NDM-1 (New Delhi metallo-beta-lactamase) and Antibiotic Resistance by Bacteria

NDM-1 Overview

NDM-1 is an abbreviated way to write New Delhi metallo-beta-lactamase, which is the name given to a new (discovered in 2009) enzyme that is able to be produced by several genera of bacteria that render the bacteria resistant to many antibiotics in common use around the world. This enzyme belongs to a group of enzymes (beta-lactamases) that are capable of breaking the chemical bonds of a beta-lactam ring, which composes an important part of many antibiotics such as drugs of the penicillin, cephalosporin, and carbapenem groups. Most of the beta-lactamase enzymes are effective on some or most of the older antibiotics like penicillins and cephalosporins. NDM-1, however, is effective on both the old and newer antibiotics (carbapenems such as imipenem) that contain a beta-lactam ring.
Klebsiella were the first bacteria identified (in 2009) to produce NDM-1 in a patient that traveled from India to England with an infection that did not respond to many antibiotics. The organism was resistant to beta-lactams and, after the organism's genetic and antibiotic resistance mechanisms were studied, NDM-1 and its genetic source were discovered. The genetic source was a plasmid termed "bla_NDM-1," and since that discovery, other bacterial genera have been found to have bla_NDM-1 integrated into other plasmids or into the bacterial chromosome, thus allowing the bacteria to produce NDM-1.
NDM-1, while effective against almost all antibiotics with beta-lactam rings, is not effective in producing antibiotic resistance against other types of antibiotics such as fluoroquinolones (for example, ciprofloxacin [Cipro] and levofloxacin [Levaquin]) or aminoglycosides (for example, gentamicin [Garamycin] and streptomycin [Streptomycin]). Unfortunately, most of the strains of bacteria that have NDM-1 also have either plasmid or chromosomal resistance against these (and other) antibiotics. The term "superbug" is often used loosely to describe organisms resistant to usually two or more antibiotics. Because bacteria that contain NDM-1 are often resistant to almost every antibiotic, bacteria with NDM-1 have been termed a superbug; some investigators consider these bacteria to represent the most dangerous superbug of all that have developed so far.
Although newly discovered in 2009 and most likely because of genetic transfer of plasmids or other chromosomal segments, NDM-1 has been found in at least four different genera of gram-negative bacteria (Klebsiella, Escherichia, Enterobacter, and Acinetobacter). In addition, people in India, Pakistan, England, Canada, Sweden, Australia, Japan, and the U.S. have been found to be infected with bacterial strains that produce NDM-1. Researchers speculate that the extremely fast spread of NDM-1 may be due to patients seeking medical care outside of their home country (for example, visitors or travelers from India); others suggest the widespread and uncontrolled use of antibiotics favors the survival of NDM-1-containing bacterial strains. Another possible reason for fast spread is that Escherichia coli (E. coli), part of the normal bacteria found in the human intestine, readily exchanges plasmids; in fact, the first identified patient infected with Klebsiella containing NDM-1 was subsequently found to have an E. coli strain, isolated from the feces, capable of producing NDM-1.

What Causes NDM-1 to Be Produced in Bacteria?

The genetic code (bla_NDM-1) located on either a plasmid or integrated into the bacterial chromosome is responsible for the synthesis of the enzyme NDM-1. Researchers suggest that environmental pressures, such as the use or overuse of antibiotics, selected for bacteria that could synthesize this enzyme to survive. Some speculate that because there are fewer restrictions on the use of antibiotics in many countries, antibiotic-resistant strains are likely to be produced in these countries; with NDM-1, some investigators suggest India is where this genetic element first developed.
Figure 1 is a schematic diagram that shows the various methods bacteria use to transfer genetic material among different bacterial types. The first method, transformation, occurs when a bacterium's cell wall breaks down during bacterial cell death and the bacterial genetic material (both chromosomal and plasmid) are released into the environment. Other nearby bacteria then can absorb the genetic material and incorporate the absorbed genes into its own plasmids or chromosome.
The second method, conjugation, occurs when two bacteria share a connection through their cell walls that allows genetic material (plasmids or gene fragments) to pass into another bacterium that can incorporate the plasmid or gene fragments into other plasmids or the chromosome.
The last method, transduction, is more complicated. The first step involves a bacteriophage (a type of virus that infects bacteria) that attaches and injects its genome (Fig. 1, white line) into a bacterium. The bacteriophage genome then "takes over" the bacterial cell and synthesizes bacteriophage parts that are reassembled into new bacteriophages. However, during reassembly, sometimes genes from plasmids or the bacterial chromosome genetic material are mistakenly put into the bacteriophage particle (Fig.1, hexagonal-shaped structure, termed a capsid) instead of only viral genes. After reassembly is done, the bacteriophage breaks open the bacterial cell wall and the new bacteriophages then can reinfect other bacteria. Not all bacteriophage-infected bacteria die; some survive. Those bacteria that are infected with bacteriophage genetic material that contained genes from bacterial plasmids or from the bacterial chromosome then can incorporate the plasmid or chromosomal genes into their own plasmids or chromosome.
These types of genetic transfers are responsible for the synthesis of the multiple enzymes like NDM-1 that allow bacteria to become resistant to many antibiotics. Such antibiotic-resistant genes are often closely linked together, and even multiple linked genes can be transferred by these methods at the same time.

 

What Are Symptoms and Signs of a Person Infected With Bacteria Carrying NDM-1?

The major sign or symptom that a person is infected with bacteria carrying NDM-1 is failure of antibiotic treatments (oral or IV) to improve the patient's condition, especially if the patient is infected with a gram-negative bacterial type and is being treated with an antibiotic that contains a beta-lactam ring structure. In addition, if the person has gone to another country (for example, India) for elective surgery or was recently treated with antibiotics for an infection and has returned to the U.S. or another industrialized country with the infection, caregivers should be suspicious that a bacteria producing NDM-1 may be causing the infection. Currently, these are the major clues to suggest infection with NDM-1.
Because NDM-1 can be carried by several types of gram-negative bacteria, the signs and symptoms of the diseases are of little or no help in distinguishing whether the patient has an organism expressing the enzyme until antibiotic treatments fail. However, because gram-negative bacteria are known to cause many diseases (for example, gastrointestinal problems, urinary tract infections, pneumonia, and some wound infections), patients with these diseases that require antibiotic treatments and are not recovering appropriately with treatments should have the gram-negative bacteria isolated and tested for antibiotic resistance.

When to Seek Medical Care for Infections by Bacteria Carrying NDM-1

Any person who has been diagnosed with an infection caused by NDM-1 and still has symptoms of the infection needs to seek medical care, even if they are taking antibiotics. Currently, most people diagnosed with NDM-1 bacterial infections are hospitalized, but some people are discharged and sent home, often with "home" being in another country. These people should seek medical care immediately to prevent further spread of the infection. In addition, any person who develops an infection with gram-negative bacteria who has had any close contact with someone known to have NDM-1 bacteria, both as an infection or as a carrier, should seek medical care and inform the caregiver of their potential association with NDM-1 bacteria.