Herbal Antibiotics: Natural Alternatives for Treating Drug-Resistant Bacteria (8 page)

Bacterial resistance grows exponentially, just like those grains of rice. In practical terms that means we will be fine for a while (say from 1945 to 2010) because, as you can see, it takes a while to get into the big numbers. Welcome to big-number territory.

MRSA, once limited to the very young, the old, and the immunocompromised, has not only emerged in the general community; it is now exceptionally virulent and infecting the healthiest population of all—young adults. As Spellberg comments, “The highly publicized
outbreaks of MRSA infections are dwarfed by the enormous number of cases that occur every day across the United States and throughout the world. Overall, healthy children, adolescents, and teenagers have been particularly heavily hit by MRSA infections, and these cases had gone unheralded until very recently.”
³

Young people, completely healthy, begin to fall ill, enter emergency rooms, and are found to have out-of-control MRSA infections. After just a simple skin break, their arms swell with cellulitis, or the infection becomes systemic and infects the blood (bacteremia), the heart (endocarditis), spinal cord (myelitis), or bones (osteomyelitis). In 2007 the state of Virginia closed 21 high schools to try to stop an MRSA infection that had killed one student and sickened others.

The situation will only get worse. We are within 5 years of MRSA being completely untreatable by any antibiotics at all.

Thirty percent of all
E. coli
urinary tract infections are resistant to treatment, up from 5 percent 10 years ago. The resistance rate has increased 50-fold in the last decade. One of the more troubling resistance mechanisms in
E. coli
is what is called “extended-spectrum beta-lactamase” resistance, or ESBL. ESBL bacteria are highly virulent and strongly resistant to a class of antibiotics called beta-lactams, some of the most potent antibiotics still useful for Gram-negative bacteria. Beta-lactamase is an enzyme that the bacteria create and use to deactivate the antibiotics.
All
the bacteria in the Gram-negative family have begun acquiring that genetic resistance information.
E. coli
and
Klebsiella
are two of the forerunners.

ESBL resistance in
E. coli
in 1990 was only 3.6 percent, by 1993 it was 14.4 percent, by 1995 it was 25 percent in Europe and as high as 40 percent in France. The only antibiotic that until recently could still treat the ESBL-resistant strains of
Klebsiella
was carbapenem and a much older antibiotic, polymyxin, that is only partially effective and often causes severe kidney damage.

Fully resistant strains of
Klebsiella
have now (as of 2011) become common and are often, like MRSA, referred to by an acronym, CRKP. It stands for carbapenem-resistant
Klebsiella pneumoniae
. It is virtually
untreatable; 40 percent of those infected with it die. “These are very serious infections, hugely complicated by the fact that the treatment options are severely limited,” is how Dr. Ajun Srinivasan of the Centers for Disease Control in Atlanta, Georgia, puts it. The first isolated reports of CRKP occurred in 1999 in New Jersey. As of 2010, Srinivasan says, “we are seeing reports of this organism from all over the country.”
⁴

In March of 2010 a severe outbreak of CRKP occurred in Southern California (another occurred in March of 2011 in Los Angeles just as I was completing this manuscript). Brad Spellberg, speaking from the Los Angeles Biomedical Research Institute near Torrance, California, commented, “In the next decade there isn't going to be anything that becomes available that's going to be able to treat these bacteria…. [There] is no current treatment for CRKP bacteria, and there might not be any in the future either.”
⁵

Neil Fishman, president of the Society for Healthcare Epidemiology of America, is more blunt: “We have lost our drug of last resort.”
⁶

Pan-resistant
Pseudomonas
and
Acinetobacter
are similarly dangerous.
Pseudomonas
has also begun to develop resistance to carbapenem antibiotics; the bacteria are now reliably treatable only by polymyxin.
Acinetobacter
,
E. coli
, and
Klebsiella
have also been promiscuously sharing a new plasmid, NDM-1, that confers resistance along a wide range of antibiotics, including carbapenem. “In many ways, this is it,” says Timothy Walsh, a microbiologist and resistant bacteria specialist at Cardiff University in the UK. “There are no antibiotics in the pipeline that have activity against NDM-1-producing Enterobacteriaceae. We have a bleak window of maybe ten years.”
⁷

Enterococcal organisms, once readily treatable, are so no longer. George Eliopoulos in the Division of Infectious Diseases at Beth Israel Deaconess Medical Center in Boston, Massachusetts, observes:

Ominously, in recent years, enterococci resistant to multiple antimicrobial agents have become increasingly prevalent in the hospital environment…. More than half of these enterococcal isolates were resistant to tetracycline, levofloxacin, and quinupristin-dalfopristin; 28 percent were resistant
to ampicillin; and approximately 20 percent were nonsusceptible to vancomycin. From ICUs in the United States, even higher rates of vancomycin resistance have been reported…. Vancomycin resistance genes originating in enterococci have now been found in several clinical isolates of
S. aureus
. This validates concerns expressed more than a decade ago that VRE may serve as a reservoir of genes that could confer upon staphylococci resistance to glycopeptides, the principal antibiotics [remaining] for treatment of infections caused by methicillin-resistant strains [MRSA].
⁸

There are
no
new antibiotics being developed to treat these resistant strains. The most recent, tigecycline, entered the market in 2005. It is active against resistant forms of
Acinetobacter
but not resistant
Pseudomonas
. Only tigecycline and that rather dangerous older antibiotic, polymyxin, can now treat
Acinetobacter
, and polymyxin itself has begun to encounter resistant forms of the bacteria. But then, so has tigecycline.

As Spellberg comments, “If we did not have tigecycline, these infections would be essentially untreatable.” But as he continues, “tigecycline resistance spread within two years of the drug's availability. Indeed, on a recent trip to visit a hospital on the East Coast, I was told that nearly all the hospital's
Acinetobacter
is already fully resistant to tigecycline.”
⁹

People who now enter hospitals, even for very minor treatments, are at serious risk of contracting untreatable infections. Over 70 percent of all pathogenic bacteria in hospitals are at least minimally resistant; the ones discussed herein are considerably more so, being resistant to most major groups of antimicrobials. As oncology nurse Sue Fischer says, “These kids come in for a short treatment and the next day they complain about a pain in their side and the next day they're gone. We open them up and find their whole body shot through with resistant bacteria that have attacked nearly every organ. Nothing works to stop it and it happens as quick as that.”
¹⁰

The first edition of this book covered 12 resistant pathogens that researchers were concerned about. There are 21 on this new list and that doesn't count the various subspecies in each genus that are now resistant (at least 40, not including variants) or several others that are lurking out there on the horizon. The problem, as many epidemiologists have warned, is increasing exponentially and there is no end in sight.

Some of these organisms, such as methicillin-resistant
Staphylococcus aureus
(MRSA), are already causing significant problems in hospitals and communities throughout the world. Others, such as
Clostridium difficile
, are becoming increasingly widespread and dangerous. And still others, such as
Stenotrophomonas maltophilia
, are just beginning their run as resistant organisms.

Most of the resistant pathogens are either Gram-positive or Gram-negative bacteria—a list is included under the respective headings that follow; there are, in addition, one parasitic protist (the malarial parasite), one mold (aspergillus), and one yeast (candida) that have now become dangerously resistant. The parasitic protist is
Plasmodium falciparum
, which causes malaria; the mold is
Aspergillus
spp. (
A. fumigatus
,
A. flavus
,
A. terres
); the yeast is
Candida
spp. (
Candida albicans
is dominant, but most species are now resistant).

Gram-positive and Gram-negative organisms are denoted as such because of their ability to take a Gram stain, one way of identifying them. Of much more importance are the differences in their cellular structure.

Just as we have skin, bacteria have an external membrane surrounding their bodies, a.k.a. the cell wall. Their interior is called the
cytoplasm
; then there is the
cytoplasmic membrane
, which covers the cytoplasm, then the
cell wall
. The cell wall consists primarily of a polymer called peptidoglycan. If the bacteria happen to be Gram-negative, they will have a second wall called the
outer membrane
. Between the two membranes in Gram-negative bacteria is a compartment, the
periplasmic space
. Gram-positive bacteria, because they lack that other membrane, have much thicker cell walls to protect them from outside events.

Because Gram-positive bacteria have only a single cell wall, even though it's thicker, they are, in general, much easier to treat. With Gram-negative bacteria, two cell walls have to be penetrated, not just one. In essence, the bacteria have two chances to identify and deactivate an antibacterial that is hostile to them. Even if an antibiotic gets into the periplasmic space, it usually will not kill the bacteria. It still has to penetrate the second wall.

Gram-negative bacteria have a series of highly synergistic reactions to antibiotics, in essence using three primary mechanisms, all highly coordinated, to resist antibiotics. The first is the double cell wall. The second is a special group of enzymes, beta-lactamases, that are especially effective in deactivating beta-lactam antibiotics (the antibiotics most often used against them). The third is a variety of multidrug efflux pumps. These efflux pumps essentially act like sump pumps; they pump out the antibiotic substances just as fast as they come in so that the bacteria are unaffected by them.

Gram-positive bacteria rely on their thicker cell wall and very, very fast efflux pumps since they don't have a periplasmic space in which to hold the antibiotics while they deal with them. Some Gram-positive
bacteria, such as the staphylococci, have incorporated the use of beta-lactamases, which they learned about from Gram-negative organisms.

Here are some general thoughts to keep in mind when you are approaching treatment of a resistant pathogen. Always remember that you are dealing with virulent, highly pathogenic microbial infections—your treatment must be focused and continual and unremitting until the outcome is decided, one way or the other.

As a general rule of thumb, follow these recommendations when dealing with a resistant infection.

Endotoxins generally come from the outer wall of Gram-negative bacteria and are released into the body when the bacteria die. In a number of diseases, bubonic plague for example, it is not the bacteria that kill you but the endotoxins that are released when they die. If you are treating a systemic infection by a Gram-negative bacteria, the use of an endotoxin scavenger and protectant is often important. Isatis (though not discussed in this book) is perhaps the best herb for this (ginger is also good). It should be included if endotoxin release may be a problem.

If you are treating a difficult infection, especially if it is Gram-negative, use a synergist to enhance the treatment. There are two forms of synergists: the first is active against the efflux pumps in the bacteria, the second helps move the herbs across the intestinal membrane and strongly into the blood. Licorice is the best synergist for Gram-negative bacteria. Piperine will potently move herbal compounds across the intestinal membrane, significantly increasing their presence in the blood. See
chapter 6
for more specifics.