Growing antimicrobial resistance and a dwindling antibiotic pipeline have resulted in an emerging postantibiotic era, as patients are now dying from bacterial infections that were once treatable. The fast-paced "Golden Age" of antibiotic development that started in the 1940s has lost momentum; from the 1980s to the early 2000s, there was a 90% decline in the approval of new antibiotics as well as the discovery of few new novel classes. Many companies have shifted away from development due to scientific, regulatory, and economic hurdles that proved antibiotic development to be less attractive compared with more lucrative therapeutic areas. National and global efforts are focusing attention toward potential solutions for reinvigorating the antibiotic pipeline and include "push" incentives such as public-private partnerships and "pull" incentives such as reimbursement reform and market exclusivity. Hybrid models of incentives, global coordination among stakeholders, and the appropriate balance of antibiotic pricing, volume of drug used, and proper antimicrobial stewardship are key to maximizing efforts toward drug development to ensure access to patients in need of these therapies.
Since the discovery, development, and US Food and Drug Administration approval of vancomycin in the 1950s, this agent has remained a mainstay for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, because of the development of new antistaphylococcal antibiotics and reports of vancomycin failures, the utility of vancomycin has recently been questioned. Although vancomycin did not undergo the strict US Food and Drug Administration approval process that is in place today to demonstrate efficacy, there is considerable information available that sheds light on the role vancomycin has in infectious diseases pharmacotherapy today. In addition, although we look to in vitro susceptibility testing to assess vancomycin activity against S. aureus, we have come to appreciate that resistance of S. aureus to vancomycin can be a continuous--rather than a categorical--phenomenon. This has resulted in clinical microbiology laboratories having difficulty identifying S. aureus that may not respond to conventional doses of vancomycin. A better understanding is needed of the pharmacodynamic relationship between vancomycin and MRSA as relates to optimal dosing strategies, including consideration for loading doses, and development of rational categorical breakpoints for susceptibility based on clinical outcomes. By better understanding these critical issues, it may be possible to optimize the use of vancomycin, resulting in a cost-effective treatment option for many patients infected with MRSA.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections increased from 2000 to 2003 in hospitalized pediatric patients in Houston. CA-MRSA was associated with greater illness than was infection with methicillin-susceptible strains. Children with CA-MRSA were younger and mostly African American. Of MRSA isolates, 4.5% had the inducible macrolide-lincosamide-streptogramin B phenotype.
Non-culture-based diagnostic strategies are needed for diagnosing invasive candidiasis (IC). We evaluated serial serum (133)--D-glucan (BG) levels in patients in the surgical trauma intensive care unit (SICU) patients with clinical evidence of IC. Serum samples from patients admitted to the SICU for a minimum of 3 days were collected twice weekly and analyzed for BG by using a Fungitell kit with a positive cutoff of >80 pg/ml. Diagnosis of IC was done using a set of predefined and validated clinical practice-based criteria. A total of 57 patients consented to participate and were enrolled. The median ICU stay was 16 days (range, 3 to 51). A total of 14 of 57 (25%) false positives were observed in the first sample (ICU day 3) and, overall, 73% of the day 3 samples had higher BG levels than subsequent samples. On the date of clinical diagnosis of IC, the sensitivity of a positive BG for identifying invasive candidiasis was 87%, with a 73% specificity. In patients with evidence of IC, the median BG value was significantly higher than those without evidence of IC (171 versus 48 pg/ml, P ؍ 0.02), respectively. In the three patients with proven IC, BG was detected 4 to 8 days prior to diagnosis. BG serum detection may be a useful tool to aid in the early diagnosis of IC in SICU patients, particularly after day 3 and in patients with at least two positive samples drawn several days apart. Elevated BG levels within the first 3 days need to be further characterized.
In the 17,108 patients receiving a fluoroquinolone or ceftriaxone, the rate of dysglycemia was greater in those receiving levofloxacin or gatifloxacin than in those receiving ceftriaxone. However, no difference was noted in the rate of glucose abnormalities with levofloxacin versus gatifloxacin. Clinicians should be aware of dysglycemic events that may occur in patients receiving fluoroquinolones, especially in those with diabetes mellitus or those receiving sulfonylureas.
The combination of growing antimicrobial resistance with a dry pipeline has resulted in infections that can no longer be treated. Specific reasons have led to companies' exit from the antibacterial space, however recent incentives are spurring interest to reinvigorate the pipeline. Areas covered: This article summarizes the available information on the discovery, developmental, and regulatory challenges in antibacterial development that have led to disinterest in the space, as well as ongoing incentives such as public-private partnerships and streamlined pathways to mend these challenges and bring new antibiotics to patients in need. Expert commentary: Clinicians should not only understand the reasons for the decline in antibiotic development that have resulted in the dry pipeline, but also the ongoing initiatives in place to build an appropriate supply. Doing so will result in greater appreciation and prudent use of these life-saving drugs when they become available.
This review summarizes the in vitro and animal model data available on antibiotic combinations with daptomycin. The majority of studies focus on the clinically relevant combinations of daptomycin with rifampicin or with gentamicin. These studies demonstrate that daptomycin does not adversely affect the activity of other antimicrobial agents that may be administered concomitantly. Overall, additive or indifferent effects with daptomycin combinations were observed; however, synergy was observed for certain isolates of vancomycin-resistant enterococci when exposed to daptomycin and rifampicin. Unexpected synergy was demonstrated against methicillin-resistant Staphylococcus aureus by daptomycin and beta-lactams. Most importantly, no in vitro antagonism of daptomycin with any other agent tested was confirmed in these studies. The most striking in vivo effects were noted in two different complicated infection models; i.e. osteomyelitis and implant infections, where rifampicin combinations with daptomycin increased efficacy and reduced the incidence of rifampicin resistance.
Appropriate use of antimicrobials in health care continues to be a challenge. Reliable and reproducible antimicrobial susceptibility testing methods are necessary to provide the clinician with valuable information that can be translated into positive clinical outcomes at the bedside. However, there are nuances with these testing methods that, if unrecognized, could lead to misinterpretation of results and inappropriate antibiotic selection. This primer describes the common antimicrobial susceptibility tests used in the clinical microbiology laboratory and reviews how subtle differences in testing methods and technique can influence reported results. Clinicians who have a thorough understanding of qualitative and quantitative methods, automated susceptibility testing systems, and commonly used screening and confirmatory tests for antibiotic-resistant organisms can strengthen institutional antibiotic stewardship programs and improve patient outcomes.
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