Scholarly article on topic 'Sepsis caused by New Delhi metallo-β-lactamase (blaNDM-1) and qnrD-producing Morganella morganii, treated successfully with fosfomycin and meropenem: case report and literature review'

Sepsis caused by New Delhi metallo-β-lactamase (blaNDM-1) and qnrD-producing Morganella morganii, treated successfully with fosfomycin and meropenem: case report and literature review Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Verónica Seija, Julio César Medina Presentado, Inés Bado, Romina Papa Ezdra, Noelia Batista, et al.

Summary Objectives The objective of this study was to describe the microbiological characteristics of an extensively drug-resistant (XDR) isolate of Morganella morganii obtained from a patient with sepsis of urinary origin and to describe the patient's clinical characteristics. We further aimed to perform a literature review of the situation in Latin America regarding Gram-negative bacillus (GNB) carriers of New Delhi metallo-β-lactamase (NDM-1) and qnr genes and current reports on the treatment of infections caused by XDR enterobacteria, with particular attention to colistin-resistant isolates. Methods The patient's clinical data were obtained from his medical history. Microbiological identification and susceptibility testing were done using the VITEK 2 Compact System. Resistance genes were detected by PCR and sequencing. Results Blood and urine cultures grew an M. morganii isolate (Mm4232) harboring NDM-1 and qnrD1. The patient was treated successfully with fosfomycin and double doses of meropenem. There are no previous reports of the use of fosfomycin and meropenem to treat infections by XDR enterobacteria harboring NDM-1 carbapenemase. Conclusions This is the first report of qnrD1 in South America. We consider that this report could be helpful to physicians implementing treatments for infections caused by XDR GNB, including colistin–carbapenem-resistant GNB.

Academic research paper on topic "Sepsis caused by New Delhi metallo-β-lactamase (blaNDM-1) and qnrD-producing Morganella morganii, treated successfully with fosfomycin and meropenem: case report and literature review"

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International Journal of Infectious Diseases

journal homepage www.elsevier.com/locate/ijid

Sepsis caused by New Delhi metallo-b-lactamase (blaNDM-1) and qnrD-producing Morganella morganii, treated successfully with fosfomycin and meropenem: case report and literature review

Veronica Seijaa1, Julio Cesar Medina Presentado b1, Iníés Badoc, Romina Papa Ezdrac, Noelia Batista3, Claudia Gutierrez3, Mariana Guiradob, Macarena Vidalb, Marcelo Nind, Rafael Vignolic'*

a Departamento de Laboratorio Clínico, Area Microbiología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay b Cátedra de Enfermedades Infecciosas, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay c Departamento de Bacteriología y Virología, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Alfredo Navarro 3051, CP 11600 Montevideo, Uruguay

d Centro de Nefrología Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

CrossMark

ARTICLE INFO

Article history:

Received 27 February 2014

Received in revised form 17 September 2014

Accepted 18 September 2014

Corresponding Editor: Eskild Petersen,

Aarhus, Denmark

Keywords: NDM-1

Morganella morganii Sepsis Meropenem Fosfomycin

SUMMARY

Objectives: The objective of this study was to describe the microbiological characteristics of an extensively drug-resistant (XDR) isolate of Morganella morganii obtained from a patient with sepsis of urinary origin and to describe the patient's clinical characteristics. We further aimed to perform a literature review of the situation in Latin America regarding Gram-negative bacillus (GNB) carriers of New Delhi metallo-p-lactamase (NDM-1) and qnr genes and current reports on the treatment of infections caused by XDR enterobacteria, with particular attention to colistin-resistant isolates. Methods: The patient's clinical data were obtained from his medical history. Microbiological identification and susceptibility testing were done using the VITEK 2 Compact System. Resistance genes were detected by PCR and sequencing.

Results: Blood and urine cultures grew an M. morganii isolate (Mm4232) harboring NDM-1 and qnrDl. The patient was treated successfully with fosfomycin and double doses of meropenem. There are no previous reports of the use of fosfomycin and meropenem to treat infections by XDR enterobacteria harboring NDM-1 carbapenemase.

Conclusions: This is the first report of qnrDl in South America. We consider that this report could be helpful to physicians implementing treatments for infections caused by XDR GNB, including colistin-carbapenem-resistant GNB.

© 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-

nc-nd/3.0/).

1. Introduction

Morganella morganii is a Gram-negative rod belonging to the Enterobacteriaceae family. It is ubiquitous in the environment and can cause nosocomial outbreaks and serious infections in immunocompromised patients.1

This species produces an inducible, chromosomally-encoded AmpC p-lactamase which is responsible for its natural resis-

* Corresponding author. Tel./Fax: +598 2487 57 95.

E-mail address: rvignoli@higiene.edu.uy (R. Vignoli).

1 Both authors contributed equally to the experimental work and the elaboration

of this report.

tance to aminopenicillins, amoxicillin-clavulanate, and first-and second-generation cephalosporins. M. morganii mutants with derepressed expression of this AmpC are resistant to third-generation cephalosporins, monobactams, and cephamycin.2 Additionally M. morganii is naturally resistant to tetracyclines, tigecycline, polymyxins, and nitrofurantoin.3 In this context, the acquisition of additional resistance genes encoding carba-penemases and/or transferable plasmid-mediated quinolone resistance mechanisms significantly reduces the therapeutic options.

The emergence of carbapenemases in Enterobacteriaceae is a growing concern, with a high impact on patient health worldwide.4 Carbapenemases are enzymes that are able to hydrolyze nearly all

http://dx.doi.org/10.1016/j.ijid.2014.09.010

1201-9712/© 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

b-lactam antibiotics, including carbapenems. These enzymes can belong to molecular classes A, B, or D: KPC (Klebsiella pneumoniae carbapenemase), NDM (New Delhi metallo-b-lactamase) or VIM (Verona integron-encoded metallo-b-lactamase), and OXA-48 (oxacillinase) are the most representative exponents of each group, respectively.5

NDM-1 was first described in 2008 in Sweden from a patient who had previously been hospitalized in New Delhi, India.6 Rapid worldwide dissemination followed.5,7,8

Several plasmid-mediated quinolone resistance (PMQR) mechanisms have been discovered during the past decade, including Qnr proteins, QepA transporters, and the acetyltransferase AAC(6')-Ib-cr.9 Different lineages of Qnr proteins have been described (QnrA, QnrB, QnrS, and more recently, QnrC and QnrD), with several allelic variants known for some of them. The qnrD gene was first described in 2009 in a human clinical isolate of Salmonella enterica serovar Kentucky and three Salmonella enterica serovar Bovismorbificans isolates from China.10 In 2011, Mazzariol et al. described the presence of qnrD in isolates of Proteus mirabilis and M. morganii, suggesting that this gene might be closely linked to the Proteeae tribe.11

In this work we present a case report of sepsis caused by an extensively drug-resistant (XDR; according to the definition proposed by Magiorakos et al.12) M. morganii isolate (Mm4232) co-harboring NDM-1 and qnrD1, which was treated successfully with fosfomycin and double doses of meropenem. In addition, we reviewed the literature on plasmid-mediated quinolone resistance and NDM-1 in Latin America, and the experience of therapeutic options for the treatment of invasive infections caused by XDR microorganisms.

2. Methods

2.1. Patients

The patient's clinical data were collected retrospectively by review of the medical records.

2.2. Bacterial identification and susceptibility assays

Bacterial identification and antibiotic susceptibility were determined using the VITEK 2 Compact System (bioMerieux, Durham, NC, USA) and Etest, in accordance with the manufacturer's recommendations. Antibiotic susceptibility to fosfomycin was determined using Etest strips containing this agent and 25 mg/ l glucose-6-phosphate, as per the manufacturer's recommendations. Susceptibility was interpreted according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (http://www.eucast.org).

2.3. Metallo-b-lactamase screening and carbapenemase screening

The imipenem-EDTA/SMA (ethylenediaminetetraacetic acid 372 mg/sodium mercaptoacetic acid 900 mg) double disk13 and Rosco Diagnostica Neo-Sensitabs KPC and MBL confirmation kit were used to detect carbapenemases. Testing was performed in accordance with the manufacturers' instructions.

2.4. Detection of antibiotic resistance genes

The presence of blaNDM and additional b-lactamases such as the blaCTx-M, blaSHv, blaTEM, blapER-2, blaoxA-1, and blaoxA-2 subgroups, was determined using PCR and sequencing, as described previous-ly.13-16 The presence of other carbapenemases such as blaIMP, blaSiM, blaSPM, blaHM, blaviM, bla^, and blaoxA-48 was sought by PCR using specific primers (see Supplementary Material, Table S1).

In order to identify additional genes responsible for the resistance profile, and associations with mobile genetic elements, we studied the following by PCR and sequencing: (1) the presence of plasmid-mediated quinolone resistance genes (qnrA, qnrB, qnrC, qnrD, qnrS, qepA, aac(6')Ib-cr), (2) the presence of class 1 and 2 integrons, and (3) the presence of insertion sequences ISEcpl, IS26, IS903, and ISCR1.17

2.5. Conjugation assays

Conjugation assays were carried out using rifampin-resistant Escherichia coli J53-2 (rifampin-resistant, non-motile, and orni-thine-negative) as recipient, as described previously.18 Salmonella enterica serovar Typhimurium harboring conjugative plasmid pSTM709 (accession number HG428759) was used as the conjugation positive control.19

3. Results

3.1. Case report

A 24-year-old man with a history of hypertension and endstage renal disease secondary to glomerulonephritis had been on hemodialysis for 7 years. Eight months before presenting to the hospital he underwent a renal transplant, which was complicated by a urinary leak (requiring insertion of a double J ureteral stent) and a urinary tract infection caused by Enterobacter cloacae; this infection was treated with piperacillin-tazobactam for 21 days. He had been taking the following medications since then: prednisone (10 mg/day), tacrolimus (4 mg/day), and mycophenolate mofetil (1 g/day).

On admission to the emergency department, the patient presented fever, dysuria, and a decreased urine output. Initial vital signs were as follows: temperature 38.2 °C, normal blood pressure, heart rate 100 beats/min, and arterial oxygen saturation of 96% when breathing air. The patient appeared ill and jaundiced; his abdomen was tender without pain. The rest of the examination was normal.

Urinalysis by dipstick test showed leukocyte esterase, nitrite, protein, and hemoglobin, and urine microscopic examination revealed 15 leukocytes and 7 erythrocytes per high-power field. In addition, laboratory studies on admission showed elements of multiple organ dysfunction such as pancytopenia, renal and hepatic failure, and high values of biomarkers such as procalcitonin (38 ng/ml; according to the manufacturer, procalcitonin values >10 ng/ml can be interpreted as indicating a high likelihood of severe sepsis or septic shock) and C-reactive protein (CRP, 129 mg/ l; reference value CRP <3 mg/l). The changes in laboratory results over time are shown in Table 1; results from the medical examination done 1 month before admission are included.

Chest radiography was normal. Computed tomography (CT) of the thorax, abdomen, and pelvis showed no alterations except for the presence of the ureteral stent.

In this immunocompromised patient with a diagnosis of sepsis, treatment with meropenem (1 g every 8 h) was initiated and doses of immunosuppressive agents were reduced: tacrolimus 2 mg/day, mycophenolate mofetil 500 mg/day, and prednisone 5 mg/day.

Urine and blood culture results were received after 48 h; both samples grew an M. morganii isolate (named in our laboratory as Mm4232), which displayed susceptibility only to fosfomycin. Testing of susceptibility to colistin and tigecycline was not done. Additionally, isolate Mm4232 was resistant to cefepime (FEP), ceftazidime (CAZ), cefotaxime (CTX), piperacillin-tazobactam (PTZ), imipenem (IMP), meropenem (MEM), ertapenem (ERT), ciprofloxacin (CIP), gentamicin (CN), amikacin (AK), and trimetho-prim-sulfamethoxazole (SXT) (see results below).

Due to the susceptibility results and considering the presence of sepsis with bacteremia and the potential risk of the emergence of resistance during fosfomycin monotherapy, we decided to use combination therapy based on meropenem, administered by extended infusion (lasting >3 h) at a dose of 2 g every 8 h, along with fosfomycin, 4 g every 8 h with daily natremia control. During hospitalization, the ureteral stent was removed without complications. After 10 days of fosfomycin and 14 days of meropenem treatment, the patient was discharged having made excellent clinical progress and with full renal function recovery (Table 1). A follow-up urine culture on day 14 was negative.

3.2. Susceptibility testing

M. morganii strain Mm4232 was only susceptible to fosfomycin (minimum inhibitory concentration (MIC) 32 mg/ml). Mm4232 was resistant to cefepime (4 mg/l), ceftazidime (>64 mg/l), cefotaxime (>64 mg/l), piperacillin-tazobactam (>128 mg/l), ertapenem (4 mg/l), meropenem (4 mg/l), imipenem (>16 mg/l), ciprofloxacin (>4 mg/l), gentamicin (>16 mg/l), amikacin (32 mg/ l), and trimethoprim-sulfamethoxazole (>320 mg/l).

3.3. Carbapenemase screening

The imipenem-EDTA double disk showed an improvement in the inhibition zone in the area between the carbapenems and the inhibitor-containing disk. The Rosco kit displayed a 7 mm difference between the meropenem disk (21 mm) and meropenem + dipicolinic acid disk (28 mm). Both results were interpreted as positive for the detection of metallo-b-lactamase.

3.4. Antibiotic resistance genes

Mm4232 was positive for blaNDM-1 and qnrD1, but was negative for other b-lactamase and plasmid-mediated quinolone resistance genes. In addition, this isolate was IS26-positive but negative for other insertion sequences and integrons. PCRs aimed at connecting IS26 with blaNDM-1 and/or qnrD1 were negative, suggesting that this IS was not surrounding resistance genes.

3.5. Conjugation assays

Results of conjugation assays were negative using M. morganii strain Mm4232, but positive using S. enterica serovar Typhimurium strain STM709. These findings suggest that both blaNDM-1 and qnrD1 were codified in non-conjugative elements. More studies are

required to determine if these genes are located in non-conjugative plasmids or the bacterial chromosome.

4. Discussion

Reports on NDM-producing isolates in Latin America and Central America are relatively few and have been published only from Mexico,20 Jamaica,21 Guatemala,22 Honduras,23 Colombia,24 Paraguay,25 and Brazil.26-28 A Pan American Health Organization (PAHO) epidemiological update has also given accounts of the presence of NDM-1 in Costa Rica, Nicaragua, Argentina, and Uruguay.29 The main characteristics of isolates and clinical cases reported in Latin America, including the one presented in this work, are shown in Table 2.

So far, most of the reported cases have resulted from outbreaks of nosocomial infections (12/17) and have been associated with a low mortality attributable to the infection itself. The treatment was recorded in 11 cases and combinations of antibiotics were used in nine of them; a carbapenem was used in eight of these combinations. Other than the case presented in this paper, fosfomycin susceptibility has only been reported in a work from Guatemala; this has not been used as a therapeutic option at any other time.

In contrast, infections and/or colonization of humans by GNB carrying qnr genes in Latin America has been better described. In brief, there are three mechanisms of plasmid-mediated quinolone resistance (PMQR): (1) protection by masking the target qnr genes, and (2) modification of the antibiotic enzyme Aac(60)-Ib-cr and efflux pumps OqxAB and QepA. The qnr genes constitute the first mechanism of transferable quinolone resistance described; reports date back to the year 1998.30 The Qnr protein binds to gyrase, causing the quinolones to recognize the less efficient target enzyme. Variants of this gene have arisen over time. qnr A came first, followed by the qnrB, qnrS, qnrC, qnrD, and qnrVC gene families. Currently, the following variants have been described: qnrA1-qnrA7, qnrB1-qnrB74, a variant of qnrC, qnrD1-qnrD2, qnrS1-qnrS9, and qnrVC1 -qnrVC6 (http://www.lahey.org/qnrStudies/).

A variety of qnr genes have been described in Latin America. In Brazil, the first report on qnr genes involved E. coli, with qnrA1 associated with blaFOX-5;31 qnrB2, qnrB8, qnrB19, qnrS1, and qnrVC32-35 were then detected. In Argentina, qnrB1, qnrB2, qnrB4, qnrB6, qnrB10, qnrB19, and qnrS have been found.36-38 In Bolivia, qnrS and qnrB;39,40 in Peru, qnrB19 and qnrS;40,41 in Uruguay, qnrA1, qnrB1, qnrB4, qnrB8-like, qnrB13, and qnrB17;14,42 and in Venezuela qnrB19,43 have been reported. The qnr genes have been described in a variety of microorganisms isolated either from

Table 1

Main laboratory results

Control (1 month before admission) Admission Day 2 Day 8 Day 13 Day 15

Urea, mg/dl 0.57 0.69 0.51 0.39 0.52 0.52

Creatinine, mg/dl 1.44 2.35 1.74 1.32 1.23 1.23

Hemoglobin, g 13.1 14 12.3 13.2 13 12

WBC count, x109/l 5.800 0.740 4.950 4.740 5.200 4.090

Neutrophils, x109/l 3.300 0.580 3.217 2.700 3.300 2.800

Total lymphocytes, x109/l 1.330 0.130 0.840 1.410 1.180 1.000

Platelet count, x109/l 159 74 83 160 160 186

Total bilirubin, mg/dl 0.46 1.64 0.75 ND 0.18 ND

Direct bilirubin, mg/dl 0.23 0.98 0.45 ND 0.12 ND

AST, U/l 39 132 50 ND 40 ND

ALT, U/l 112 123 122 ND 121 ND

Procalcitonin, ng/ml ND 38 31.4 2.29 0.13 ND

Na, mEq/ml 140 128 131 134 132 133

CRP, mg/l ND 129 ND ND 18 ND

Tacrolimus trough concentration, ng/ml 14 11.4 ND 9.4 ND 8.6

WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein; ND, not determined.

Table 2

Main features of clinical reports of human infections due to New Delhi metallo-b-lactamase-producing Gram-negative bacteria in Latin America

Country Year Microorga- Sex/age Site of Underlying Antibiotic Antibiotic Therapy Microbiological Outbreak Ref.

nisma (years) infection condition resistance susceptibility outcome and (observations) (yes/no)

Uruguay 2013 M. morganii M/24 Urosepsis Renal transplant; on immunosuppressive therapy with prednisone, tacrolimus, and mycophenolate TGC, CRB, PTZ, CIP, CN, AK, SXT, and natural resistance to TIG, COL and NT FOS FOS/MEM Success No This work

Guatemala 2011 K. pneumoniae ND/1 Nosocomial pneumonia/ septic shock ND TGC, CRB, PTZ, CIP, CHL, NT CN, AK, NAL, TIG, FOS, COL PTZ/AK Success Yes 22

Guatemala 2011 K. pneumoniae ND/ND Tracheal secretion Head and neck trauma from gunfire TGC, CRB, PTZ, CIP, CHL, NT CN, AK, NAL, TIG, FOS, COL ND Death (non- infectious-related cause) Yes 22

Colombia 2011 K. pneumoniae F/23 days BSI Preterm, placenta abruptio, severe perinatal asphyxia, enterocolitis TGC, CRB, AK ATM, CIP, TET, TGC, COL MEM/R1F Success Yes 24

Colombia 2011 K. pneumoniae M/9 days NEC Preterm, chorioamnionitis TGC, CRB, AK ATM, CIP, TET, TGC, COL 1PM/C1P Success Yes 24

Colombia 2011 K. pneumoniae M/90 days BSI Meconium aspiration syndrome, severe perinatal asphyxia, hypoxic-ischemic encephalopathy TGC, CRB, AK ATM, CIP, TET, TGC, COL 1PM/C1P Success Yes 24

Colombia 2011 K. pneumoniae M/10 days BSI Preterm, toxemic mother, severe perinatal asphyxia, pneumonia in utero TGC, CRB, AK ATM, CIP, TET, TGC, COL 1PM/C1P Death (non- infectious-related cause) Yes 24

Colombia 2012 K. pneumoniae F/1 BSI Pneumonia in utero with spontaneous pneumothorax, closed thoracostomy (3 days) TGC, CRB, AK ATM, CIP, TET, TGC, COL 1PM/C1P Success Yes 24

Colombia 2012 K. pneumoniae F/13 Fulminant NEC Preterm, chorioamnionitis, pneumonia in utero TGC, CRB, AK ATM, CIP, TET, TGC, COL NT Death Yes 24

Mexico 2012 P. rettgeri M/22 UTI ND TGC, CRB, CIP, COL, CN TIG ND Death (non- infectious-related cause) Yes 20

Mexico 2012 P. rettgeri M/16 UTI ND TGC, CRB, CIP, COL, CN TIG ND Death (non- infectious-related cause) Yes 20

Mexico 2012 P. rettgeri F/50 UTI ND TGC, CRB, CIP, COL CN, TIG ND Success Yes 20

Mexico 2012 P. rettgeri F/53 UTI ND TGC, CRB, CIP, COL, CN, TIG ND Success Yes 20

Honduras 2012 A. baumannii M/76 1A1 Peritoneal dialysis TGC, CRB, CIP, AK, CN, SXT COL, TIG T1G Success No 23

Brazil 2013 P. rettgeri ND/ND Diabetic foot infection Diabetic peripheral vascular disease TGC, IMP, CN, and natural resistance to TIG, COL, and NT MEM, ERT, AK AMC Toe amputation was required No 26

Paraguay 2012 A. pittii ND/7 CSF ND TGC, CRB, PTZ CN, AK, NAL, CIP, COL, TIG SXT, C1P, AK Death (non- infectious-related cause) No 25

Paraguay 2012 A. pittii ND/2 Sepsis Acute lymphocytic leukemia TGC, CRB, PTZ CN, AK, NAL, CIP, COL, TIG MEM, AK Success No 25

AK, amikacin; AMC, Amoxicillin-Clavulanic acid; ATM, Aztreonam; BSI, blood stream infection; CHL, chloramphenicol; CIP, ciprofloxacin; CN, gentamicin; COL, Colistin; CRB, carbapenems; CSF, cerebrospinal fluid; ERT, ertapenem; F, female; FOS, fosfomycin; 1A1, Intra-abdominal Infection; IPM, imipenem; M, male; MEM, meropenem; NAL, nalidixic acid; ND, not determined; NEC, necrotizing enterocolitis; NT, nitrofurantoin; PTZ, piperacillin-tazobactam; RIF, rifampin; SXT, trimethoprim-sulfamethoxazole; TET, tetracycline; TGC, third-generation cephalosporins including ceftazidime and cefotaxime; TIG, tigecycline; UT1, urinary tract infection. a Morganella morganii; Klebsiella pneumoniae; Providentia rettgeri; Acinetobacter baumannii; Acinetobacter pittii.

colonization, or from nosocomial and community-acquired

infections.14,38,40,42

Meanwhile, the association of NDM and PMQR has been reported in Guatemala, Colombia, and Brazil.22,24,27 In Guatemala, two K. pneumoniae ST17 isolates producing NDM-1, aac(6')Ib-cr, and qnrB1 with the presence of two extended-spectrum b-lactamases (ESBL), CTX-M-15 and SHV-12, have been reported.22 In Colombia a K. pneumoniae isolate (ST1043) carrying qnrA1, associated with ESBL CTX-M-15, has been reported.24 Finally, an Enterobacter hormaechei strain carrying NDM-1 in conjunction with qnrB4 and CTX-M-15 has been described in

Brazil.27

Most clinical bacteria reported with NDM-1 remain susceptible in vitro only to colistin and to either or both tigecycline and fosfomycin.44 This was not the case for our isolate.

M. morganii is naturally resistant to tigecycline and to polymyxins.3 In addition, the Mm4232 isolate was resistant to all b-lactam antibiotics, including carbapenems and in combinations with inhibitors, aminoglycosides, and trimethoprim-sulfa-methoxazole. Taking into account this antibiotic resistance profile, the Mm4232 isolate was considered to be XDR. This extensive pattern of drug resistance left only fosfomycin as an option for treatment.

There have been no randomized clinical studies on how to treat infections caused by carbapenemase-producing Enterobacteriaceae. Evidence comes from non-randomized studies with a retrospective design. The majority of studies refer to KPC-producers, and some to VIM-producers and carbapenem-resistant isolates. NDM-producers are hardly mentioned.45 The available evidence suggests that infections caused by carbapenemase-producers have better outcomes when combination therapy is

used.46,47

Tigecycline in combination with colistin, carbapenem in combination with colistin, and tigecycline in combination with gentamicin are the most commonly administered antibiotic regimens among the published studies and might result in lower mortality than other antibiotic combinations.48-54 In general, carbapenems are administered to patients infected with strains for which the MICs are low (4 mg/l and probably up to 8 mg/l). There are studies that mention an important increase in survival when a carbapenem is administered in combination with another drug. It is important that a high-dose prolonged infusion regimen is administered to drive the pharmacokinetic/pharmacodynamic (PK/PD) profile towards acceptable exposures.50,51,55

Fosfomycin represents a potential last-resort treatment option for infections caused by carbapenemase-producers.47 In vitro studies have demonstrated fosfomycin synergy in combination with imipenem and meropenem in 74% and 70% of KPC-producing K. pneumoniae isolates, respectively.56 Fosfomycin in combination with colistin, gentamicin, or piperacillin-tazobactam has shown a promising clinical success rate (100%) in the treatment of serious infections caused by carbapenem-resistant K. pneumoniae.57 However, the potential emergence of resistance during therapy has been reported.58

In a recent study, Pontikis et al. described a series of patients with infections caused by XDR Pseudomonas aeruginosa and K. pneumoniae, according to the definition used in our work. These patients were treated with fosfomycin in combination with various antibiotics, including meropenem in some cases.59 However, it is not clear how many cases received the fosfomycin-meropenem combination, or what the cure rate was for this. None of these microorganisms were NDM carbapenemase-producers.

In Uruguay, the surveillance of carbapenemase-producing isolates is done by the Ministry of Public Health (http:// www.msp.gub.uy), but the dissemination of the results is poor.29,60 So far, there have been no reports combining the detection of

different resistance genes and the clinical outcomes of infected patients. We recently reported the detection and control of the first outbreak in our country caused by KPC-producing K. pneumoniae ST258.61

In this paper we reported the successful management of an immunocompromised patient with urosepsis produced by XDR M. morganii only susceptible to fosfomycin. The patient was treated with meropenem and fosfomycin and showed a clinical improvement and reduction of acute-phase markers such as procalcitonin and CRP.

Fosfomycin is rarely used in Latin America and there are very few reports on its susceptibility.22 Similarly, the use of the fosfomycin-meropenem combination for XDR strains is poorly reported and it is not easy to interpret the results of such a therapeutic combination.59

To our knowledge this is the first report of severe sepsis caused by WaNDM-1-producing XDR M. morganii. In this context we consider that our report could be helpful to physicians and provides well-documented information on an alternative treatment for infections caused by XDR GNB, including colistin-carbapenem-resistant GNB.

To date qnrDl has not been reported in Latin America and more studies will be required to evaluate the dissemination of this PMQR gene in other species of Enterobacteriaceae.

Acknowledgements

This work was supported in part by grants from CSIC (Comisión Sectorial de Investigacion Científica, Uruguay) to R.V.

Ethics: The study did not interfere with the patient's treatment (clinical or paraclinical). Data were handled and results are presented without disclosing the identity of the patient.

Conflict of interest: Nothing to declare.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijid.2014.09.010.

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