Bad Bugs and Fewer Drugs

In the pre-antibiotic era, what today is considered a relatively “simple” infection could wipe out an entire family, village, or even countryside. Similarly, surgical mortality (from infection) averaged 40 percent. Today, infectious diseases are responsible, annually, for more than 13 million deaths and greater than 25 percent of mortality. Infections caused by antibiotic-resistant bacteria — often contracted by patients in hospitals — are a consistent problem. In the United States, the annual estimate is 2 million individuals acquire a healthcare-associated infection, resulting in almost 100,000 deaths. Of the microorganisms causing these hospital-acquired infections, 70 percent are resistant to at least one antibiotic. Multi-drug-resistant organisms (MDROs) are not uncommon and have become a complex medical, social, and public health issue — and we, the medical community, have unwittingly created this problem. We know we are not taking sufficient action to prevent and to preclude the emergence of antibiotic-resistant organisms. Furthermore, there are no novel antimicrobials in the advanced stages of development, particularly those that have activity against gram-negative bacteria already resistant to all available antibacterial agents (Boucher H, et al. Clin Infect Dis 2009; 48:1-12). The pipeline to develop antimicrobial drugs is dry. Only five major pharmaceutical companies still have active antibacterial discovery programs. We have what we have and slowly we’re losing them.

As surely as Alexander Fleming discovered the first antibiotic some 80 years ago, he also “invented” the platform for the creation of MDROs. We are the “distribution network.” Penicillin was introduced in 1943. Penicillin-resistant Staphylococcus aureus was first identified in the 1950s in hospitals and nurseries. Fortunately, new antibiotics were discovered, so the problem was usually academic, rather than patient-threatening. By the 1970s, methicillin-resistant S. aureus (MRSA) had emerged, and one of those “new” antibiotics, vancomycin, came into widespread use. By the 1990s, vancomycin-resistant enterococci (VRE) emerged — and most of these organisms are also resistant to traditional, first-line antimicrobial agents.

In June 2002, the first vancomycin-resistant S. aureus was reported. Today, many, many bacterial pathogens are penicillin-resistant, including more than 95 percent of staphylococci and 30–50 percent of pneumococci. Methicillin-resistant Staph aureus (MRSA) has become a common cause of skin and soft-tissue infections, as well as necrotizing fasciitis and pneumonia. It is often mistaken for a spider bite when first seen. A single clone, USA300, is responsible for most community-associated MRSA infection in the United States. MRSA is an example of a microbe that has adapted to the point where it poses frequent, serious clinical challenges in many medical practices. The spread of this organism has shown how rapidly MRDOs can disseminate. From almost zero in 1999 to worldwide distribution in just a few short years.

Our “newer” antibiotics, such as  the fluoroquinolones, along with the third- and fourth-generation cephalosporins, were in use for only a few years before we began to see a similar pattern of the emergence of resistant organisms. Basically, with each new antimicrobial agent, the pathogens have found a way to outsmart it. Charles Darwin (1809-1882) wrote, “It is not the strongest of species that survive, nor the most intelligent, but the ones most responsive to change.”

Bacteria have evolved numerous mechanisms to evade antimicrobials. Chromosomal mutations are an important source of resistance to some antimicrobials. Acquisition of resistant genes or gene clusters via conjugation, transposition, or transformation accounts for most antimicrobial resistance. These mechanisms also enhance the possibility of multi-drug resistance. Once resistant isolates are present in a population, exposure to antimicrobials favors their survival. Reducing antimicrobial selection pressure is a key to preventing antimicrobial resistance.

Nosocomial, gram-negative infections also present a serious risk to our hospitalized patients. A survey of more than 50,000 isolates of Pseudomonas aeruginosa (specimens collected 1999–2002) revealed that 25 percent were multi-drug resistant. Acinetobacter baumannii, a nonmotile, gram-negative bacillus commonly found in soil, wastewater, and skin flora (especially healthcare personnel and hospital environment) is rapidly becoming unmanageable. Environmental contamination may play a role. Multi-drug-resistant strains are now common in some parts of the world. Careful attention to infection prevention guidelines, including hand hygiene, adherence to contact precautions, and environmental disinfection, are among important steps for control. About half of Acinetobacter infections present as sepsis (with fatality rates ~ 50 percent) or as ventilator-associated pneumonias. Acinetobacter also is a cause for urinary tract, skin, soft tissue, and surgical wound infections. Outbreaks have been reported in U.S. military and civilian personnel who were wounded while serving in Iraq and Afghanistan.

Our primary infectious disease challenges for the 21st century include both improved management and reducing medical community practices that contribute to the transmission and acquisition of existing MDROs and to emergence of new MDROs (see Table 1).

Table 1. Emerging Multi-drug-resistant Organisms of Clinical Interest: Organism and Antibiotic Resistance • Comments

• Vancomycin or Glycopeptide Intermediate or resistant Staphylococcus aureus (VISA, VRSA, GISA, GRSA) • If this results in an outbreak, it will transform medicine; so far, every case has been sensitive to something.
• E. coli resistant to trimthoprim-sulfa, cephalosporins, fluoroquinolones • In some areas in the United States, it is a challenge to choose empiric therapy.
• Extended-Spectrum β-lactamase (ESBL) producing gram-negative bacteria; should be considered resistant to penicillins and cephalosporins • E. coli or Klebsiella pneumoniae but can be transferred to Proteus mirabilis, Citrobacter Serratia and other enteric bacilli.
• Klebsiella pneumoniae producing carbapenemases (KPCs) • Currently not a prevalent pathogen in the West.
• Salmonella; fluoroquinolone resistance • An issue with animals, antibiotics used as growth enhancers.
• Quinolone-resistant camphylobacter: Likely a result of quinolone overuse.
• Vancomycin-resistant enterococci; E. faecium infections (more than 90 percent of VRE isolates) resistant to vancomycin, almost 100 percent to ampicillin • Recent survey 494 U.S. hospitals VRE rate 10 percent across all patient groups, rates as high as 70 percent among high-risk groups; cause of blood stream infections, endocarditis, meningitis, intraabdominal infections.
• Penicillin-resistant Streptococcus pneumoniae; 40 percent resistant strains around the world • Largely a pediatric problem, otitis media, and meningitis
• Clostridium difficile-associated Disease (CDAD), increased virulence and refractory to treatment • Increased incidence, increased morbidity (recurrent infections, need for colectomy), and increased mortality.
• Pseudomonas aeruginosa • 24.9 percent MDR isolates between 1999 and 2002.
• Candida spp • Increased candidal infections particularly in ICUs.
• Malaria • Chloroquine and/or pyrimethamine, Sulfadoxine resistance (Thailand and Kenya).
• MDR Tuberculosis • Resistant to isoniazid and rifampin.

And this is a worldwide problem. In 1995, antimicrobial resistance contributed to more than 88,000 deaths in 2 million patients, one death every six minutes. The CDC estimates antibiotic resistance costs U.S. society $4–5 billion annually.

We each know the primary cause, which results in MDROs, is the indiscriminate and/or overuse of antibiotics by physicians and inconsistent compliance by patients. Antibiotics create selective pressure, killing sensitive organisms but allowing drug-resistant mutants to survive. Antibiotics are the second most frequently prescribed group of medications in the United States — second only to drugs acting on the central nervous system. According to the CDC, fully 75 percent of all antibiotic prescriptions from office-based physicians are for upper respiratory infection symptoms — sore throat, runny nose, congestion, coughing, earache — and, as we know, such symptoms are most often caused by viruses, not bacteria. Even bacteria-caused versions of these infections are typically self-limiting in otherwise healthy patients.

The buck stops with the doctor. Physicians must become more willing to and even aggressive in saying “no” to the uninformed, well-intended patient’s demand for antibiotics, antibiotics that we know in many situations are irrelevant to the subject’s symptoms. We are the first-line stewards of some of the most precious resources in our treatment arsenal — antibiotics — and we have to “protect” future patients.

It is a difficult path to follow. When was the last time we told a young mother we would not administer “a prescription of penicillin” to her child due to the symptoms of a common cold? A “prescription” that makes the mother feel she has done the right thing? Again, it is not an easy path, but we must educate the patient and we must follow it.

What can we do? What must we do? We each know the answers.

• Make sure that the bacterial or fungal pathogen is known or highly suspected prior to administering the correct antibiotic, and prescribe as narrow a spectrum drug as medically feasible. Withhold antibiotics if the etiologic agent is viral, i.e., rhinovirus.
• When empiric antibiotic treatment is unavailable, be quick to change to a narrower spectrum drug when susceptibilities are available.
• Check microbiology lab reports, especially susceptibilities.
• Treat infection, not colonization, e.g., bacteria colonizing decubiti, asymptomatic urinary tract colonization in the elderly.
• Consult the experts when treating infections caused by MDROs.
• Vaccinate! (e.g., pneumococci, pertussis, influenza).
• Promote personal hygiene, e.g., hand hygiene, “cover your cough.”
• Emphatically instruct patients to take the full course of the drug prescribed. We know that suboptimal dosing remains a key driver of creating antimicrobial resistance.
• Microbes are living, respirating creatures subject to change and responding to the respective antibiotic environment. Medical practices of even 30 years ago may not make sense today. Stay alert to updates on emerging trends and prescribing recommendations.

Joshua Lederberg describes our future interaction with bacteria as episodes of a suspense thriller titled "Our Wits Versus Their Genes" (Science 2000;288: 287-93): “Human intelligence, culture, and technology have left all other plant and animal species out of the competition … but we have too many illusions that we can govern the microbes that remain our competitors of last resort for domination of the planet. In natural evolutionary competition, there is no guarantee that we will find ourselves the survivors.”