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

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

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.

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

The best treatment for an infection caused by bacteria that make NDM-1 is to determine which antibiotics the NDM-1 strain is susceptible (not resistant) to and use those antibiotics for patient treatment. One antibiotic, colistin, which is infrequently used because of its toxicity, is often the only antibiotic to which NDM-1-producing bacteria are susceptible. However, some NDM-1-producing bacteria have shown sensitivity to tigecycline (Tygacil) and a few to aztreonam (Azactam). However, these antibiotics should not be used without first determining the resistance/susceptibility pattern for the individual infecting bacterial strain. Antibiotic resistance/susceptibility patterns for bacteria are routinely done in labs that grow isolated bacterial strains in the presence of antibiotic-impregnated disks. Resistant bacteria grow up to the disk edge, while bacteria susceptible to being inhibited or killed by the antibiotic leave a clear space of no growth that extends away from the disk edge. The larger the clear space, the more susceptible is the bacterial strain to the antibiotic (see example, Figure 2). Most NDM-1-producing bacteria show no clear space. One problem with this test is that it takes about two days to get results.

Kirby-Bauer disk test for antibiotic resistance/susceptibility pattern. SOURCE: CDC/Gilda L. Jones

Researchers at GlaxoSmithKline have identified a new antibiotic compound that may inhibit bacterial topoisomerase function in NDM-1-containing bacteria. Consequently, the bacterial replication (growth) is inhibited or stopped. Unfortunately, the compound has not gone through any clinical trials and is not likely to be commercially available very soon, since no clinical trials are currently scheduled.

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.

Mechanisms that allow genes that code for drug resistance to be shared among various bacterial strains and different bacterial genera