Emerging Antibiotics: Will We Have What We Need?

Laura A. Stokowski, RN, MS

Disclosures

February 03, 2010

In This Article

A (Brief) Review of Bacterial Resistance

The outer structural matrix of the bacterium influences both susceptibility and resistance to antibiotics (Figure). All bacteria have cell membranes surrounding the cytoplasm, but gram-negative bacteria also have a thin layer of peptidoglycan and an additional outer lipopolysaccharide membrane. The cell membrane of a gram-positive bacterium is covered by a much thicker peptidoglycan cell wall. Bacteria are classified as gram-negative or gram-positive on the basis of how much color these structures retain when stained with a purple dye; the thicker peptidoglycan of the gram-positive bacteria holds more dye. Because these outer coverings control access to the antibiotic's target areas, changes in these structures can alter the ability of the antibiotic to reach its target and determine the intracellular drug concentration.

Figure. Diagram of physical features of gram-positive and gram-negative bacterial cell walls. Wikimedia Commons, public domain image. http://commons.wikimedia.org/wiki/File:Gram-Cell-Wall.jpg#file

Mechanisms of resistance. Resistance can be either inherent -- as exemplified by the inability of vancomycin to penetrate the cell wall of gram-negative bacteria -- or acquired. Acquired resistance is a change in the bacterium's genetic composition that permits clinical resistance to drugs that were once active against it. Acquired resistance can reduce the effectiveness of an antibiotic or render the antibiotic completely ineffective against the bacterium.[2]

Bacteria can also become resistant to other classes of antibiotics (cross-resistance) or transfer their resistance genes to other microbes and species (co-resistance). The strategies used by bacteria to resist the actions of antibiotics include [2]:

  • Reduced outer membrane permeability;

  • Reduced cytoplasmic membrane transport;

  • Increased efflux/decreased influx of antibiotic;

  • Neutralization of antibiotic by enzymes;

  • Target modification; and

  • Target elimination.

Inactivating enzymes such as beta-lactamases (class 1 chromosomal beta-lactamases and extended-spectrum beta-lactamases) and carbapenemases are increasingly responsible for antibiotic failure. Target alteration involving modification of penicillin binding proteins is the primary mode of penicillin resistance of a number of serious pathogens, including Streptococcus pneumoniae, Neisseria meningitidis, and Enterococcus faecium.[2] Individual resistance mechanisms can act synergistically to strengthen antimicrobial resistance, a problem that has broadened the spectrum of resistance now seen in some gram-negative pathogens.[3] The evolutionary changes now conferring resistance to beta-lactam antibiotics and other emerging mechanisms of resistance among gram-negative bacteria are beyond serious -- they are truly frightening.

Pathogens of Highest Concern

The most serious, life-threatening infections are caused by a group of drug-resistant bacteria that the Infectious Diseases Society of America (IDSA) has labeled the "ESKAPE" pathogens, because they effectively escape the effects of antibacterial drugs.[4] (Table)

Table. The ESKAPE Pathogens

E Enterococcus faecium Third most common cause of HCA BSI. Increasing resistance to vancomycin.
S Staphylococcus aureus (MRSA) Emerging resistance to current drugs and significant drug toxicities. Lack of oral agents for step-down therapy
K Klebsiella
Escherichia coli
K pneumoniae
ESBL-producing organisms increasing in frequency and severity; associated with increasing mortality. K pneumoniae carbapenemases causing severe infections in LTCF. Few active agents; nothing in development
A Acinetobacter baumannii Increasing worldwide, recent surge reported in hospitals.[5] Very high mortality. Carbapenem-resistant.
P Pseudomonas aeruginosa Increasing P. aeruginosa infections in US and worldwide. Resistant to carbapenems, quinolones, aminoglycosides
E Enterobacter species MDR HCA infections increasing; resistance via ESBLs, carbapenemases, and cephalosporinases

HCA = healthcare associated; BSI = bloodstream infection; MRSA = methicillin resistant S aureus; ESBL = extended-spectrum beta-lactamase; LTCF = long-term care facility; MDR = multiple drug-resistant

Is the Pharmaceutical Cupboard Bare?

Brad Spellberg, MD, Associate Professor of Medicine, Geffen School of Medicine at UCLA, Division of General Internal Medicine, Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, is the author of a book about this issue called Rising Plague: The Global Threat from Deadly Bacteria and our Dwindling Arsenal to Fight Them. I recently asked Dr. Spellberg to comment on our nearly empty antibiotic pipeline.

"It needs to be recognized that antibiotics have a unique feature that distinguishes them from all other drugs," explained Dr. Spellberg. "And that is that antibiotics effective today will probably not be effective 15-20 years from now. That's something that is not true of any other class of drugs, and thus we have a critical public health need to continually develop new antibiotics.

"The economic and regulatory climates have changed so that the drug companies aren't making new antibiotics. We've been talking about antibiotic stewardship since the 1950s. It used to be 'new bug, new drug,' but not anymore. We are already seeing infections resistant to all of the antibiotics that we have now, and the number will increase at a geometric rate over the next 5 years."

It's not that there aren't any antibiotics in development. There are, but they won't solve our real problems. The antibiotics aimed at gram-negative infections that are currently in development have mechanisms of action similar to the drugs we already have available. Ceftobiprole and ceftaroline, for example, have both completed phase 3 trials, but they are essentially the same as cefepime, a drug already on the market. A gram-negative organism resistant to cefepime, then, will also be resistant to both ceftobiprole and ceftaroline. So, explains Dr. Spellberg, the real problem is that there are no gram-negative antibiotics in the pipeline that will work against bacteria already resistant to the drugs we have.

The evidence backs up such assertions. In 2009, the IDSA published their latest assessment of the strength of the drug development pipeline for novel therapeutic agents to treat drug-resistant infections.[4] The findings were grim. Not only is the number of antibiotics in phase 2 or phase 3 clinical development disappointingly low, but this is clearly not a recent trend. The number of drugs that have made it through the developmental process and received FDA approval has plummeted in recent years. From 1983 through 2007, systemic antibacterial approvals declined by 75%. Fewer drug discovery efforts and drugs in early-phase trials prove that pharmaceutical companies have retreated from antibacterial research and development. Of grave concern is the lack of systemically administered antimicrobials in advanced development that have activity against gram-negative bacteria or bacteria that are already resistant to all drugs in our current armamentarium.[4]

Discovering new classes of antibiotics has become increasingly difficult.[3] Moreover, major pharmaceutical companies have simply lost interest in the antibiotics market because these drugs are not as profitable as drugs that treat chronic diseases and lifestyle factors.[6] Antibiotics are short-term drugs, taken only until the infection is gone, not daily for years and years by hundreds of thousands of people. It is extremely expensive to develop and establish safety and efficacy of a new antibiotic, especially because there is no guarantee that the drug will be approved even after a huge investment of time and money.

To understand why pharmaceutical companies have backed away from antibiotic development, it helps to understand the drug approval process, and in particular, some of the hurdles that must be overcome in getting regulatory approval for a new drug.

The Drug Approval Process

According to Dr. Spellberg, the few antibiotics that are trickling through the system are getting stopped by the FDA. "Most healthcare professionals do not completely understand the FDA process," says Dr. Spelling. "It is a huge impediment to getting a new antibiotic to market."

Imagine, he said, that a pharmaceutical company has developed a new antibiotic to treat community-acquired bacterial pneumonia, a major source of drug-resistance right now. The drug company is told by the FDA that their clinical trials need to prove that the new drug is not inferior to the old drug, with reduced all-cause mortality as the primary endpoint. No clinical endpoints will suffice; in other words, it doesn't matter if patients get better faster. That kind of trial, says Dr. Spellberg, is impossible. "You would need a sample size of 5000 patients to do a study like that. It can't be done." Unfortunately, this scenario isn't fantasy. It's really happening.

Statisticians argue that it should be easy to prove superiority of a new antibiotic because of all the drug resistance out there, "but they are missing a central concept," adds Dr. Spellberg. "To prove that a new drug is superior to the comparator, you would need to enroll patients whose infections are resistant to the comparator. But you can't do that. In a study, you would have to exclude the very patients in whom you would be able to demonstrate superiority. It's a conundrum that can't be solved."

It's also a conundrum that is perpetuated by the fact that statisticians (people who generally have never seen and certainly haven't treated a case of pneumonia or any other life-threatening infection) outnumber clinicians at the regulatory level, and it is the statisticians who are making the decisions.

Dr. Spellberg explains the IDSA's position. "We are advocating solely for patients. We understand the FDA's role, but it should not be so rigorous that it kills the production of new drugs. There has to be a middle ground. There is a saying: 'The perfect is the enemy of the good.' If you are going to demand perfect data, you are never gong to get it. You are going to have to accept imperfect data if it is robust enough to support efficacy."

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