ADRIENNE T. TERICO, PHARMD, BCPS

CASE: Presence of New Delhi Metallo-ß-lactamase-1 in a Female Patient

An 84-year-old woman presented to the emergency department (ED) with chief complaint of trouble breathing, lower abdominal pain, and diarrhea for 4 days.

Afebrile, vital signs within normal limits, white blood cell (WBC) count of 8 K/µL

Urinalysis results: positive nitrite, small leukocyte esterase, 7 to 20 WBCs per high power field

Discharged from ED with prescription for trimethoprim/sulfamethoxazole for a urinary tract infection

Patient returned to ED, complaining of shortness of breath, left-sided chest pain, and a nonproductive cough.  

Urine culture from early August ED visit reviewed: Escherichia coli resistant to penicillins, cephalosporins, carbapenems, fluoroquinolones, and trimethoprim—sulfamethoxazole found; retained susceptibility to aztreonam

Concerning for possible metallo-ß-lactamase (MBL) production

Patient was admitted for observation because of chest pain, and a consult to the Infectious Diseases (ID) service was obtained.

No findings to support diagnosis of an acute bacterial infection; afebrile, WBC count 8.5 K/µL

Repeat urine culture sent with additional testing requested		

Identical organism grew—susceptible to aztreonam, tigecycline, nitrofurantoin, and colistin.

Resistant to ceftazidime—avibactam, also consistent with MBL production

Two outside laboratories confirmed the presence of the New Delhi metallo-ß-lactamase-1 (NDM-1) enzyme by polymerase chain reaction.

Thorough history obtained to determine where patient may have acquired this organism		

Neither patient nor close contacts including family, friends, and visiting health care workers traveled internationally.

Review of accessible records revealed 10 courses of antibiotics over the past 4 years.

Decided to observe patient off antibiotics		

Plan to start fosfomycin if she developed symptoms of cystitis

PREVALENCE AND IMPACT OF CARBAPENEM RESISTANCE AND

METALLO-ß-LACTAMASE—PRODUCING ORGANISMS IN THE

Over the past decade, carbapenem resistance in Enterobacteriaceae has

become more prevalent worldwide, and the United States has been no

exception. In the latest report compiled by the CDC, there were an estimated

9300 infections caused by carbapenem-resistant Enterobacteriaceae

carbapenemases (KPCs), which are serine-based carbapenemases

that have been reported in every state of the United States

except for Idaho. Metallo-ß-lactamases (MBLs), which are dependent on

zinc for the hydrolysis of ß-lactams, occur more frequently in other countries,

such as Greece, India, and across the Middle East.

β-lactamase-1 (NDM-1) is an MBL that has become widespread in India

over the past decade and is rarely encountered in the United States. As of

June 2017, only 230 NDM isolates had been reported in the United States,

in addition to the 41 and 30 reported isolates of Verona integron—encoded

metallo-β-lactamase (VIM)— and inosine-5’-monophosphate (IMP) –producing

CRE, which are also MBLs. Only 3 NDM-1 isolates were reported in

the state where the patient discussed was evaluated.

underestimate the prevalence of MBL-producing organisms, as laboratory

testing is not always accessible or optimal and there is not mandatory

reporting of carbapenem resistance in every state.

Carbapenem resistance in gram-negative bacteria can be attributed to

production of carbapenemases or may be the result of multiple resistance

mechanisms at work—such as altered permeability of the cell wall preventing

carbapenem entry, along with cephalosporinase production that would

additionally confer resistance to penicillins and cephalosporins.

when carbapenemase production is the suspected mode of resistance, multiple

factors affect the ability of currently available antimicrobials to eradicate

these organisms. These include the class of the carbapenemase (zinc or

serine based), antibacterial minimum inhibitory concentrations, the level of

expression of the gene encoding for the carbapenemase, the bacterial inoculum,

and the ability to achieve adequate antibacterial concentrations to

eradicate those inoculums at the site of infection.

Because of the many possible mechanisms for carbapenem resistance,

MBL production cannot be identified on a susceptibility panel alone. Since

aztreonam is hydrolyzed by serine-based carbapenemases, such as KPC but

not MBL, an organism resistant to all ß-lactams except aztreonam may raise

suspicion for an MBL-producing organism. However, many MBL-producing

organisms possess other modes of antibacterial resistance, including

extended spectrum ß-lactamases (ESBLs) or cephalosporinases, which

would confer resistance to aztreonam. Similarly, an organism resistant to

ceftazidime—avibactam and meropenem–vaborbactam, which are active

against many serine carbapenemase producers but not MBLs, may prompt

 These suspicions should be confirmed by molecular

testing, such as polymerase chain reaction with sequencing.

tests may not be readily available in clinical laboratories, warranting outsourcing

to other labs, increasing the time to results and, inevitably, time to

When it comes to treatment of MBL-producing organisms, the

antimicrobials that are currently available are less than ideal.

The agents most frequently associated with preserved activity

are colistin, tigecycline, and fosfomycin.

limited by narrow therapeutic indices, intermediate susceptibility,

or sources of infection where drug concentrations achieved

are suboptimal. Newly approved therapies such as ceftazidime—

avibactam and meropenem—vaborbactam are

active only against serine carbapenemases and

possess no activity against MBL producers.

A majority of the data surrounding treatment of

CREs lie in combination therapy with antibacterials

from multiple classes. Most of these studies include

KPC producers, with few studies evaluating treatment

907 patients with systemic infections, 188 of whom

were infected with isolates producing the MBL VIM

enzyme, demonstrated that combination therapy

with 2 or more agents was superior to monotherapy

and associated with a survival benefit (27.4% vs

of mortality (18.8%) was observed in patients who

received carbapenem therapy as part of their combination

The data on treating NDM MBLs are largely limited

to case reports. Clinical success was described

in a neutropenic patient on active chemotherapy

treated with polymyxin B in combination with

aztreonam, until the isolate was found to be resistant

to aztreonam, at which point an extended infusion of meropenem

describe a burn patient who became bacteremic with a susceptible

Pseudomonas aeruginosa and an NDM-1 K. pneumoniae. The

patient was initiated on colistin, amikacin, and enteral rifampin

Fosfomycin has retained activity against many MBL blood

and urinary isolates in vitro, but its oral preparation is the only

formulation available in the United States at this time, precluding

its use in systemic infections because of suboptimal concentrations

like nitrofurantoin, is largely limited to uncomplicated urinary

tract infections (UTIs). The remaining cases reported in the literature

on treatment of NDM isolates are of patients who were

treated with oral fosfomycin or nitrofurantoin for UTIs. A pediatric

patient from New Delhi who developed a UTI with NDM-1

was initiated on tigecycline for 5 days with transition to 1 dose of

oral fosfomycin, which sterilized her urine.

2 cases of NDM Enterobacteriaceae causing complicated UTIs

in renal transplant patients successfully treated using the “double

carbapenem” strategy plus oral fosfomycin.

improved clinically, and urine cultures were sterilized. Rogers

et al described treatment of 2 isolates, 1 eradicated by nitrofurantoin

monotherapy, while colistin and rifampin were used for

the second infection, as no oral options remained active. Both

treatment option, as the drug is not hydrolyzed by MBLs, there is a lack of evidence utilizing aztreonam as monotherapy

for infections caused by MBL-producing organisms. However,

aztreonam—avibactam specifically targets MBLs and is currently

being studied in phase 2 trials. When avibactam is added to aztreonam,

it also restores activity against other ß-lactamases that

may be expressed simultaneously, such as ESBLs or serine-based

 In vitro studies demonstrate potent activity

against CREs, serine carbapenemase— and MBL-producing organisms alike, with more than 98% of Enterobacteriaceae isolates being inhibited.

shown that using ceftazidime—avibactam paired with aztreonam

with clinical success, including in 1 patient who was bacteremic

for 26 days on alternative therapy but cleared cultures hours

There are 2 more therapies targeted for MBLs in the pipeline.

Cefiderocol is a siderophore cephalosporin that is stable against

carbapenemases, including MBLs. In vitro, it has shown excellent

activity against KPC and MBL strains, including NDM.

is a monobactam with activity against an array of drug-resistant

organisms. In vitro, it has demonstrated potent activity against

carbapenemase-producing organisms, including MBLs.

In conclusion, evidence for treatment of infections caused by

MBL-producing organisms is scarce. With each case, benefits and

risks of treatment must be considered. Site of infection, source

control, ability to optimally dose antimicrobials without compromising

safety, and severity of illness should play a role in the decision

of which antimicrobials to initiate. The clinical successes

described in the limited available evidence may be multifactorial

and should be interpreted carefully. An important consideration

when evaluating this literature is that it may be confounded by

the fact that acquisition of resistance genes frequently comes at a

fitness cost for organisms, which may make them less virulent.

There is great anticipation for newer agents in the pipeline that

Special thanks to the Maryland Department of Health and the lab of Barry Kreiswirth, PhD, at the Public Health Research Institute Center at Rutgers Medical School for testing the isolate via polymerase chain reaction to detect the NDM-1 enzyme.  

Dr. Terico is an infectious diseases clinical pharmacy specialist practicing in Philadelphia, Pennsylvania. She is a graduate of Temple University School of Pharmacy and completed 2 years of post-graduate training at Temple University Hospital. She is an active member of SIDP. 

Dr. Pace graduated from Temple University School of Medicine, Philadelphia, Pennsylvania. He completed a residency in internal medicine at Temple University Hospital and a fellowship in infectious disease at Hahnemann University Hospital, also Philadelphia. Dr. Pace is board-certified in internal medicine and infectious disease.  

CDC. Antibiotic resistance threats in the United States, 2013. cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed December 6, 2017.

Tängdén T, Giske CG. Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control. 

2015;277(5):501-512. doi: 10.1111/joim.12342.

Healthcare-associated infections: tracking CRE. CDC website. cdc.gov/hai/organisms/cre/trackingcre.html. Updated November 2017. Accessed December 6, 2017.

Bonomo RA, Burd EM, Conly J, et al. Carbapenemase-producing organisms: a global scourge! [published October 16, 2017]. 

Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. 

. 2007;20(3):440-458. doi: 10.1128/CMR.00001-07.

Bidenbach D, Bouchillon S, Hackel M, et al. Dissemination of NDM metallo-β-lactamase genes among clinical isolates of Enterobacteriaceae

collected during the SMART global surveillance study from 2008 to 2012. 

 2015;59(2):826-830. doi: 10.1128/AAC.03938-14.

Wei WJ, Yang HF, Ye Y, Li JB. New Delhi metallo-β-lactamase-mediated carbapenem resistance: origin, diagnosis, treatment and public health concern. 

2015;128(14):1969-1976. doi: 10.4103/0366-6999.160566.

Chibabhai V, Nana T, Bosman N, Thomas T, Lowman W. Were all carbapenemases created equal? Treatment of NDM-producing extensively drug-resistant Enterobacteriaceae: a case report and literature review [published September 15, 2017]. 

Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with gram-negative bacteria: restoring the miracle or false dawn? 

. 2017;23(10):704-712. doi: 10.1016/j.cmi.2017.09.001.

Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. 

. 2014;20(9):862-872. doi:10.1111/1469-0691.12697.

Chien JMF, Koh TH, Chan KS, Chuah TH, Tan TT. Successful treatment of NDM-1 

, 2012; 44(4):312-314. doi: 10.3109/00365548.2011.633549. 

Petersen-Morfin S, Bocanegra-Ibarias P, Morfin-Otero R, et al. New Delhi Metallo-beta-lactamase (NDM-1)- producing 

 2017;18:805-809. doi: 10.12659/AJCR.903992.

Demir T, Buyukguclu T. Fosfomycin: in vitro efficacy against multidrug-resistant isolates beyond urinary isolates. 

. 2017;8:164-168. doi: 10.1016/j.jgar.2016.11.011.

Green DA, Srinivas N, Watz N, et al. A pediatric case of New Delhi Metallo-β-lactamase-1-producing Enterobacteriaceae in the United States. 

. 2013;32(11):1291-1294. doi: 10.1097/INF.0b013e31829eca34. 

Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemase-producing 

2011;55(6):3002-3004. doi: 10.1128/AAC.01420-10.

Rosa R, Rudin SD, Rojas LJ, et al. “Double carbapenem” and oral fosfomycin for the treatment of complicated urinary tract infections caused by blaNDM-harboring Enterobacteriaceae in kidney transplantation [published October 24, 2017]. 

Rogers BA, Sidjabat HE, Silvey A, et al. Treatment options for New Delhi Metallo-beta-lactamase-harboring Enterobacteriaceae. 

. 2013;19(2):100-103. doi: 10.1089/mdr.2012.0063.

Karlowsky JA, Kazmierczak KM, de Jonge BLM, et al. 

activity of aztreonam-avibactam against Enterobacteriaceae and 

isolated by clinical laboratories in 40 countries from 2012 to 2015. 

2017;61(9):e00472-17. doi: 10.1128/AAC.00472-17.

activities of ceftazidime-avibactam, aztreonam-avibactam, and a panel of older and contemporary antimicrobial agents against carbapenemase-producing gram-negative bacilli. 

2015;59(12):7842-7846. doi: 10.1128/AAC.02019-15.

Marshall S, Hujer AM, Rojas LJ, et al. Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? 

2017:61(4):e02243-16. doi: 10.1128/AAC.02243-16.

Wenzler E, Deraedt MF, Harrington AT, Danizger LH. Synergistic activity of ceftazidime-avibactam and aztreonam against serine and metallo-β-lactamase-producing gram-negative pathogens. 

2017(88):352-354. doi: 10.1016/j.diagmicrobio.2017.05.009.

Davido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A. Ceftazidime-avibactam and aztreonam, an interesting strategy to overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae and 

2017;61(9):e01008-17. doi: 10.1128/AAC.01008-17.

Mojica MF, Ouellette CP, Leber A, et al. Successful treatment of bloodstream infection due to metallo-β-lactamase-producing 

2016;60(9):5130-5134. doi: 10.1128/AAC.00264-16.

antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. 

2016;60(2):729-734. doi: 10.1128/AAC.01695-15.

Mendes R, Rhomberg PR, Schaefer B, et al. 

activity of LYS228 against Enterobacteriaceae, including molecularly characterized multidrug-resistant isolates. Presented June 3, 2017 at: American Society of Microbiology Meeting 2017; New Orleans, LA.

Schulz zur Wiesch P, Engelstädter J, Bonhoeffer S. Compensation of fitness costs and reversibility of antibiotic resistance mutations. 

. 2010;54(5):2085-2095. doi:10.1128/AAC.01460-09. 

Articles

A rare metallo-ß-lactamase makes its way into the United States via an 84-year-old patient.
 

ADRIENNE T. TERICO, PHARMD, BCPS

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