Antibiotics are the compounds we think of when we hear the term “wonder drug”; no other class of therapeutic agents can claim to match their impact on medicine and medical practice. Alas, they have also become the poster child for the concept of too much of a good thing. Their indiscriminant use and misuse has hastened the evolutionary counterattack, selecting and promoting bacterial strains with significantly reduced sensitivity to antibiotic control. In recent years we have seen reports of growing numbers of bacterial isolates that can thrive despite exposure to multiple, high-dose antibiotic treatments. Despite this threat, progress in development of new ocular anti-infectives has slowed to a trickle in the past decade. Fortunately, we see this trend beginning to shift as the battle for septic superiority begins to heat up. This month we examine the forces acting on new antibiotic drug discovery and take a look at what the future may hold for the prevention and treatment of infectious conditions of the eye.

It’s hard to overestimate the problem of drug-resistant pathogens. In the United States alone, microorganisms live with a constant pressure to respond to more than 15 million kg of antibiotic introduced into the environment annually.1 Recent Centers for Disease Control and Prevention estimates suggest that somewhere between 20,000 to 40,000 people (old and young) die in the United States annually from bacterial infections resistant to antibiotic therapy. While ocular infections rarely lead to death, there is significant morbidity associated with infectious keratitis, uveitis and endophthalmitis due to resistant strains of microbes.

A number of studies have established that antibiotic therapy leads to dramatic changes in both the relative populations of commensal species and the frequency of antibiotic resistance.2,3 Data from the human biome project has established a basic paradigm that with antibiotic therapy comes a decrease in the diversity of commensal species, as well as a trend toward increased pathogenicity of bacteria that are normally innocuous.4 Based on the 2009

ARMOR study,there is an increasing incidence of resistant pathogens taken from bacterial eye infections in the United States, including methicillin-resistant coagulase-negative Staphylococcus strains and methicillin-resistant Staphylococcus aureus.5 Additionally, a 2008 New York Eye and Ear Infirmary study demonstrated that the incidence of both S. aureus and MRSA increased dramatically in bacterial conjunctivitis patients from 1998 to 2008.6 Moreover, gram negatives such as Acinetobacter or Pseudomonas are now typically resistant to multiple antibiotics, and have expanded their range such that they are no longer considered primarily nosocomial pathogens.7

Antimicrobial Development

What’s clear is that combating the problem of antibiotic resistance requires a combination of three elements: infection control; antibiotic stewardship; and development of new compounds.1 Infection control and stewardship are the public-health policies and procedures implemented at hospitals and other health-care facilities that will combine the strictest hygiene protocols with spare, judicious use of the most potent antibiotics only in those cases where infection by a resistant microbial strain is established. There is also a need for new therapeutics, including the next generation of existing drug classes, as well as agents with new mechanisms of action.

It may seem surprising that as we watched the issue of antibiotic resistance grow ever more problematic, progress in development of new anti-infectives ground to a halt. This reflects a mixed bag of forces acting on this therapeutic space. In ophthalmology, the dearth of new products is due in part to the high efficacy of fourth-generation fluoroquinolones that have occupied the largest segment of the market since their introduction in 2003. At the same time, many pharmaceutical companies exited the antibiotic development arena, preferring to focus on other therapeutic areas. A number of advocacy groups and governmental agencies have voiced their concerns about this therapeutic innovation vacuum. The Infectious Disease Society of America proposed a response to the need in 2010, with the “10 x ’20 Initiative,” a global commitment to develop 10 new antibacterial agents by 2020.8 In 2012, the U.S. Congress passed the Generating Antibiotic Incentives Now Act, a program that provides for extended patent exclusivity and accelerated review for new antibiotics targeted toward serious and life-threatening infectious diseases.9 This is a key step, since the biggest impediment to new antibacterial drug development is the lack of an economic incentive: Regardless of demand, it’s not feasible to bring a new drug to market with no possibility of recouping the costs of clinical development. The jury is out on whether these initiatives will lead to improved tools to combat ocular infections.

Assessing the Need

Ocular indications for anti-infective therapy include bacterial conjunctivitis, blepharitis, bacterial keratitis and endophthalmitis. Each of these conditions is most commonly associated with a handful of causative bacterial agents, and while the strains remain the same, rates of resistance are on the rise across the board. For example, while S. aureus is the most common culprit in bacterial conjunctivitis, the strains of S. aureus cultured from conjunctiva between 1994 and 2003 showed a threefold increase in ciprofloxacin resistance, and an almost tenfold increase in MRSA (4.4 percent to 42.6 percent).7 While most acute infections involve S. aureus or S. pneumoniae, gram negative pathogens such as H. influenzae are also seen, particularly in the pediatric population. It’s important to note that while external infections such as bacterial conjunctivitis are generally self-limiting, there remains a sound rationale for the use of topical antibiotics to shorten both the duration and the severity of the infections.10,11

Rates of resistance for organisms that cause infections such as endophthalmitis are on the rise. 
Resistance to virtually all classes of antibiotics has been documented for each of the bacterial species commonly associated with ocular infection, leading to a progression from first-line agents such as a macrolide (e.g., erythromycin) to aminoglycosides (e.g., tobramycin) and finally to a fluoroquinolone such as moxifloxacin.3 Fluoroquinolones are Food and Drug Administration-approved for treatment of ocular infections such as bacterial conjunctivitis, but they are also currently used as a prophylactic treatment after surgical procedures. The desire for prophylaxis is certainly understandable given the consequences of infection and current standard of care. It’s important to note, however, that studies designed to support such use have been equivocal. In addition, ophthalmologists’ preference for later-generation flurorquinolones because of their high potency, though well-intentioned, may not represent the ideal in antibiotic stewardship. A study published in 2013 found that nearly half of endophthalmitis-cultured bacteria were resistant to fluoroquinolones, while no such resistance was found in a similar study conducted 10 years earlier.12 Use of prophylactic antibiotics is an important issue, and while the likelihood of a patient developing endophthalmitis following these procedures is low (0.02 to 0.7 percent),7 the aging population and exponential growth of intravitreal injection as a treatment paradigm has dramatically increased the numbers of at-risk patients. Even a low risk of this type of infection becomes problematic when it’s caused by a treatment-resistant strain.

Pipeline Perspective

With the slowdown in development, the ophthalmic medicine cabinet for bacterial infections hasn’t changed much in the past decade. Thankfully, there are encouraging signs of activity, an array of new compounds in the development pipeline, and the hope that some of these will be formulated and tested for ocular indications. Newer classes of compounds include anti-microbial peptides, bacterial biosynthetic inhibitors, biologicals and a host of next-generation compounds.13,14 A number of glycopeptide compounds such as Oritavancin (The Medicines Company) that act by inhibiting cell wall biosynthesis have shown promise against gram positive organisms, including MRSA. While similar in action to vancomycin, compounds such as Oritavancin are active against most vancomycin-resistant strains. A related compound, Telavancin (Theravance), was approved for IV use against MRSA infections in 2009, but has seen limited use due to production issues.

Carbapenems are the most recently developed family of beta-lactam antibiotics and, like penicillins and cephalosporins, they exhibit broad-spectrum activity against gram positive and gram negative bacteria. None of the currently approved compounds have ocular indications, but several are in development. Another next-generation candidate is Plazomicin (Achaogen), a new aminoglycoside which, like its predecessors tobramycin and gentamycin, acts by inhibiting bacterial protein synthesis. Early studies suggest it’s more potent than others in this class, but a final verdict will come from ongoing studies.

An Alternative Approach to Infection Control 
In a recent perspective piece, noted infectious disease expert Brad Spellberg, MD, suggested that an alternative solution to the problem of antibiotic resistance is to develop therapies that “do not drive resistance.”1 The clinical outcomes of infection derive from host response as well as microbial growth, he says, so if our goal is to prevent the sequela of the infection-inflammation tête-à-tête, perhaps we should rethink our entire strategy. As an example, he cited the action of lipopolysaccharide inhibitors that prevent gram negatives such as Acinetobacter from synthesizing the LPS that initiates the inflammatory response. The bacteria are rendered harmless and their growth is minimized by enhanced phagocytosis. Because the inhibitor is not harmful to the bacteria, it creates much less selective pressure, and a lower risk of resistance.                       
As the most powerful group in the ocular antibiotic arsenal, improving on the existing fluoroquinolones is a logical place for enhancing therapeutic efficacy. A number of next-generation fluoroquinolones are in development, including delafloxacin (Melinta Therapeutics), JnJ-Q2 (Furiex Pharma) and ACH-702 (Achillion Pharma). All fluoroquinolones target some combination of topoisomerase IV and DNA gyrase, two bacterial enzymes that are paramount to DNA replication and thus the proliferation of invading bacteria. While the various fluoroquinolones differ in their specificity for each enzyme, these two shared mechanisms have led to the emergence of pathogens that show varying degrees of resistance to all fluoroquinolones. Widespread usage of the latest generation of fluoroquinolones makes the potential for this “cross-resistance” among ocular pathogens a real concern for public-health officials and ophthalmologists. Based on the emergence of resistant pathogens and the potential for cross-resistance, there is a need for a novel antibiotic that avoids the common mechanism of resistance.

ACH-702 has demonstrated the ability to kill fluoroquinolone-resistant S. aureus. Unlike the first generation of this drug class, ACH-702 has the ability to inhibit topoisomerase and DNA gyrase in resistant bacterial strains, and also demonstrated a 128-fold increase in the minimal inhibitory concentrations compared to moxifloxacin in resistant S. aureus clinical isolates.15 It’s thought that this new fluoroquinolone also exhibits a unique enzyme inhibitory activity against bacterial DNA primase, a novel bacterial target. This action is important for two reasons: it provides an MOA distinct from topoisomerase and DNA gyrase inhibition; and it allows the compound to target and kill metabolically active bacteria even in a non-dividing state. The unique features of ACH-702 represent the types of molecular strategies necessary to defeat the process of antibiotic resistance.

As with other candidate therapeutics, new antimicrobials will still require testing in an ocular setting before they can be brought to market for ophthalmic indications. Despite these hurdles, there does seem to be a renewed effort to identify and develop compounds that can address the problem of antibiotic resistance. For those whose sight is threatened by multidrug-resistant bacteria, these compounds will definitely qualify as wonder drugs.  REVIEW

Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Mr. Shapiro is vice president for anti-infectives at Ora Inc, where Dr. McLaughlin is a medical writer.

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