Within a year or so, however, we had our first methicillin-resistant S. aureus (MRSA). Reviewing the table "Our Culpable Climb to GRiEF and Catastrostaph," you can see that not much really happened during the first 20 years or so after methicillin appeared. In 1980, only 1-2 percent of all isolates were resistant. However, by the end of the decade, it had accelerated to 18 percent and another decade later, it had doubled again, from 17 to 35-40 percent resistant. In many large teaching hospitals today in 2002, we see about 50 percent methicillin resistance. One thing you might notice is that the increase in resistance was originally arithmetic--that is it increased by just a few percent--but this resistance became geometric--that is increasing by more than 10 fold--over the last 20 years.

Cohabitating in a host's sputum and perhaps partners in crime to causing a deadly pneumonia are two of the most virulent and ubiquitous killers in the hospital setting: Staphylococcus aureus (the purple-stained cocci growing in clusters) and Pseudomonas aeruginosa (small, pink and rod-shaped). The longer a patient stays in the hospital, the more likely he or she is to acquire or, under certain conditions, transmit these to others. One course of antibiotics is all it may take to shift these shifty malicious microbes from fairly susceptible to highly resistant populations.

Clinical Microbiology Labs, University of Michigan Health System, Regents of the University of Michigan

Enterococcus gs are the enterococci. In the table, you will notice that there is a progression in the enterococcus column from AGRE to PRE to VRE, which I also call "GRiEF." The first penicillin-resistant enterococcus (PRE) did not appear until 40 years after penicillin was already introduced and 30 years after vancomycin was introduced. However from 1989 to 1993 there was an increase in resistance from 0.3 percent to 8 percent--a twenty-five-fold increase--which continued to increase with time and did plateau. While this increase has leveled off, the bad news is, it has not gone away.

There is an interrelationship between methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). Vancomycin use increased 2.5 fold in the United States from 1987 to 1995. The increased use of vancomycin is because of the increase in MRSA, for which vancomycin was the drug of choice. This secondarily led to an increase in VRE. It is important to realize that controlling vancomycin alone does not control VRE and vancomycin is not the only antibiotic that potentiates vancomycin resistance. (More on this later.)

Referring back to the first column on S. aureus, I want to draw your attention to the emergence of GISA--a S. aureus strain that is only intermediately resistant to vancomycin. The first GISA was found in 1996 in a four-month-old male with a surgical wound infection in Japan. The first isolate was found in the US in 1997. As of the year 2000, there were about 11 of these GISAs known worldwide, eight of which were in the United States. This is not a highly resistant bug, like VRSA or “Catastrostaph” would be, but it is still something that is annoying, increasing, and on the horizon for medical professionals to deal with in the future.

	Discussion
	{Dis: Should scientists continue to do research on gene transmission in microbes if there is a risk of creating a "super bug"?}

The reason why we are so concerned with vancomycin-resistant enterococcus (VRE), is because VRE + MRSA could lead to VRSA--a vancomycin-resistant S. aureus or "Catastrostaph," as I call it. In 1991 a scientist named Nobel was able to show in the laboratory that VRE could transmit its highly resistant gene to S. aureus and cause the proliferation of this super bug. Nobel was so concerned about it that he destroyed his isolates. Other researchers have tried to reproduce his results and they found it difficult.

In June 2002, however, the first VRSA found in clinical practice was isolated in a Michigan resident. The patient had diabetes, was on hemodialysis for chronic renal failure and had chronic foot ulcers. The VRSA was isolated from the dialysis catheter after over one year of antibiotic therapy--including vancomycin--for the foot ulcers. Also, both VRSA and VRE were found at the ulcer site. The infection appeared to respond to trimethoprim / sulfamethoxazole, to which it remained susceptible. Given the ubiquity and virulence of S. aureus, with VRSA we could have a veritable antibacterial Armageddon.

Pneumococcus (Streptococcus pneumoniae) mn of the table, you can see that penicillin-resistant Streptococcus pneumoniae (PRSA) appears from 1978 onward. While this is more of a problem in children rather than in adults, because of the use of antibiotics for otitis media, it is still an advancing concern. Resistant strains have been appearing in 30-50 percent of isolates now for quite some time, but you can see that the first resistant organisms did not appear until 1978, 35 years after penicillin was marketed. That occurred first in Africa and France, but soon it spread to the United States, though it was still in fairly low numbers, just 5 percent in the late 1980s. This organism very commonly causes respiratory infections and the real concern is with children.

Clinical Microbiology Labs, University of Michigan Health System, Regents of the University of Michigan As the saying goes, "E. coli happens." Here is a wound drainage with the most commonly found organism within our own bowels (and apparently also on the beaches of the Great Lakes): E. coli (pink-stained rod) cohabitating with the round and purple streptococci. Fortunately, E. coli is among the organisms most easily treated with antibiotics. However, in recent years, there has been increased E. coli resistance to antibiotics. The "the SEALS of the E. coli navy" of the E. coli populations are those that obtain multiple genes through natural selection, mutation and "insemination" from other bacteria to produce extended Spectrum Beta-Lactamases (ESBLs) and other resistance factors that can lead to a virtually untreatable microbe.

Clinical Microbiology Labs, University of Michigan Health System, Regents of the University of Michigan Streptococcus pneumoniae. These purple-stained "diplococci" (referred to as such because they often grow in pairs) reside in the host's central nervous system, likely causing life-threatening meningitis. Just ten years ago, less than 10 percent of these organisms would fail to respond to penicillin. However, ten years later, the number had risen to about 30-40 percent.

Gram-negative Rods

	Ready Reference
	E. Coli Gram stain Pseudomonas aeruginosa The On-Line Medical Dictionary

In the last column of the table, I mention the so-called gram-negative rod organisms (GNRs), and E. coli and Klebsiella pneumoniae come to mind with their ability to produce ESBLs or Extended Spectrum Beta-Lactamases. These organisms (that produce ESBLs) are usually quite resistant to antibiotics and this is highly unusual (because E. coli and Klebsiella are usually sensitive to most antibiotics). The ESBLs are resistant to a number of very broad-spectrum antibiotics and what makes it more nefarious is that usually, in in vitro microbiologic testing, they appear sensitive. However, they rapidly acquire resistance and result in clinical failures. We have now identified the ESBLs and, following along with the table, we did not see those until 1983 in Germany. In the United States, ESBLs spread from fairly low numbers up to our current numbers, measured in the year 2000 at about 4 percent resistance for E. coli and 9 percent for Klebsiella pneumoniae. Unfortunately, the percentage of resistant strains has been increasing. Notice too, the short period of time in which these strains emerged.

Pseudomonas aeruginosa

	Ready Reference
	Klebsiella Lactam The McGraw Hill Concise Encyclopedia of Science and Technology

Finally, we can touch upon the quinolone antibiotics, ciprofloxacin (cipro) being one of the prototypes. These are the only oral agents we have that are active against Pseudomonas aeruginosa. In order to treat Pseudomonas, we have to use intravenous antibiotics unless we use the quinolones; ciprofloxacin (cipro) has only been on the market since 1986-1987. However, you will notice that resistance was only 1-2 percent when it was first marketed, but increased all the way up to 24 percent in 1998 and in 2000 has approached 30 percent. These are indeed precious antibiotics.

One study on Pseudomonas aeruginosa resistance to the quinolones suggests that although resistance is increasing--as it is with all antibiotics--it is doing so at an even greater rate with the quinolone antibiotics. We are literally prescribing these precious agents into a premature senescence.

	Discussion
	Ciprofloxacin (cipro) made headlines in 2001 when it was used to treat cases of anthrax among US postal workers and others known to be at risk. {Dis: Should cipro be readily available to the general public as protection against the terrorist threat of anthrax?}

After the anthrax scares in the US in 2001, about 10,000 (or more) postal employees were put on antibiotics like ciprofloxacin/doxycycline. Especially in the case of ciprofloxacin, this may bode ill. Many of these patients were put on these antibiotics for sixty days--not the usual seven-, ten-, or fourteen-day course of antibiotics for most infections. As a result, in a year or two we are possibly going to see even more resistance to ciprofloxacin and other fluoroquinolones.

We will cover similar ramifications of the broad-spectrum antibiotic era--that is, the prevalence and over-use of antibiotics today--in the sessions that follow.

The small pink rods growing from this patient's sputum (medical nomenclature for "spit") are the stained silhouettes of one of the grim reapers of the intensive care unit. The highly antibiotic-resistant Pseudomonas aeruginosa likes to frequent moist hardware such as ventilators and urinary catheters in the sickest of the sick. In 1990, only about 1 in 20 of these strains were resistant to cipro. By the year 2000, this had ominously increased to 1 in 4.

Clinical Microbiology Labs, University of Michigan Health System, Regents of the University of Michigan