Serratia marcescens

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


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. marcescensS. liquefaciens and S. odorifera are best known (3167). 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 KlebsiellaEnterobacter,Serratia and Citrobacter (KESC) grouping (1317).

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 (8695).

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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.

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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 (7274). The organism has also been described as an important cause of ocular infection with high incidence in contact lens-related keratitis (42192).

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 (8103), 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 (11123). 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 (2368). The recovery of epidemic strains of S. marcescens from hand cultures of hospital staff has been reported consistently in epidemiologic studies (3949). 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).

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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 (5861). 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.

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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 (4974).

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 (2552). 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 (3444). 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 (35117). 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 (120121). 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 (2970). 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 EnterobacteriaceaeS. 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 (63884). 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 (6974).

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 (1949). 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 (1569). 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 (2880). 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 (2283).

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 (4879). 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 (22108), 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 (1859). This confirmatory methods is simple to perform, but interpretation of results has proven difficult (27116). 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 (102118).

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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 (45127) 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.

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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.


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.

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Table 1. Comparative Activity of Antibiotics Against S. marcescens

Antibiotic Susceptibility
(MIC µg/ml) a
Susceptibility b
2007 c
1999-2008 d
TEST Study
2007 e
TEST Study
Latin America
2004-2010 f
  Susceptible   Resistant
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
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
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
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
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
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  
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

Pip/tazobactam, piperacillin/tazobactam; SD, single dose.


Yu VL.  Serratia infection in the surgical patient.  Infections In Surgery 1984:127-184.

Yu VL. Serratia Maarcescens. Historical Perspective and Clinical Review.  N Engl J Med 1979;300:887-893.

Victor L. Yu:  Serratia marcescens: Masquerader of Blood.

Guided Medline Search For Historical Aspects

Serratia marcescens