Antibiotic Resistance

Summary Points

• Antibiotic resistance causes tens of thousands of deaths each year.
• Almost all infections could be controlled, but finding an effective antibiotic (because of widespread drug resistance) typically requires two to three days. Labs use bacterial cultures to test antibiotic susceptibility and resistance. Cultures require extensive growth and thus cause significant delays.
• With critically ill patients in the ICU, the physician cannot wait for lab results before attempting to control an infection. They must start therapy within a few hours of symptom onset. Therefore they try antibiotic combinations.
• These empiric antibiotic combinations fail in approximately 20% to 40% of cases. Switching drugs after receiving lab results fails to improve the outcome.
• ICU physicians urgently need rapid bacterial identification and antibiotic susceptibility testing that produces accurate results within a few hours after the patient presents with symptoms.

A Brief History of Antibiotic Resistance

Powerful antibiotics first became commercially available in the 1940s and have saved untold millions of lives. Many antibiotics originated from natural sources – one type of organism producing chemical weapons against others. Many different types of organism, including bacteria themselves, produce toxins against bacteria. In response, bacteria evolve defenses. They include resistance to the antibiotics produced by other organisms.

Fleming's original agar “Staph” plate with mold (large mass to the left) that produced penicillin. Numerous bacterial colonies grew on the right, outside of the effective penicillin gradient.

Perhaps the earliest practical example is penicillin, the first marketed modern antibiotic. Fleming famously discovered penicillin in 1928, produced by the Penicillium chrysogenum mold (formerly identified as P. notatum but later found to be identical to P. chrysogenum). A decade later, Florey, Chain, Heatley, and Abraham (Oxford) began studies on Fleming's “mould juice.” They demonstrated the therapeutic potential in a mouse infection study in 1940, in one of medicine's greatest experiments. Human studies began in 1941. Production efforts grew to the point where adequate supplies became available by D-Day (1944). At war's end, penicillin became widely available and won widespread acceptance. For a fascinating account of penicillin's history, read The Mold in Dr. Florey's Coat by Eric Lax.

The researchers themselves had already observed and used penicillin-resistant bacteria in their own studies. In his 1945 Nobel Prize lecture, Fleming himself warned of the danger of resistance –

“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body… …and by exposing his microbes to non-lethal quantities of the drug make them resistant.”

Indeed, it took little time for Staphylococcus aureus (the commonly infectious “Staph”) to develop resistance to penicillin. In 1947 physicians observed the first case of clinical resistance.

The war of “bugs vs. drugs” had begun.

With few exceptions, each introduction of a new antibiotic has been followed within a few years by the first cases of resistance. Resistance then spreads. In addition, more variations of resistance mechanism against the same drug may also continue to emerge over time, compounding the problem.

Antibiotic Resistance Spreads Quickly

Scientists have characterized several fundamentally different mechanisms of antibiotic resistance, and hundreds of variants. Bacteria also share resistance-encoding genes in a number of ways.

Bacteria can share genes without mating and exchanging DNA one-to-one. They can even adopt loose genes from other species, or become infected by viruses that can move genes from one bacterium to others.

Bacteria can also acquire multiple different genes for resistance, making them resistant to multiple families of antibiotic drugs. Such MDR strains (Multiple Drug Resistance) present the greatest clinical challenge. And they are becoming more common.

However, “pan-resistant” strains (resistant to all available antibiotics) are still fortunately rare. Therefore, effective drugs do exist for almost all infections. But finding an effective drug out of the 90-100 available antibiotics requires laboratory testing of each individual infection. This takes time. Today's methods rely on bacterial cultures, and cultures typically require two to three days to provide enough bacteria for analysis.

Antibiotic Resistance Has Real Impact

Critically ill patients have weakened defenses. When they become infected after already becoming critically ill, they can soon become overwhelmed. Their infections tend to emerge as “fulminant” – appearing suddenly and progressing rapidly. An infection compounds the effects of their underlying medical problems. When a critically ill patient shows signs of infection, the physician cannot wait for lab cultures before taking action.

In the absence of guidance by specific tests, standardized antibiotic combinations that use broad-spectrum antibiotics no longer assure effective control. Widespread, complex antibiotic resistance reduces the chance that any particular antibiotic will have any effect. This type of “empiric” combination therapy typically fails in 20% to 40% of cases of serious infection in the ICU.

It seems logical that changing drugs after receiving lab results should improve outcomes. When physicians fail to see the expected response in the expected time, they also switch to different antibiotics even though lab results are still not available.

Unfortunately, research shows that these strategies usually fail. A switch to lab-proven antibiotics, even as soon as 24 hours, fails to improve patient outcomes. A serious infection can overwhelm a debilitated patient rather quickly. For critically-ill patients who contract an infection, the only solution would be to rapidly identify the exact antibiotics that should yield the quickest and strongest infection control.

In the ICU, time is life.

Antibiotic Resistance: A Few Web Resources

The Wellcome Trust (UK) has a superb collection of informative articles on its Web site. For a directory of review articles, visit their Web page entitled “Antibiotic Resistance: An Unwinnable War?”

The Infectious Diseases Society of America has an excellent downloadable overview of public policy issues on their Web site, entitled “Bad Bugs, No Drugs”. An update followed in the Society's journal, Clinical Infectious Diseases, entitled “Bad Bugs Need Drugs” (subscription may be required).

The same journal recently published an excellent review of antibiotic strategies (subscription may be required).

Other Web resources include the Web site for the Centers for Disease Control (CDC).