AntibioDx

Keywords::

• antibioDx
• bloodstream infections
• PNA FISH

Increasing resistance to existing antibiotics is threatening our ability to combat infections. While multidrug-resistant bacteria (‘super bugs’), against which currently available antibiotics are ineffective, have become increasingly prevalent [1] and the number of new compounds in development has significantly decreased [2], an even more pressing problem is at play: ineffective treatment of life-threatening infections is rarely due to a lack of effective antibiotics but, rather, is due to the inappropriate use of existing drugs. Fighting resistance by continually developing new antibiotics is an uphill battle with the emergence of resistance linked to inappropriate or overuse of antibiotics. Diagnostic tests that facilitate smarter use of antimicrobials are needed to reduce resistance, increase the lifetime of existing antibiotics and reduce the pressure for continued development of new compounds. More importantly, such diagnostic tests can improve patient care by helping to focus antimicrobial treatment and thus have significant antimicrobial impact – antibioDx.

Theory versus practice: many patients are not receiving appropriate therapy

The importance of timely and appropriate institution of antibiotics is well recognized and supported by numerous publications. Conversely, in patients with infections, delayed administration of antibiotics increases rates of morbidity and mortality. Therefore, treatment guidelines for critically ill patients with suspected bloodstream infections (BSIs) recommend early coverage with broad-spectrum antibiotic therapy until laboratory identification and susceptibility data become available, supporting discontinuation or de-escalation to therapy targeting the specific microorganisms and their susceptibility patterns.

Ibrahim et al. studied whether patients being treated for BSI in intensive-care units were receiving effective treatment when laboratory identification results became available. None (0%) of the patients with bacteremia due to vancomycin-resistant enterococci (VRE), 5% of patients with candidemia and 67% of patients with bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA) received adequate antimicrobial therapy [3]. Likewise, Soriano et al. showed that only 41% of patients with MRSA bacteremia received empiric vancomycin therapy despite hospital guidelines recommending vancomycin as the empiric treatment of choice when infection due to MRSA is suspected [4]. Both studies also showed increased mortality among patients on inadequate therapy. Regarding the time to initiation of therapy for patients with candidemia, Garey et al. reported that only 40% received antifungal therapy at the day of blood collection and 12% did not receive antifungal therapy until day 3 or later [5]. The delay directly correlated with increased mortality. Thus, despite a broad consensus that critically ill patients with BSIs should be covered with broad-spectrum antibiotics, many patients remain inadequately treated.

Physician dilemma: how to select antibiotics before knowing the infectious agents, if any

Early therapy is important, but during the early stages of evaluating an infected patient, clinicians rarely have information about the infectious agent and its antibiotic susceptibility pattern or whether it is an infection at all. The dilemma is also encountered in infectious disease guidelines that recommend early empiric therapy and also discourage the overuse of antibiotics [6]. The clinician is confronted with a major decision: ‘to treat or not to treat?’, and if electing to treat a series of related decisions: how broad a coverage is needed, how much toxicity to be tolerated and can a cheaper alternative be found? Although broad-spectrum antibiotics are frequently recommended, no antibiotic is approved for all microorganisms. This may result in off-label use in the case of infections caused by microorganisms for which the antibiotic is not approved, even if effective. More importantly, well intentioned but unfocused use of antibiotics may lead to ineffective therapy. For example, vancomycin is often used as an empiric therapy for infections with Gram-positive cocci that are ultimately discovered to be VRE, as discussed previously.

In the absence of confirmed infection, risk factors and clinical suspicion are often used to support therapeutic decisions, but even statistically significant trends still leave questions of doubt. For example, Souvenir et al. showed that the intuitive clinical impression of the attending physician could predict contamination of blood cultures with coagulase-negative staphylococci with 95% accuracy [7]. Yet nearly half of the patients with contaminated blood cultures received antimicrobial therapy, with vancomycin being misused in approximately a third of the cases. Sobel points out in an editorial on differentiation between Candida albicans and non-albicans candidemia that, “Unfortunately, the authors [Chow et al.], in a large respective study failed to identify unique risk factors,” and continues, “The results are similar to a previous study performed by Shorr et al. which also failed to identify unique risk factors for characteristics of non-albicansCandida invasive disease” [8].

New antibiotics have limited impact on patient outcome

Inadequate antimicrobial therapy is rarely due the lack of effective antibiotics, but, as exemplified above, is often due to incorrect or delayed prescription of an existing antibiotic. This is also illustrated by clinical studies of new antibiotics supporting US FDA approval based on noninferiority to existing antibiotics. Daptomycin for the treatment of S. aureus bacteremia and caspofungin for the treatment of candidemia are recent examples [9,10]. New antibiotics are therefore associated with the same issues related to optimal usage as existing antibiotics. Moreover, their higher cost and associated restrictions often limit their broader usage. New antibiotics therefore tend to become additional tools for physicians as back-up for resistance to existing antibiotics.

Diagnostic information that drives better use of existing antibiotics improves patient outcome

Peptide nucleic acid probes (PNA) FISH^® (AdvanDx, MA, USA) refers to novel rapid in vitro diagnostic kits cleared by the FDA for use as an aid in the diagnosis of BSIs [11]. The kits allow clinical microbiology laboratories to identify the infectious agents in hours rather than days following positive blood culture findings. Forrest et al. showed that the use of S. aureus PNA FISH for distinguishing S. aureus from coagulase-negative staphylococci reduced length of stay and hospital costs by resulting in the discontinuation of vancomycin therapy for patients in whom the positive blood culture was due to contamination with coagulase-negative staphylococci [12], that is, the overuse of antibiotics described previously by Souvonir was reduced. Moreover, in a study by Ly et al., rapid reporting of bloodstream S. aureus, a serious infectious agent, was associated with reduced mortality and decreased inappropriate antimicrobial use [13]. The results were ascribed to better effective therapy by ruling out the potential of contamination. Similarly, in patients with VRE bacteremia, Forrest et al. showed that implementation of E. faecalis/OE PNA FISH™ (AdvanDx) reduced the time for switching from initial inadequate therapy (as reported by Ibrahim [3]) to targeted effective therapy from 3.1 to 1.3 days, thereby reducing the 30‑day mortality rate from 45 to 26% [14]. Other studies have demonstrated that the use of a PNA FISH test for distinguishing C. albicans from non-C. albicans candidemia reduced antifungal costs by US$1700/patient without compromising patient safety by encouraging earlier de-escalation from broad-spectrum echinocandin to generic fluconazole for the treatment of C. albicans[15]. Preliminary studies indicate potential improvements in patient care for patients with non-C. albicans candidemia by an earlier switch from fluconazole to more aggressive therapy [16,17]. The challenge brought on by a lack of identifiable clinical risk factors for non-C. albicans candidemia pointed out by Sobel above is addressed by PNA FISH.

AntibioDx

In summary, ineffective treatment of BSIs is rarely due to a lack of effective antibiotics but by a lack of laboratory information to select an effective antibiotic. By providing important information leading to better and/or earlier selection of effective antibiotic therapy, PNA FISH is an example of an antibioDx, a diagnostic test with antimicrobial impact. Better use of existing antibiotics owing to using an antibioDx offers a personalized approach where patients are treated based on individual diagnostic information rather than the current empiric approach relying on continued development of novel broad-spectrum antibiotics. In addition, inappropriate use or overuse of antibiotics due to empiric coverage is reduced through earlier discontinuation or targeted therapy, potentially limiting the development of resistance and thereby increasing the life-time of existing antibiotics.

Financial & competing interests disclosure

Henrik Stender is cofounder and vice president of AdvanDx. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.