122. Yoon HJ, Choi JY, Park YS, Kim CO, Kim JM, Yong DE, Lee KW, Song YG. Outbreaks of Serratia marcescens bacteriuria in a neurosurgical intensive care unit of a tertiary care teaching hospital: a clinical, epidemiologic, and laboratory perspective. Am J Infect Control 2005;33:595-601. [PubMed]

123. Young VM, Moody MR, Morris MJ. Distribution of Serratia marcescens serotypes in cancer patients. J Med Microbiol 1980;13:333-339. [PubMed]

124. Yu VL. Serratia marcescens: historical perspective and clinical review. N Engl J Med 1979;300:887-893. [PubMed]

125. Yu VL. Serratia infection in the surgical patient. Infect Surg 1984;3:127-134.

126. Yu VL, Oakes CA, Axnick KJ, Merigan TC. Patient factors contributing to the emergence of gentamicin-resistant Serratia marcescens. Am J Med 1979; 66: 468-472. [PubMed]

127. Zhanel GG, Baudry PJ, Tailor F, Cox L, Hoban DJ, Karlowsky JA. Determination of the pharmacodynamic activity of clinically achievable tigecycline serum concentrations against clinical isolates of Escherichia coli with extended-spectrum beta-lactamases, AmpC beta-lactamases and reduced susceptibility to carbapenems using an in vitro model. J Antimicrob Chemother 2009; 64: 824-828. [PubMed]

Tables

Table 1. Comparative Activity of Antibiotics Against S. marcescens

Antibiotic	Susceptibility criteria (MIC µg/ml) ^a		Natural Antibiotic Susceptibility ^b (n=77)	MYSTIC Europe 2007 ^c (n=195)		MYSTIC US 1999-2008 ^d (n=145)		TEST Study USA 2007 ^e (n=427)	TEST Study Latin America 2004-2010 ^f (n=1,126)
	Susceptible	Resistant		MYSTIC Europe 2007 ^c (n=195)		MYSTIC US 1999-2008 ^d (n=145)		TEST Study USA 2007 ^e (n=427)	TEST Study Latin America 2004-2010 ^f (n=1,126)
	Susceptible	Resistant		MIC50	MIC90	MIC50	MIC90	MIC90	MIC50	MIC90
Penicillins										MIC90
Ampicillin	≤8	≥32	Resistant	NR	NR	NR	NR	≥64	NR	NR
b-lactam/b-lactamase inhibitor combinations
Amoxicillin/clavulanic	≤8/4	≥32/16	Resistant	NR	NR	NR	NR	≥64	≥64	≥64
Piperacillin/tazobactam	≤16/4	≥128/4	Susceptible	2	32	≤8	≤8	8	2	64
Cephalosporins
Cefuroxime	≤8	≥32	Resistant	NR	NR	NR	NR	NR	NR	NR
Cefotaxime	≤1	≥4	Susceptible	NR	NR	NR	NR	NR	NR	NR
Ceftriaxone	≤1	≥4	Susceptible	NR	NR	≤0.25	2	8	0.5	≥128
Ceftazidime	≤4	≥16	Susceptible	0.5	2	≤0.12	0.5	≤8	≤8	32
Cefepime	≤8	≥32	Susceptible	NR	NR	≤0.12	0.25	1	≤0.5	32
Carbapenems
Imipenem	≤4	≥16	Susceptible	0.5	2	0.5	1	0.25	0.5	1
Meropenem	≤4	≥16	Susceptible	0.03	0.13	0.06	0.06	0.25	≤0.06	0.25
Ertapenem	≤2	≥8	Susceptible	NR	NR	≤0.03	0.06	NR	NR	NR
Fluoroquinolones
Ciprofloxacin	≤1	≥4	Susceptible	0.13	1	≤0.25	1	NR	NR	NR
Levofloxacin	≤2	≥8	Susceptible	NR	NR	≤0.5	2	2	0.25	4
Aminoglycosides
Gentamicin	≤4	≥16	Susceptible	0.5	2	NR	NR	NR	NR	NR
Amikacin	≤16	≥64	Susceptible	NR	NR	NR	NR	4	2	64
Tobramycin	≤4	≥16	Intermediate	1	4	≤2	4	NR	NR	NR
Miscellaneous
Minocylcine	≤4	≥16	Susceptible	NR	NR	NR	NR	8	4	16
Tigecyline	≤2	≥8	Susceptible	NR	NR	NR	NR	2	1	2

^a MIC, minimum inhibitory concentration; MIC susceptibility criteria determined using CLSI MIC interpretative standards (18). For Tigecycline the FDA approved breakpoints were applied (110)
^b Natural antibiotic susceptibility of S. marcescens. Data are for S. marcescens (77 isolates) (101)
^c MYSTIC Europe Program, 2007. Data are for the following Serratia species: S. marcescens (170 isolates), S. liquefaciens(19 isolates), unidentified Serratia species (3 isolates), S. fonticola (2 isolates), and S. odorifera (1 isolate) (109)
^d MYSTIC US Program,1999-2008. Data are for the following Serratia species: S. marcescens (119 isolates), S. liquefaciens (5 isolates), and unidentified Serratia species (21 isolates) (85)
^e Tigecycline Evaluation and Surveillance Trial (TEST) US surveillance study 2007. Data are for S. marcescens (427 isolates) (26)
^f Tigecycline Evaluation and Surveillance Trial (TEST) Latin America surveillance study 2004-2010. Data are for S. marcescens (1,126 isolates) (32)

NR, not reported.

Table 2. Antimicrobial Therapy for S. marcescens

Antibiotic	Usual Dose	Comments
Third-generation cephalosporins/b-lactamase inhibitor combinations		Inadvisable for treatment of infection where resistance is likely to develop. Remain the treatment of choice for UTI and uncomplicated infection. Often combined with aminoglycosides.
Cefotaxime	1¡V2 g q. 4¡V8 h
Ceftriaxone	1¡V2 g q. 24 h
Ceftazidime	1¡V2 g q. 8 h
Pip/ tazobactam	4-5 g q 8 h
Fourth-generation cephalosporins		Effective treatment option where resistance to third-generation cephalosporins is evident or likely to develop. Active against AmpC chromosomal b-lactamase-producing strains but precluded for the treatment of ESBL-positive isolates.
Cefepime	1 g q. 12 h
Cefpirome	1¡V2 g q 12 h
Carbapenems		Considered the treatment of choice when cephalosporin resistance is evident or likely to develop.
Imipenem	0.5¡V1 g q. 6 h
Meropenem	1g q. 8 h
Fluoroquinolones		Prudent to avoid for treatment of serious infection due to the ready development of resistance. Can be used for the treatment of uncomplicated UTI.
Ciprofloxacin	400¡V800 mg q. 12 h	Oral formulations can be used in UTI.
Ofloxacin	200¡V400 mg q.12 h
Levofloxacin	500 mg q. 24 h
Norfloxacin	400 mg p.o b.i.d.	No i.v. formulation, only for UTI.
Aminoglycosides		No longer treatment of choice. Maybe combined with third-generation cephalosporins for the treatment of UTI or combined with fourth-generation cephalosporins or carbapenems for the treatment of serious infection.
Gentamicin	3¡V5 mg/kg/day x SD	Most frequently used of the aminoglycosides.
Tobramycin	3¡V5 mg/kg/day x SD
Amikacin	15 mg/kg/day x SD	Frequently active against gentamicin-resistant S. marcescens.
Netilmicin	4-6 mg/kg/day x SD
Miscellaneous
Tigecycline	50 mg ¡V/12 h after a 100 mg loading dose	Treatment option where cephalosporin resistance is evident or likely to develop. Active against AmpC-producing and ESBL-positive isolates. Unsuitable for UTI.
Aztreonam	1¡V2 g q. 6¡V8 h
Trimethoprim-sulfamethoxazole	960 mg b.d. or 120 mg/kg 2¡V4 dose/24h	Usually active; suitable for UTI but rarely used as sole agent for more serious infections