FW: PRO/EDR> Bacterioides fragilis - USA: (WA) ex India susp, multidrug resistance

[Maffei, Joanne]

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Subject: PRO/EDR> Bacterioides fragilis - USA: (WA) ex India susp, multidrug resistance


BACTEROIDES FRAGILIS - USA: (WASHINGTON) ex INDIA SUSPECTED, MULTIDRUG RESISTANCE
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Date: Fri 30 Aug 2013
Source: CDC. MMWR Morb Mortal Wkly Rep 2013; 62(34); 694-6 [edited] <http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6234a2.htm?s_cid=mm6234a2_w>


Multidrug-resistant _Bacteroides fragilis_ -- Seattle, Washington,
2013
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The _Bacteroides fragilis_ group consists of species of obligate anaerobic bacteria that inhabit the human gut. They are among the leading pathogens isolated in the setting of intra-abdominal infections. _B. fragilis_ strains, especially in the USA, are virtually always susceptible to metronidazole, carbapenems, and beta-lactam antibiotics (1). Although isolated cases of resistance to single agents have been reported, multidrug-resistant (MDR) _B.
fragilis_ strains are exceptionally rare (1,2). In May 2013, an MDR _B. fragilis_ strain was isolated from the bloodstream and intra-abdominal abscesses of a patient who had recently received health care in India. This is only the 2nd published case of MDR _B.
fragilis_ in the USA.

This report summarizes the case and highlights the need for awareness of multidrug-resistant organisms (MDROs) in returning travelers who have received inpatient medical care outside the USA, both for timely implementation of proper infection control measures and to ensure administration of appropriate antimicrobials.

Case report
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A USA-born man aged 70-79 years, with past medical history notable only for benign prostatic hyperplasia, traveled to India for pleasure, arriving 7 Nov 2012. After traveling in India for one month, he developed progressive abdominal pain and sought medical attention at a hospital in Jaipur on 11 Dec 2012. During a 4-day hospitalization, he underwent colonoscopy with biopsy of a suspicious mass and was found to have a well-differentiated adenocarcinoma of the colon.
Computerized tomography (CT) of the abdomen demonstrated multiple large liver lesions as well as pericolonic lymphadenopathy suggesting metastatic cancer. During his admission, he received one unit of packed red blood cells and several doses of unspecified intravenous antibiotics.

He was advised to undergo surgical resection of his cecal mass but decided to travel to New Delhi to seek a 2nd medical opinion. There, he was hospitalized during 5-9 Jan 2013. Based on limited records from that admission, it does not appear that antibiotics were administered at that time. The patient then returned to the USA and was evaluated at a cancer center in Seattle, Washington, where he received 5 cycles of chemotherapy as an outpatient in early February 2013. He received 3 days of oral levofloxacin for a brief episode of neutropenia during chemotherapy.

In May 2013, after chemotherapy, the patient was admitted to the University of Washington Medical Center for a complex tumor resection.
He received single doses of preoperative cefazolin and metronidazole.
On postoperative day 4, he developed leukocytosis with a maximum white blood cell count of 25 000/microL. Blood cultures were obtained but yielded no growth. A CT scan of the abdomen revealed multiple fluid collections suggesting abscesses. Vancomycin and piperacillin/tazobactam were initiated, and the patient underwent radiographically guided percutaneous drainage. The fluid grew a pan-susceptible _Escherichia coli_, and antibiotics were narrowed to ceftriaxone. The leukocyte count improved initially, but then increased again several days later. Repeat blood cultures drawn through a central catheter showed anaerobic Gram negative rods, and piperacillin/tazobactam coverage was restarted.

Follow-up blood cultures drawn 2 days later demonstrated no growth. A repeat CT scan for persistent fever, 10 days after drain placement, demonstrated a ring-enhancing fluid collection in the abdomen and right flank and pelvic fluid collections. Vancomycin was added to the patient's antimicrobial regimen, and an additional percutaneous drain was placed. Fluid was sent immediately for microbiologic testing. Gram stain of the fluid revealed 4+ polymorphonuclear cells and 3+ Gram negative bacilli, with a pure culture of anaerobic Gram negative rods isolated in culture.

Both blood culture and abdominal fluid culture isolates were identified as _B. fragilis_. Both isolates demonstrated high levels of resistance by epsilometer test (E-test) to multiple antibiotics, including metronidazole, imipenem, piperacillin/tazobactam, and clindamycin. Resistance to cefotetan, ampicillin/sulbactam, and moxifloxacin also was observed.

The patient was placed under contact precautions (3), and antimicrobials were changed temporarily to imipenem and metronidazole while additional susceptibilities were performed, including to tigecycline, minocycline, and linezolid. Cultures from additional percutaneous drains placed in the intra-abdominal fluid collections also grew MDR _B. fragilis_. Species identification was confirmed as _Bacteroides fragilis_ ssp. _fragilis_ by biochemical testing, mass spectrometry, and molecular sequencing. Microbiologic testing for the blood isolate demonstrated susceptibility to minocycline, linezolid, and tigecycline. Based on a published report of successful use of linezolid for the treatment of an intra-abdominal infection with MDR _B. fragilis_ (4), the patient's regimen was changed to linezolid and ertapenem to treat this organism and other probable Gram negative rods associated with his intra-abdominal abscesses.

The patient remained afebrile with negative subsequent blood cultures.
He was discharged from the hospital on an outpatient regimen of oral linezolid and parenteral ertapenem. His abdominal abscesses gradually resolved, and his antibiotics were discontinued after approximately 4 weeks of treatment. He remains under strict contact precautions during all inpatient and outpatient health-care treatments.

[Authors: Kalapila A, Pergam S, Pottinger P, et al]

Editorial note
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A national survey of the susceptibility of _B. fragilis_ analyzed approximately 6000 isolates from 13 medical centers during 1981-2007 for antimicrobial resistance. The survey noted less than 1 percent resistance in the _B. fragilis_ group to imipenem/cilastin, and only 3 isolates demonstrated resistance to metronidazole (1). In Europe, resistance to imipenem/cilastin or metronidazole has been reported in only 1-2 percent of isolates (2). There are different mechanisms of resistance to these antimicrobial agents. The cfiA gene, which is typically chromosomal, encodes for metallo-beta lactamases that confer carbapenem resistance (5). Metronidazole resistance, however, has been reported as typically caused by nim genes that are either located on plasmids or on the chromosome (5). _B. fragilis_ isolates that simultaneously express multiple mechanisms of resistance to different antibiotic classes are exceedingly rare, with only a handful of case reports worldwide. Testing for molecular mechanisms of resistance to metronidazole and carbapenems in the described patient's isolate are under way.

In this report, the patient received short courses of 6 antibiotics during his admission to the University of Washington Medical Center, which might have played a role in the genesis of his MDR _B.
fragilis_. However, before that admission, he had traveled to India, where he was hospitalized twice and underwent an invasive procedure.
Recently, cases of carbapenem-resistant Enterobacteriaceae (CRE) have been associated with inpatient admissions in medical facilities outside of the USA, including in hospitals in India (6). Although metronidazole resistance in _B. fragilis_ has been reported in India (7), it is extremely rare throughout the world.

This is only the 2nd case of MDR _B. fragilis_ infection reported in a USA hospital with resistance to both carbapenems and metronidazole.
The 1st case, reported in 2011, was in a USA Army soldier with MDR _B.
fragilis_ isolated from blood and tissue following an injury sustained in Afghanistan (8).

Recent interest in infection control measures surrounding MDROs focuses on CRE infections in returning travelers, especially those coming from the Indian subcontinent. The case described in this report, as well as the previous MDR _B. fragilis_ case in the USA (8), suggests that other MDR bacteria that pose a potential public health threat could be associated with recent international travel. The most recent Clinical and Laboratory Standards Institute guidelines do not recommend routine susceptibility testing of anaerobes except in the case of serious infections or failure of standard antimicrobial therapies (9). Therefore, heightened vigilance is needed for the possibility of MDROs in patients who have received health care outside the United States. Most importantly, this case reinforces the importance of identifying patients at risk for MDROs and implementing early empiric contact precautions and other infection control measures for patients who received inpatient medical treatment outside of the USA (3).

Although _B. fragilis_ has long been considered reliably susceptible to a number of broad-spectrum anti-anaerobic drugs (1), the case in this report and others like it (10) suggest clinicians should no longer rely on cumulative susceptibility data from surveys alone to direct treatment and should consider requesting susceptibility testing when treating serious infections caused by _B. fragilis_. Nonetheless, drainage of abscesses and surgical debridement of involved tissue remain the cornerstones for treating most anaerobic infections.

This case also suggests an expanding scope of multidrug resistance and the need for improved antibiotic stewardship. Similar to the Enterobacteriaceae, _B. fragilis_ is a normal part of the human lower intestinal microbiota. Increasing clinical infections caused by MDRO strains of such disparate bacteria as Enterobacteriaceae and _B.
fragilis_ might be a sentinel for a larger expansion of resistance.

Although antibiotics have saved countless lives and allowed modern medicine to advance rapidly, their use to treat infections is a global public health resource that needs to be carefully conserved, both in the USA and abroad.

References
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1. Snydman DR, Jacobus NV, McDermott LA, et al: Lessons learned from the anaerobe survey: historical perspective and review of the most recent data (2005-2007). Clin Infect Dis 2010; 50: Suppl 1: S26-S33; [available at <http://cid.oxfordjournals.org/content/50/Supplement_1/S26.long>].
2. Nagy E, Urban E, Nord CE, ESCMID Study Group on Antimicrobial Resistance in Anaerobic Bacteria: Antimicrobial susceptibility of _Bacteroides fragilis_ group isolates in Europe: 20 years of experience. Clin Microbiol Infect 2011; 17(3): 371-9; [available at http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2010.03256.x/full].
3. CDC: New carbapenem-resistant Enterobacteriaceae warrant additional action by healthcare providers. CDC Health Alert Network. Atlanta, GA:
US Department of Health and Human Services, CDC; 2013. Available at <http://emergency.cdc.gov/han/han00341.asp>.
4. Wareham DW, Wilks M, Ahmed D, Brazier JS, Millar M: Anaerobic sepsis due to multidrug-resistant _Bacteroides fragilis_; microbiological cure and clinical response with linezolid therapy.
Clin Infect Dis 2005; 40(7): e67-e8; [available at <http://cid.oxfordjournals.org/content/40/7/e67.long>.
5. Soki J, Eitel Z, Urban E, Nagy E, ESCMID Study Group on Antimicrobial Resistance in Anaerobic Bacteria: Molecular analysis of the carbapenem and metronidazole resistance mechanisms of _Bacteroides_ strains reported in a Europe-wide antibiotic resistance survey. Int J Antimicrob Agents 2013; 41(2): 122-5; [available at <http://www.sciencedirect.com/science/article/pii/S0924857912003858>].
6. Gupta N, Limbago BM, Patel JB, Kallen AJ: Carbapenem-resistant
Enterobacteriaceae: epidemiology and prevention. Clin Infect Dis 2011;
53(1): 60-7; [available at
<http://cid.oxfordjournals.org/content/53/1/60.full.pdf+html>].
7. Chaudhry R, Mathur P, Dhawan B, Kumar L: Emergence of metronidazole-resistant _Bacteroides fragilis_, India. Emerg Infect Dis 2001; 7(3): 485-6; [available at <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631797/pdf/11384542.pdf>].
8. Sherwood JE, Fraser S, Citron DM, et al: Multidrug resistant _Bacteroides fragilis_ recovered from blood and severe leg wounds caused by an improvised explosive device (IED) in Afghanistan.
Anaerobe 2011; 17(4): 152-5; [abstract available at <http://www.sciencedirect.com/science/article/pii/S1075996411000229>].
9. Clinical Laboratory Standards Institute: Methods of antimicrobial susceptibility testing of anaerobic bacteria; approved standards.
M11-A7. Wayne, PA: Clinical Laboratory Standards Institute; 2007.
10. Schapiro JM, Gupta R, Stefansson E, Fang FC, Limaye AP: Isolation of metronidazole-resistant _Bacteroides fragilis_ carrying the nimA nitroreductase gene from a patient in Washington state. J Clin Microbiol 2004; 42(9): 4127-9; [available at <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC516330/>].

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Communicated by:
ProMED-mail
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[Indeed, it is not clear whether this multidrug resistant anaerobic organism was acquired inside or outside the borders of the USA. This case adds to the importance of underscoring the need for rational, well-thought out global control of antimicrobial use.

Most laboratories do not perform antimicrobial sensitivities for anaerobic isolates but that may be a thing of the past. - Mod.LL

A HealthMap/ProMED-mail map can be accessed at:
<http://healthmap.org/r/6dEe>.]

[see also:
2012
----
Gram negative bacilli, MDR - USA: (MD) KPC, nosocomial, fatal
20120917.1297252
Gram negative bacilli, MDR - Chile: ex Italy, KPC, nosocomial
20120319.1074688
Gram negative bacilli, MDR - Brazil: (SC) KPC, nosocomial
20120220.1047007
2011
----
Gram negative bacilli, multidrug resistance, nosocomial - Canada: (QC)
20110919.2852
Gram negative bacilli, multidrug resistance - Panama, Netherlands 20110731.2303] .................................................ll/mj/dk
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