Abstract
We describe a 16-year-old neutropenic patient from the Middle East with bloodstream infection caused by two carbapenemase-producing Escherichia coli isolates that we characterized by whole-genome sequencing. While one displayed meropenem resistance and was blaNDM positive, the other demonstrated meropenem susceptibility yet harbored blaOXA181 (which encodes a blaOXA48-like enzyme). This report highlights the challenge of laboratory detection of blaOXA48-like enzymes and the clinical implications of genotypic resistance detection in carbapenemase-producing Enterobacteriaceae.
CASE PRESENTATION
A 16-year-old girl from Kuwait had been in the United States for 1 month prior to hospitalization at our facility for treatment of acute myelogenous leukemia. She developed a fever of 39.2°C and exhibited neutropenia. A blood culture obtained through her central venous catheter (CVC) grew Escherichia coli susceptible to most antimicrobial agents tested (Table 1, isolate 1). She defervesced after antimicrobial treatment with cefepime; follow-up blood cultures were negative.
TABLE 1.
Phenotypic antimicrobial susceptibility test results and molecular and phenotypic carbapenemase testing of E. coli bloodstream isolatesa
| Isolate | MIC (μg/ml) of: |
PCR for blaKPC and blaNDM | Carba NP | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Piperacillin-tazobactam | Cefepime | Ceftriaxone | Ertapenem | Meropenem | Aztreonam | Ciprofloxacin | Amikacin | Gentamicin | Tobramycin | TMP-SMX | Minocycline | Tigecycline | Colistin | Polymyxin B | |||
| 1 | ≤16/4 (I) | ≤2 (S) | ≤1 (S) | ≤0.25 (S) | ≤0.12 (S) | ≤4 (S) | ≤1 (S) | ≤8 (S) | ≤1 (S) | ≤1 (S) | >2/38 (R) | ND | ND | ND | ND | ND | ND |
| 2 | >64/4 (R) | >16 (R) | >32 (R) | >1 (R) | 128 (R) | >16 (R) | >2 (R) | ≤8 (S) | >8 (R) | >8 (R) | >2/38 (R) | >8 (R) | 0.12 (S) | ≤2 | ≤2 | + | ND |
| 3 | >64/4 (R) | >16 (R) | >32 (R) | 1 (I) | ≤0.12 (S) | >16 (R) | >2 (R) | ≤8 (S) | >8 (R) | 8 (I) | >2/38 (R) | >8 (R) | ND | ND | ND | − | − |
S, susceptible; I, intermediate; R, resistant; TMP-SMX, trimethoprim-sulfamethizole; −, negative; +, positive; ND, not done. All isolates were resistant to ampicillin. Breakpoint MICs are reported in all cases except for isolate 2 and meropenem, for which the actual MIC is shown. Boldface indicates differences in carbapenem MICs between isolates 2 and 3.
Five days later, while still neutropenic and receiving cefepime, she developed a new fever, hypotension, and diarrhea. Blood cultures again grew E. coli (Table 1, isolate 2), but this time the isolate was resistant to multiple drug classes, including meropenem (MIC, 128 μg/ml) and ertapenem (MIC, >1 μg/ml). This prompted the clinical laboratory to perform a previously described PCR assay targeting the genes encoding Klebsiella pneumoniae carbapenemase (blaKPC) and New Delhi metallo-β-lactamase (MBL) (blaNDM); the isolate was blaNDM positive (1). The isolate was susceptible to amikacin, polymyxin B, and tigecycline, all of which were administered along with rifampin.
Blood cultures remained positive for 4 days, including 2 days after effective therapy was started, despite removal of the CVC. The CVC tip culture was negative. During this time, she remained neutropenic and developed pulmonary infiltrates and increased oxygen requirement, prompting transfer to the intensive care unit. Sputum cultures showed no bacterial growth. Echocardiogram and abdominal computed tomography results were unremarkable. She did not require vasopressor support or mechanical ventilation. Susceptibility testing of a blood isolate obtained toward the end of the 4-day period revealed E. coli with susceptibilities that differed from those of the two previous isolates (Table 1, isolate 3). The most notable discrepancy was the meropenem MIC, which was >128 μg/ml for isolate 2 but ≤0.12 μg/ml for isolate 3. Because isolate 3 was ertapenem intermediate (MIC, 1 μg/ml), PCR for blaKPC and blaNDM and the Carba NP assay (2) were performed on it and were negative. Isolate 3 also had a pulsed-field gel electrophoresis profile different from that of isolate 2.
CHALLENGE QUESTION
OXA-48 carbapenemases may be challenging to detect in clinical isolates. Which of the following is the most sensitive means to detect them?
A. Carba NP test
B. Ertapenem MIC
C. Nucleic acid amplification test
D. BYG Carba test
E. Meropenem MIC
TREATMENT AND OUTCOME
The child remained persistently febrile for over 1 week despite clearance of bacteremia (Fig. 1). During this time, caspofungin was initiated for empirical treatment of fungal infection. She developed significant nausea and vomiting, prompting discontinuation of tigecycline and rifampin, but treatment with polymyxin B and amikacin was continued. Granulocyte colony-stimulating factor was initiated to hasten neutrophil recovery. The patient's fever resolved with the recovery of her neutrophil count (Fig. 1). She developed proteinuria, glucosuria, and renal insufficiency (her estimated creatinine clearance decreased from 118 to 58 ml/min) after 2 weeks of antibiotic therapy. All antimicrobial agents were then discontinued, with no recurrence of infection. She returned to her home country 7 days after hospital discharge. No other patients with carbapenemase-producing strains were identified during or after her hospitalization. We suspect that the bacteremia in this patient was from intestinal translocation because there were multiple E. coli strains in her blood, the catheter tip culture was negative, and bacteremia persisted after CVC removal.
FIG 1.
Antimicrobial agents, temperature, leukocyte count, and timing of E. coli isolation from the blood of a 16-year-old neutropenic patient. The following antibiotics were administered at the indicated doses: amikacin at 18 mg/kg of body weight every 12 h (Q12 h), colistin at 2.5 mg/kg Q12 h, meropenem at 1 g Q8 h administered over 3 h, polymyxin B at 12,000 units/kg Q12 h, rifampin at 7.5 mg/kg Q12 h, and tigecycline at 100 mg Q12 h. G-CSF, granulocyte colony-stimulating factor.
We sought to determine whether the difference in phenotypic susceptibility between E. coli blood isolates 2 and 3 represented a loss of the blaNDM gene by isolate 2 or infection with a new strain. The isolates were lysed as previously described (1); the resultant nucleic acid was assayed with the Check-Points CT103XL microarray (Check-Points BV, Wageningen, The Netherlands). Whole-genome sequencing of isolates 2 and 3 was performed with the Illumina MiSeq platform using the TruSeq v3 paired-end and Nextera mate pair libraries (Illumina, Inc., San Diego, CA). Sequence data were processed using Trimmomatic 0.32, followed by assembly generation with SPAdes 3.1.1 and resistance gene annotation with ResFams 1.2 (3) and ResFinder 2.1 (4). Isolates 2 and 3 represented different sequence types (ST) by the Achtman scheme of multilocus sequencing typing: ST1284 (phylogroup A) and a novel single-locus variant of ST410 (phylogroup B1), containing recA allele 126 rather than allele 7 (5). Both STs have been identified among E. coli isolates from animal and human hosts (6, 7). ST410 has been described as a potentially pandemic multidrug-resistant clone (7).
Results using the Check-Points assay and whole-genome sequencing were comparable. Both isolates contained class A, C, and D β-lactamase genes along with other antibiotic resistance genes (Table 2). Isolate 2, the phenotypically carbapenem-resistant strain, harbored the class B carbapenemase blaNDM-5. Isolate 3, which was ertapenem intermediate, meropenem susceptible, and negative by the Carba NP assay, carried blaOXA-181, a blaOXA-48-like gene. Our patient thus had bloodstream infections with two E. coli strains harboring different carbapenemase genes prevalent in the Middle East (8).
TABLE 2.
Whole-genome sequencing resistome analysis of E. coli bloodstream isolates 2 and 3a
| Isolate | Sequence type | Resistance gene | Function |
|---|---|---|---|
| 2 | 1284 | aac(6′)-Ib-cr | Fluoroquinolone-acetylating aminoglycoside acetyltransferase |
| aadA5 | ANT(3″)-Ia family aminoglycoside nucleotidyltransferase | ||
| catB3 | Chloramphenicol acetyltransferase | ||
| mph(A) | Macrolide 2′-phosphotransferase I | ||
| blaCTX-M-15 | Class A β-lactamase | ||
| blaNDM-5 | Class B carbapenem-hydrolyzing metallo-β-lactamase | ||
| blaAmpC-EC66 | Class C β-lactamase | ||
| blaCMY-42 | Class C β-lactamase | ||
| blaOXA-1 | Class D β-lactamase | ||
| tetA | Tetracycline resistance MFS efflux pump | ||
| macB | Macrolide export ATP-binding/permease protein | ||
| macA | Macrolide export | ||
| tolC | Multidrug efflux | ||
| mexE | MexE family multidrug efflux RND transporter | ||
| acrB | Multidrug efflux RND transporter permease subunit | ||
| acrD | Multidrug efflux RND transporter permease subunit | ||
| acrF | MDR efflux pump AcrAB transcriptional activator | ||
| marA | Multidrug efflux RND transporter permease subunit | ||
| emrB | Multidrug efflux system protein | ||
| emrE | SMR antibiotic efflux pump | ||
| mdtB | Multidrug efflux system | ||
| mdtC | Multidrug efflux system | ||
| mdtF | Multidrug efflux RND transporter permease subunit | ||
| 3 | 410 | aac(6′)Ib-cr | Fluoroquinolone-acetylating aminoglycoside acetyltransferase |
| aadA5 | Aminoglycoside nucleotidyltransferase | ||
| aacC3 | Aminoglycoside-(3)-N-acetyltransferase III | ||
| strB | Streptomycin phosphotransferase | ||
| strA | Streptomycin resistance | ||
| qnrS | Quinolone resistance protein | ||
| catB3 | Chloramphenicol acetyltransferase | ||
| blaCTX-M-15 | Class A β-lactamase | ||
| blaTEM-1B | Class A β-lactamase | ||
| blaAmpC | Class C β-lactamase | ||
| blaCMY-2 | Class C β-lactamase | ||
| blaOXA-181 | Class D carbapenem-hydrolyzing β-lactamase | ||
| blaOXA-1 | Class D β-lactamase | ||
| mph(A) | Macrolide 2′-phosphotransferase I | ||
| tetA | Tetracycline resistance MFS efflux pump | ||
| floR | Florfenicol-chloramphenicol resistance | ||
| mexE | MexE family multidrug efflux RND transporter | ||
| acrB | Multidrug efflux RND transporter | ||
| acrD | Multidrug efflux | ||
| tolC | Outer membrane protein, multidrug efflux | ||
| ABC efflux gene | Multidrug ABC transporter ATP-binding protein | ||
| emrB | Multidrug efflux system protein | ||
| msbA | ATP-binding multidrug transporter | ||
| macB | Efflux pump subunit | ||
| macA | Efflux pump subunit | ||
| mdtC | Multidrug efflux |
MFS, major facilitator superfamily; SMR, small multidrug resistance family; RND, resistance-nodulation-cell division superfamily. The majority of resistance genes were on mobile genetic elements. Both isolates harbored a plasmid containing aac(6′)Ib-cr, blaOXA-1, and catB3.
Among the most genetically diverse carbapenemase genes are the Ambler class D β-lactamases, which include the oxacillinases (OXA). blaOXA-181, found in isolate 3 from our patient, is a variant of blaOXA-48. The OXA-48 enzyme hydrolyzes carbapenems at a low level and may therefore be difficult to detect using phenotypic antimicrobial susceptibility testing methods and carbapenemase assays such as the Carba NP test, leading to its notoriety as a “phantom menace” (9). As isolate 3 illustrates, there may be discordance between phenotypic and genotypic resistance among strains carrying blaOXA-48-like genes as their sole carbapenemase. In our opinion, molecular testing for the presence of carbapenemases should be performed, if possible, on Enterobacteriaceae isolates that are phenotypically resistant or intermediately susceptible to any carbapenems, because the presence of carbapenemase genes has infection control and treatment implications. The answer to the challenge question is C, the nucleic acid amplification test.
Had this patient been infected with isolate 3 only (containing blaoxa-181), reliance solely on phenotypic susceptibility to meropenem might have led clinicians to not place her on strict contact precautions, thus risking the spread of a carbapenemase-producing strain within the hospital. The patient did not undergo rectal screening for colonization with carbapenem-resistant Enterobacteriaceae (CRE). Our hospital now conducts CRE screening for patients who reside overseas. Had this patient been identified as CRE colonized prior to her infection, she might have been placed on earlier, effective antibiotic therapy.
Because carbapenemases vary in their hydrolyzing abilities, the type of carbapenemase present in CRE can guide antibiotic therapy. For example, metallo-β-lactamases such as NDM (isolate 2) do not hydrolyze the monobactam aztreonam, which can be effective against NDM-producing strains. OXA-48 carbapenemases (isolate 3) are relatively inactive against cephalosporins and carbapenems; thus, carbapenems may be effective against OXA-48-producing strains. For this patient, treatment was targeted at the most resistant strain, the blaNDM-5-expressing strain. Because of the patient's profound neutropenia, we initiated combination antibiotic therapy with multiple agents, which has been associated with increased survival compared with that after monotherapy (10). Polymyxin B was chosen over colistin because the former achieves more-reliable serum levels (11). Individualized pharmacokinetic analysis was used to guide amikacin dosing and to achieve peak levels of 40 to 60 μg/ml and undetectable trough levels. Rifampin was added briefly due to its reported synergistic activity with polymyxins (12). Tigecycline was given but discontinued due to the patient's nausea and vomiting (11). Extended-infusion meropenem was included briefly to treat the OXA-producing strain but was discontinued because it was unlikely to be active against the NDM-producing strain, for which the meropenem MIC was >128 μg/ml.
In conclusion, this case of a neutropenic adolescent with bloodstream infection caused by multiple carbapenemase-producing E. coli strains highlights the challenges of laboratory detection and treatment of carbapenemase-producing Enterobacteriaceae, the possibility of infections with strains harboring different carbapenemases, and the importation of carbapenemase-producing strains from areas of high endemicity (8).
COMMENTARY
The case presented by Hasassri and colleagues is a prime example of the challenges facing clinicians with regard to carbapenem-resistant enterobacteriaceae (CRE). In an interconnected world with ever-changing clinical and molecular epidemiologies, these challenges are amplified. In the United States, although an increase in the incidence of OXA-48-producing CRE has recently been recognized, Klebsiella pneumoniae carbapenemase (KPC) continues to be the predominant carbapenemase produced by enterobacteriaceae (13). Invasive infections due to CRE are often associated with mortality rates exceeding 50%, with the worst outcomes being seen in the most vulnerable patient populations, such as the case presented here. High mortality rates in patients with CRE infections are driven by significant delays in the time to implementation of appropriate antimicrobial therapy, in addition to patient-specific characteristics (such as age and severity of illness) (19). In some instances, due to delays in processing antimicrobial susceptibility results, appropriate antimicrobial therapy will not be initiated until day 5 of treatment or later, and these “appropriate” treatment options come with significant limitations. Thus, epidemiologic clues for early identification of patients at increased risk for CRE infection are important to recognize. This case accentuates the importance of understanding not just national but international epidemiology, as the patient presented with pathogens producing carbapenemases (NDM and OXA-48 like) that are endemic to Kuwait (14). Clinicians need to be aware of these geographic risks and should consider empirically covering CRE in high-risk, hemodynamically unstable patients. Infection control specialists should also consider screening travelers from areas where CRE are endemic for asymptomatic colonization.
This case also emphasizes the important role that rapid diagnostics can play in the early identification of carbapenemase-producing isolates both to enhance infection control measures (i.e., the rapid placement of the patient in contact isolation) and to optimize treatment decisions (i.e., the clinicians can get both faster and more-detailed information regarding resistance determinants, which can help clinicians to more rapidly provide effective therapy and better interpret MIC results). It is important to appreciate that rapid identification of carbapenemase-producing pathogens will impact clinical care only if the results are acted upon quickly. Effective and timely communication of results from the clinical microbiology laboratory to clinicians, stewardship personnel, and/or infection control personnel is necessary to optimize the potential benefits of rapid diagnostics.
While molecular methods, as emphasized in this case, are critical for early identification and management of CRE patients, they are not helpful in the identification of carbapenem-resistant pathogens that do not produce carbapenemases (e.g., in Enterobacteriaceae that might produce AmpC or extended-spectrum β-lactamases in combination with porin mutations). These carbapenem-resistant pathogens that do not produce carbapenemases pose therapeutic and infection control challenges that are not adequately addressed by currently available rapid diagnostics.
This case also highlights the therapeutic difficulties in treating invasive infections due to carbapenemase-producing Enterobacteriaceae, particularly those due to metallo-β-lactamase (MBL) producers. All currently available therapeutic options have limitations that might adversely impact patient outcomes. These limitations are accentuated in the present case by the presence of neutropenia and, given an impaired immune system, the need for bactericidal antimicrobial activity. Polymyxins, aminoglycosides, and tigecycline, while often demonstrating in vitro activities against CRE, have pharmacokinetic limitations and are unable in some instances to safely achieve bactericidal concentrations at the site of infection (15). The role of carbapenems as a component of combination regimens for treatment of CRE remains controversial, as there is a disconnect between our inability to demonstrate bactericidal activity in animal modeling even when pharmacokinetic/pharmacodynamic targets are reached (16) and clinical data suggesting improved outcomes when these targets are met (17, 18). Carbapenems appear to be most effective when the MIC for the CRE pathogen is ≤8 mg/liter. As demonstrated in this case, carbapenem MICs can vary greatly depending on the type of carbapenemase present and are usually >8 when MBLs are present.
Due to limitations in currently available treatment options and based on published studies, agents with activity against the cellular outer membranes of CRE (i.e., polymyxins and aminoglycosides, the latter of which has secondary mechanisms of action that increase outer membrane permeability) are being increasingly used to enhance the activities of other agents used in combination regimens. While multiple retrospective analyses have reported that 2 to 3 drug combinations with in vitro activity against CRE have been associated with decreased mortality (17, 18), significant unknowns regarding which combinations are optimal remain. In this case, the patient was definitively treated (after tigecycline and rifampin were stopped due to potential toxicity) with polymyxin B plus amikacin. The concern with this regimen is additive nephrotoxicity, which, while mild and reversible in this adolescent, might have been associated with significant nephrotoxicity in an elderly patient. Additionally, as new β-lactamase inhibitor combinations become available to clinicians, the therapeutic role of these agents in treating CRE will need to be delineated. Ceftazidime-avibactam is the first of these agents to come to market in the United States, and while this drug combination is active against many carbapenemase producers (notably KPC and OXA-48), it, like other novel inhibitor combinations nearing approval, lacks MBL-inhibitory activity. The high cost of these newer agents and their targeted activities against only certain carbapenemases make effective use of rapid diagnostics particularly important from both clinical and economic perspectives.
ACKNOWLEDGMENTS
The case authors thank Robert Bonomo, Yohei Doi, and Louis Rice for their helpful guidance while caring for this patient. We thank the staff of the Clinical Microbiology Laboratory at the Mayo Clinic for performing additional antimicrobial susceptibility testing and pulsed-field gel electrophoresis and sequencing analyses.
This journal section presents a real, challenging case involving multidrug-resistant organisms. The case authors present the rationale for their therapeutic strategy and discuss the impact of mechanisms of resistance on clinical outcome. Expert clinicians then provide a commentary on the case.
Funding Statement
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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