In Our Hospitals Things Are Getting Critical

The chart from the Centers for Disease Control (Fig. 3.2) shows the increase in multiply resistant staph (MRSA), enterococci (VRE) and Pseudomonas aeruginosa (FQRP) over the last 30 years in US hospital intensive care units. The ICU is the last place we want to see very resistant pathogens, and yet this is where they seem to be the most frequent.

Table 3.1 below shows the latest data from the Centers for Disease Control on frequency of resistance of these and other pathogens to key antibiotics. The data specifically represent ICU infections that were associated with devices such as intravenous catheters, breathing tubes and urinary catheters.

In Europe, the situation is not much different. The chart below (Fig. 3.3) shows the state of resistance in key pathogens isolated from bloodstream infections in Europe. The rates of MRSA infection are not very different from those in the US - hovering around 30%. About 20% of European bloodstream isolates of Pseudomonas aeruginosa are resistant to our last line antibiotic class, the carbapenems.

Cdcp Resistant Strains Spread
  1. 3.2 Resistance rates in US intensive care units over time. MRSA - methicillin-resistant Staphylococcus aureus. VRE - Vanomycin-resistant enterococcus. FQRP - Fluoroquinolone (ciprofloxacin) resistant Pseudomonas aeruginosa. From the CDC and the Infectious Diseases Society of America with permission
  2. 3.2 Resistance rates in US intensive care units over time. MRSA - methicillin-resistant Staphylococcus aureus. VRE - Vanomycin-resistant enterococcus. FQRP - Fluoroquinolone (ciprofloxacin) resistant Pseudomonas aeruginosa. From the CDC and the Infectious Diseases Society of America with permission

Table 3.1 Pathogens causing device-associated infections in US hospital ICUs January 2007 to October 2007

Pathogen %

MRSA 56

Vancomycin resistant E. faecalis 7

Vancomycin resistant E. faecium 80

Carbapenem-resistant Pseudomonas aeruginosa 25

Klebsiella pneumoniae resistant to new cephalosporins 25

Carbapenem-resistant Acinetobacter baumanii 35

  1. 3.3 Population-weighted, average proportion of resistant isolates among blood isolates of bacteria frequently responsible for bloodstream infections, EU Member States, Iceland and Norway, 2002-2007. Taken from The Bacterial Challenge, a Time to React, published by the European Centre for Disease Prevention and Control and the European Medicines Agency
  2. 3.3 Population-weighted, average proportion of resistant isolates among blood isolates of bacteria frequently responsible for bloodstream infections, EU Member States, Iceland and Norway, 2002-2007. Taken from The Bacterial Challenge, a Time to React, published by the European Centre for Disease Prevention and Control and the European Medicines Agency

For the MRSA and the vancomycin-resistant enterococci, we now have two antibiotics that will work. One is only available intravenously, not orally, and does not have regulatory approval specifically for treatment of enterococcal infections. Resistance to both has been reported.

The situation in Gram negative bacteria is becoming even more alarming. In years past, we had a wide choice of antibiotics active against these bacteria. The sulfa drugs and tetracycline worked. Ampicillin or the combination of amoxicillin (similar to ampicillin) plus an inhibitor of the enzyme that destroys ampicillin, B-lactamase, worked (Augmentin). Most of the cephalosporins (similar to ampi-cillin but with activity against a wider array of bacteria) were also effective. Hospitals had the luxury of deciding which of the many effective drugs they would put on their formularies. In many parts of the world, including the US, those days are long gone.

In many hospitals and chronic care facilities today, resistance has gotten to the point where only one (essentially) class of antibiotics is left for physicians and patients, the carbapenems. For many physicians and patients, our antibiotic of last resort has become our drug of first choice. Given the "you use it you lose it" rule of antibiotics, you can guess what is happening now. These Gram negative pathogens, especially Klebsiella have acquired a gene for a new enzyme (B-lactamase) that can destroy the carbapenems. Its called KPC for Klebsiella pneumoniae carbapene-mase. The first one of these was isolated from a patient in North Carolina in 1996. The new enzyme destroys the penicillins like ampicillin, even our most modern cephalosporins, and our last line drugs, the carbapenems. KPC is not inhbited by currently marketed B-lactamase inhibitors - so those combinations like Augmentin and others are not effective. In addition, these bacteria are frequently resistant to multiple other antibiotics, even the quinolones like ciprofloxacin or levofloxacin. To treat infections by these pan-resistant strains, physicians are going back to our old friend (not), colisitin.

KPC Klebsiella are now spread throughout the world. We don't have good survey data for many geographic locales. (I can't understand why this is so). In New York City, about 30% of hospital Klebseilla carry KPC. The strains are also widespread in urban hospitals of Pennsylvania and New Jersey. Israel, Greece and China also have suffered significant epidemics of infection with these strains.

As I noted above, our antibiotic class of last resort, the carbapenems, has now become our antibiotic of first choice for many Gram negative infections. This is not a good sign. Unfortunately, about 25% of US ICU isolates of Pseudomonas and 35% of Acinetobacter are also resistant to carbapenems. In many of these cases, we are again back to colistin that I remember from my days of training in the 1970s (see Chapter 1). Because colisitin was developed and marketed so long ago, we think it may work, but we don't know how well and we know it is toxic but we don't know how toxic.

Acinetobacter has become a big problem in the military. Our soldiers wounded in Iraq and Afghanistan are being transferred back to the military hospital at Landstuhl in Germany or Walter Reed here in the US with multi-resistant Acinetobacter infections. One outbreak of Acinetobacter infection involved 70 soldiers and six medical evacuation centers and military hospitals. Ten percent of the strains were resistant to carbapenems, our last line of defense against these organisms. A separate study of Acinetobacter from returning soldiers showed a 36% resistance rate to the carbapenems. For most of these strains, the therapeutic choice is very limited if one exists at all. Crude mortality rates from Acinetobacter infections vary from 16 to 43% overall and they tend to increase when the Acinetobacter are resistant to multiple antibiotics.

The Infectious Diseases Society of America, an organization of physicians specializing in the treatment of infectious diseases, has developed a priority list of bacteria for which we desperately need new antibiotics and often, where we also need more information on the antibiotics we already have. Their acronym for these bacteria is ESKAPE. The list below is taken almost directly from the Society's latest publication on this topic.

E: E.faecium (VRE) has consistently identified as the third most frequent cause of nosocomial bloodstream infection in the United States. Vancomycin resistance likewise continues to increase, with a rate of ~60% among E.faecium isolates.

S: S. aureus (MRSA). Despite the addition of several new agents to treat MRSA infection, clinicians are routinely faced with treatment challenges involving patients with invasive disease. Although criteria for treating skin and skin-structure infection due to community associated MRSA are evolving, the need is great for oral agents for step-down therapy for the group of patients who require initial parenteral therapy. Novel classes are clearly needed for MRSA, because current drug classes exhibit treatment-limiting toxicities and emerging resistance.

K: ESBL-producing E. coli and Klebsiella species. ESBL producing strains are those that produce enzymes that inactivate most penicillin and cephalosporin antibiotics before they can kill the bacteria. Infection due to ESBL-producing E. coli and Klebsiella species continue to increase in frequency and severity. Despite this growing, serious problem, the molecules in late stage development represent only incremental advances over existing carbapenems.

More K: K. pneumoniae Carbapenem-Hydrolyzing Enzymes. Carbapenem-resistant Enterobacteriaceae are increasingly recognized as the cause of sporadic and outbreak infections in the United States and Europe. These organisms cause severe infections among residents of long-term-care facilities and are not easily detected in the clinical microbiology laboratory. Little is known with regard to optimal antimicrobial therapy, and few drugs demonstrate activity. Tigecycline (a relative of tetracycline active against many resistant bacteria) and the polymyxins, including colistin have been used in individual cases with variable success. There are currently no antibacterials in advanced development for these resistant pathogens.

A: A. baumannii. The incidence of infection due to multiply resistant Acinetobacter species continues to increase globally. Unfortunately, as in 2006, we cannot identify candidate compounds in late stage development for treatment of resistant Acinetobacter infection; this pathogen is emblematic of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline.

P: P. aeruginosa. Rates of infection due to resistant P. aeruginosa continue to increase in the United States and globally, as does resistance to both the quinolones and carbapenems. Recent reports also document resistance to the polymyxins like colistin. To date, no drugs in clinical development address the issue of carbapenem resistance or offer a less toxic alternative to the polymyxins.

E: Enterobacter Species. Enterobacter species cause an increasing number of health care-associated infections and are increasingly resistant to multiple antibacterials. Other than colistin and perhaps tigecycline, few antibacterials are active against these resistant organisms, and we found no drug in late stage development for these pathogens.

Drs. Elemam, Rahimian, and Mandell of St. Vincent's Hospital in New York recently expressed their frustration in describing two cases of infection caused by Klebsiella resistant to all known antibiotics. They said, "It is a rarity for a physician in the developed world to have a patient die of an overwhelming infection for which there are no therapeutic options. These cases were the first instance in our clinical experience in which we had no effective treatment to offer. Trends in urban hospitals are often the harbinger of the future. We share these cases to highlight some troubling issues that soon may be relevant to increasing numbers of physicians and patients across the United States." For the ESKAPE organisms, we are going back to a pre-antibiotic era.

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