CDIs Increasing in Children

New research published in Emerging Infections Diseases suggests a more than 80 percent increase in the number of childhood hospitalizations due to Clostridium difficile between 1997 and 2006. The study (ahead of print, see pdf here), led by Marya Zilberberg, drew statistics from multiple databases of pediatric hospitalizations. In the ten years examined, the number of children hospitalized for C. difficile infection (CDI) increased from 7.24 per 10,000 hospitalizations to 12.80. In 1997, there were 4,626 pediatric hospitalizations for CDI, compared to 8,417 in 2006 – an average increase of 9 percent each year.

In that time, practitioners have also recognized the spread of a more virulent form of C. difficile that causes more hospitalizations and has elevated case-fatality rates. CDIs are almost exclusively hospital-acquired; they do not affect healthy people in the community. C. difficile is a common, generally harmless commensal bacteria. But in patients taking long-term, low doses of antibiotics, changes in bacterial communities can offset the microbial balance and allow C. difficile to run rampant in the system. And the symptoms of CDI – diarrhea and a range of intestinal conditions – make it especially dangerous in a hospital setting, where it can be unwittingly transferred by patients and practitioners or through contamination in the environment. CDI is costly for both patients and hospitals – an IDSA/SHEA report cites a $3.2 billion annual price tag for U.S. hospitals for CDI management, and a 16.7% one-year mortality rate for patients. It’s also complicated to eliminate from the environment because as a spore-forming bacteria it can withstand treatment with alcohol-based cleaning products.

But while CDI in adults consistently shows up in healthcare settings following antibiotic treatment, its epidemiology appears to be different in children. Many cases of pediatric CDI, Zilberberg and her colleagues explain, are community-based in origin with no recent history of antibiotic treatment. In addition, many neonates are colonized with C. difficile but do not get sick, whereas cases of CDI jump to 32.01 per 10,000 hospitalizations for non-newborns less than one year old and peak in children aged one to four. In light of their observed increases in CDI and as a more virulent strain predominates, the authors call for more research on C. difficile, especially targeted at this non-newborn infant population.

IDSA Calls for 10 New Antibacterial Drugs by 2020

“Microbial evolution causing antibiotic resistance is constant; our collective efforts at antibiotic discovery must be constant.”

In the 2010 April 15 issue of Clinical Infectious Diseases, the Infectious Diseases Society of America outlines its “10 x ’20 Initiative,” calling for a global effort to develop 10 new antibiotics by 2020. The initiative originated in a letter written to U.S. President Barack Obama and Swedish Prime Minister Fredrick Reinfeldt urging the creation of an Antibacterial Drug Development Work Group following their announcement of an agreement to establish a transatlantic task force on antimicrobial resistance at their November 2009 summit. IDSA calls for a commitment from a diverse group of U.S. and international leaders, healthcare providers and researchers, public health organizations, and patients themselves.

The policy article references the lack of incentives for pharmaceutical companies to develop new antibiotics (see “Drug Development: Where are the New Antibiotics?” below) and sets the stakes for its challenge:

“The antibiotic pipeline problem may change the practice of medicine as we know it. Advanced interventions currently taken for granted – for example, surgery, cancer treatment, transplantation, and care of premature babies – could become impossible as antibiotic options become fewer.”

IDSA also points to the need to develop better diagnostic tests that will allow doctors to quickly distinguish between drug-resistant and drug-susceptible infections, and treat patients accordingly. This would help halt the spread of drug-resistant infections in healthcare facilities and allow for newer antibiotics to be saved for the most dangerous resistant cases. You can read more on IDSA’s “Bad Bugs No Drugs” campaign, including patient stories of drug-resistant infections here.

The Microbiology of Antibiotic Resistance, Part 2: Bacterial Reproduction and Mechanisms of Resistance

Bacteria populate some of the most extreme and diverse environments in the world – from hydrothermal vents, located thousands of feet below sea level, to deep within the human body. This ability to cope with and adapt to ever changing environments in order to survive can be partially attributed to favorable evolutionary traits, which allow bacteria to quickly mutate and acclimate to new a environmental stressor, such as the presence of an antibiotic. These mechanisms of resistance are either natural (inherent) or acquired resistances (1).

With a natural resistance, bacteria may be resistant to the environmental stressor due to inherent structural or chemical characteristics. For example, a Gram-negative bacteria’s double cell wall acts as a permeability barrier against some antibiotics, preventing the drug’s uptake by the bacteria and thus eliminating its ability to affect the cell.

Acquired resistance can be further classified into vertical and horizontal gene transfer with vertical transfer temporally preceding horizontal gene transfer. One out of every 10⁸ - 10⁹ chromosomal replications will result in an unlinked point mutation that leads to antibiotic resistance. With the fast growth and high frequency of bacterial replication, it does not take long for resistance to appear in a bacterial population. Once resistance genes develop through mutations, they are transferred to all the bacteria’s progeny during DNA replication. In a stressed environment, with the presence of antibiotics for example, the wild type bacterial genome will not be able to survive and this spontaneous mutation, imparting resistance, will allow the mutant antibiotic-resistant bacteria and its progeny to grow, flourish and overtake the entire bacterial population (2).

Once a bacterium has acquired a favorable spontaneous mutation, it can also pass the mutation onto other non-progeny bacteria through horizontal gene transfer, which involves the lateral transfer of genetic material between individual bacteria of the same of different species. This transfer usually involves the acquisition and maintenance of the supplementary genetic information on accessory DNA pieces termed plasmids.
These plasmids exist separately from the main bacterial chromosome; carry their own unique genes, sometimes as many as 300; and are able to duplicate themselves independently. Each bacterial cell may have as many as 1000 copies of a single plasmid and are able to have several unique plasmids concurrently. The benefits of this come with the information that plasmids can carry, which allow bacteria to perform new functions and create new products that are not coded in their chromosomal genetics. Some of these new traits will allow bacteria to survive in extreme environments, while others confer important functions to bacteria, such as antibiotic resistance. Many times, two plasmids, frequently ones that carry genes for antibiotic resistance, are able to combine to form one large plasmid or exchange pieces of their DNA to create more diversity on a single plasmid. Thus, a single bacterium can acquire multiple antibiotic resistance genes from one plasmid.

Through the exchange and uptake of different plasmids, one bacterium can gain the ability to survive through a wide variety of environmental stresses. Plasmid exchange occurs in bacteria through horizontal gene transfer, even between distantly related bacteria. When one bacterial cell acquires antibiotic resistance, it can quickly transfer this resistance to several other species of bacteria through one of three common methods: conjuction, the transfer of genetic material, usually a plasmid, through cell-to-cell contact, usually by pili; transformation, the introduction, uptake and expression of foreign genetic material; and transduction the transfer of DNA by a bacteriophage (bacterial virus) (3).

Drug Development: Where are the New Antibiotics?

As resistance to antibiotics continues to develop and spread, the medical community can no longer afford to ignore a distressing reality: the lack of new antibiotics in the development pipeline. Resistance is causing current antibiotics to lose their efficacy, and we are left without viable alternatives. This is largely a result of the regulations and economics of drug development, a process that makes antibiotics undesirable classes of drugs to produce and market.

Drug development is a heavily-regulated, step-by-step process that is meant to ensure that a drug is safe and effective before it appears on the market. Pre-clinical studies in animal subjects or test tubes aim establish the drug’s general safety. Phase 0 trials, a new addition to the regulatory process, involve very low, single doses of the drug given to human subjects to test its effects against what was seen in pre-clinical studies. In Phase I trials, small groups of humans are given escalating doses of the drug to find the proper therapeutic dose and again to check the safety of the product. Phase II involves a larger group of human subjects and is intended to confirm the safety and efficacy of the drug at a pre-determined dosage. Phase III studies are much more extensive, involving randomized, double-blind trials with large human groups; the end-goal of Phase III trials is a regulatory submission. Once the drug is approved, Phase IV trials continue to monitor drug’s effects once it is being marketed and sold.

This exhaustive process often takes eight to ten years from beginning to end and costs, based on multiple estimates, between $800 million and $1.7 billion per drug. Many new drugs get rejected along the way when efficacy expectations are not met or unforeseen side effects arise in trials. Because of the costs and risks associated with this process, the likelihood of a drug getting to market, and the potential profits if it does, are the guiding factors that determine what drugs a company will invest in. A drug’s net present value, or NPV, is risk-adjusted to calculate the attractiveness of a drug in development. And for new antibiotics, the costs and benefits often don’t add up.

Antibiotics cost as much and take as long as other drug classes to develop and test but often bring in less revenue for the companies that produce them. While a patient requiring antibiotic treatment will often only need medication for 1-2 weeks, those on heart, cholesterol, or blood pressure medications will take these drugs for years, if not decades, of their lives. In addition, the burden of antibiotic resistance means that new drugs will inherently become less useful – and therefore less marketable – over time, and that doctors will be pressured not to prescribe the drug unless it is absolutely necessary. And while a broad-spectrum antibiotic that can be used for a range of infections is more profitable for the pharmaceutical company, resistance trends mean that narrow-spectrum drugs are preferred in the clinical community.

Most of the antibiotics in the development pipeline are part of the same drug classes as those that are marketed now – meaning resistance is likely to develop sooner, because the drugs work by similar mechanisms. The Infectious Diseases Society of America reports that since 1998, ten new antibiotics have been approved by the FDA, and only two of those work on novel targets and are thus not at risk for cross-resistance. The lack of new antibiotics is especially a problem for gram-negative bacterial infections, which are more difficult to target than gram-positive bacteria.

Some professionals in the field believe that market conditions are creating renewed interest in antibiotic development, but others argue that regulatory action must be taken to make these classes of drugs more appealing (more profitable) for pharmaceutical companies. For example, the government could approve patent extensions for antibiotics, meaning that pharmaceutical companies could be the sole marketer of these drugs for longer before generics were made available, increasing the window of maximum revenue. Currently, U.S. drug patents have a 20-year duration that begins before the start of clinical trials. But even if regulatory measures are taken, the danger of coming up empty handed for treatment of resistant infections remains. Finding new modes of action and targets for antibiotics remains a challenge, and any new drug still faces a decade-long process of testing and development before it may be approved.