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Developers of new drugs for resistant pathogens thus face a conundrum. Ideally, they would develop data on the new product in the face of resistant pathogens before the onset of a widespread public health concern.
But until such an outbreak, there will be at least one existing reliable agent for the UDR bacteria currently extant. That such reliable agents exist is desirable for society, of course, but what it demands is that infected patients be treated either with a reliable agent or something in equipoise with it.
Even in those worrisome scenarios in which there is no currently reliable agent for UDR, the development of the first new product that addresses resistance resets the standard of care, as the new agent becomes the new reliable intervention.
The result is that in the desirable presence of a reliable agent for current UDR bacteria, development of new antibiotics must rely on non-inferiority design in the UDR setting.
Although the pivotal UDR trial does not directly establish evidence of effectiveness in populations for which existing antibiotics are less effective or ineffective, two lines of logic suggest the new agent is likely to be effective in a future setting when currently reliable agents fail.
First, and generally limited to agents acting by a mechanism different from that of existing agents, emergence of resistance to the currently reliable comparator will usually have no impact on the microbiologic activity of the new drug: the new drug is expected to retain the activity demonstrated in the UDR study whether or not the older drug retains its activity i.
Second, data in second-line non-UDR settings in which older agents have failed can often provide at least a small-scale demonstration of the potential of the new compound. While, for the reasons discussed, non-inferiority designs are often necessary for products in the Standalone, Transform , and Restore categories, a demonstration of superiority becomes preferable and perhaps required for Augment and sometimes for Restore as discussed below.
Regulations generally require that each component of a fixed-combination product contribute to its claimed effects, such as enhancements to the safety or effectiveness of the principal active component For example, AUGMENT might offer incremental value by simplifying dosing or reducing the side-effects of EXISTING as some formulation improvements of traditional antibiotics have done.
But absent a plausible additional clinical benefit, Augment developers will struggle to justify reasons to undertake clinical trials. A hurdle similar to that for Augment may also occasionally arise for Restore.
Consider a novel beta-lactamase inhibitor BLI that protects a beta-lactam BL antibiotic from destruction by beta-lactamase enzymes.
If, however, the relevant bacteria are very rare, it may be almost impossible to show the advantage of the combination. Non-inferiority designs can therefore be used to evaluate products in the Standalone , Transform , and Restore categories without waiting for resistance to develop such that effective therapy is unavailable Table 4.
Although the primary benefit of such products derives from their theorized abilities to address future resistance, perhaps as demonstrated by laboratory or animal data, the non-inferiority clinical design means that robust evidence of effectiveness in such future human populations is not available at the time of approval.
Given their intriguing potential properties Table 1 , it is sometimes suggested that non-traditional products could perhaps be exempt from the normal regulatory approval rules.
However, there is typically no reason for such products to be exempt from the usual requirements to demonstrate safety and efficacy. For example, if an effect on a clinical outcome cannot be used, efficacy could perhaps be established by showing an impact on a surrogate outcome measure such as microbiome change.
Unless such standards for surrogate markers of efficacy are met, evidence of impact on a novel endpoint might be hypothesis-generating but could not be used to support approval. All pharmaceutical products must a show which individuals can benefit from the product, b demonstrate a way to identify those individuals, and c document the benefit received from the product.
Clear answers to these questions are required for product approval and acceptance. To achieve this, one of two types of trial designs can be used 55 , 56 , 57 , 58 , Each design has strengths and weaknesses.
Superiority trials are more compelling and are preferred whenever possible. Because they demonstrate that NEW improves on EXISTING or on placebo , a positive outcome shows simultaneously: 1 the advantage of NEW, and 2 that the group of individuals are likely to benefit from NEW can be identified.
In contrast, a non-inferiority demonstration of similar outcomes between NEW and EXISTING could mean either that a NEW and EXISTING both indeed had similar benefits subject to the non-inferiority margin and statistical limits of the study, or b NEW and EXISTING both did nothing and hence appear to have similar efficacy, which could occur, for example, if inadequate screening led to the enrollment of subjects with viral pneumonia in a trial intended to test two treatments for bacterial pneumonia.
In practice, there are many ways that non-inferiority trials can produce flawed results 28 , Although superiority trials would thus seem the natural choice, the need to show superiority becomes a weakness in the setting of bacterial infections given their acute onset, high morbidity and mortality risk, lack of timely precision diagnosis, and the importance of immediately beginning a reliable therapy 27 , Except for trivial situations, acute infections are associated with striking risks when not treated promptly and properly.
It is thus imperative to offer effective therapy if at all possible. However, when a safe and highly effective therapy serves as the comparator in a trial, it is unlikely that a new product would more effectively clear an infection than the comparator.
Furthermore, efforts to control the spread of drug-resistant infections make it more difficult to enroll the patients needed for a superiority design trial. While it might be hoped that modern molecular diagnostics could solve this problem, practical considerations reduce their impact.
Even if diagnostics could rapidly identify cases of interest, cases must be screened to find a single case of interest. As diagnostic tests never have perfect sensitivity or specificity, the required number to screen would be even higher. The speed with which most infections progress also works against case finding.
Unlike rare genetic disease or tumors where there is time to refer to a specialty center, acute infections progress to produce substantial morbidity and mortality over hours to a few days.
With the exception of a small number of chronic bacterial infections, this means that the patient with the rare bacterium must present at a facility already running the relevant trial.
If empirical therapy proves adequate to eradicate the organism, the ability to demonstrate the activity of the test product is further diminished. Thus, superiority designs work ethically and methodologically only where there is truly no proven alternative.
This may be the case in truly grave public health circumstances involving resistant pathogens, but once a novel effective therapy is created, superiority designs again become difficult. In contrast, non-inferiority designs allow trials to proceed without requiring resistance to develop to the point that effective therapy is widely unavailable.
The real value of the new agent resides in its theorized but not yet fully proven utility to future patients Table 4 and ref. An important challenge could arise for any of the four categories depending on the product.
Antibiotic development relies heavily on dose selection based on prediction from animal models of the antibiotic exposures pharmacokinetics PK and pharmacodynamics PD likely to be efficacious 60 , Traditionally, the concept of minimum inhibitory concentration MIC has been central to the mathematical underpinnings of PK-PD.
The MIC is the minimum concentration of a drug that prevents visible growth in a laboratory test tube or Petri dish.
It is also used as a key element when determining the drug concentration levels required to obtain an effective response Given the extensive experience with MIC-based PK—PD to predict efficacy 63 , 64 , a demonstration that efficacy should follow from a given drug concentration 65 can support approval of an antibacterial agent based on a single-clinical trial Some non-traditional products in development lack an MIC, such as agents designed to absorb bacteria-produced toxins while leaving the bacteria themselves unaffected.
A compelling demonstration of clinical activity for such products may require more clinical data than for products with supportive MIC-based PK—PD evidence.
This challenge might be less for products designed to lower the MIC of an existing drug when part of a combination 25 , Traditionally, antimicrobial products have been developed to provide direct benefits to the individuals receiving treatment. Although these products have always produced positive externalities in the form of reduced opportunities for transmission to third parties 33 , companies have recently begun to develop products designed to benefit third parties while offering only occasional benefits to the treated individual.
For example, a product may focus on preventing colonization and hence seeking to reduce the risk of infection rather than treating clinical symptoms after invasive infection develops. MBL is an enzyme that can degrade certain antibiotics, including carbapenems, and bacteria producing it are considered highly antibiotic-resistant.
By preventing acquisition of MBL-producing bacteria, Z-3 could both reduce the risk of an infection due to such an organism as well as minimize opportunities for the MBL gene to spread. As there are relatively few reliable agents for treating infections due to MBL-producing bacteria, the second benefit reduced transmission has public health implications.
Although Z-3 would not prevent infections associated with gut flora such as UTI and appendicitis, such infections should not be due to MBL-producing bacteria but rather to less difficult-to-treat strains.
Thus, Z-3 may offer some benefit to the treated person, but its potentially greater value comes from the public health benefit to others through reduced transmission of the difficult-to-treat bacteria. Measuring those public health benefits is challenging.
This effect is sometimes but not always mediated in part by preventing colonization 34 , In the case of Z-3, the major emphasis would be on preventing colonization with MBL-producing bacteria and extrapolating from lowered colonization rates to predict both individual and population-level clinical benefit, as clinical infections caused by non-MBL-producing bacteria in individual patients may not be reduced.
Preventing colonization with MBL-producing bacteria by Z-3 could offer some benefit to treated individuals by reducing the risk of developing invasive MBL-producing bacterial disease, but the individual benefit might be quite small due to the infrequency of such colonization and the fact that, even if colonized, the individual might not develop invasive disease.
It might be possible to resolve these difficulties by developing and validating a surrogate marker, but that is not an easy task and the most obvious surrogate lack of detectable colonization with resistant strains is not acceptable due to the inability to demonstrate that it is reasonably likely to predict clinical benefit.
In studies to date, the linkage between elimination of carriage and subsequent disease has been inconsistent 36 , 37 , presumably both because it is technically difficult to prove absence of carriage in every possible nook and cranny of the human body, and because pathogens can be acquired at any time from new environmental exposure.
This leads to a significant challenge when the primary benefit of a proposed product accrues only in a much larger population than those directly treated. This raises important questions about how pivotal trials for a product like Z-3 should be designed, and to what extent regulators should take into account positive externalities that benefit both current and future populations not receiving direct interventions in the clinical study These products also pose challenges related to market demand that may prove to be more difficult to overcome than the regulatory considerations.
In parallel to the scientific and regulatory issues that have been discussed so far, there are also ethical considerations that must be addressed.
First, and most fundamental, is the question of whether it is ethically acceptable to carry out non-inferiority trials when developing new antimicrobial agents. Outside a trial, those who might be asked to enroll would be treated with a reliable drug, i.
Within the trial, they would be randomized either to the novel intervention or the reliable standard-of-care drug. However, in a non-inferiority trial, that novel intervention is not hypothesized to leave the participant better off than he or she would have been outside the trial, given that superiority is not expected.
Instead, the only hypotheses are that participants randomized to the intervention arm of the trial could do as well as they would have done outside the study best case or potentially worse.
Equipoise may still be satisfied in this scenario, as the expectation is that the novel intervention will be an acceptable clinical substitute for the established older drug such that no participant is made knowingly worse off as a result of randomization Nonetheless, except for those individual participants who turn out to be infected with a resistant pathogen, enrollment entails an entirely risk-based proposition compared to accepting standard care outside the study.
Non-inferiority trials have been criticized on these grounds, particularly on the basis that it is inappropriate to ask participants to accept such risks for the moderate or even low social value traditionally associated with non-inferiority design 40 , These criticisms are inapposite here, however.
Unlike non-infectious disease products approved based on non-inferiority trials, new antibiotics approved based on such trials offer the promise of substantial social value if they are believed, based on non-clinical evidence, to be able to address future resistant infections potentially, including those occurring in current study participants.
Moreover, even if the new intervention is somewhat inferior to the proven effective current product, it could still be a useful treatment option in the face of future resistance when the current product is no longer effective.
Thus, despite their non-inferiority designs, these trials are not focused on current non-inferiority , but rather future superiority Table 4. Although it may be important to take steps to reserve new interventions for use only in the future as a matter of stewardship, that is for regulators, prescribers, and payers to consider 42 , 43 ; it does not dictate whether the study itself evaluates a worthwhile clinical question.
Hypothetically, it would be ideal to instead conduct superiority trials exclusively in patients with infections resistant to available therapies, since they would potentially be able to derive direct clinical benefit from study participation and the resulting data would be stronger.
However, as noted above, the logistics of such a design may be impractical until such point as the fully drug-resistant bacteria are endemic see Box 1 , which would represent a global public health calamity. In other words, it would be unethical to wait to develop novel antibiotics until resistant diseases become more widespread—and it is only at that point that superiority trials might be feasible.
For these reasons, if we conclude that these are new products worth having because they have sufficient social value 44 , the impracticability of superiority designs and the fact that much of what is worrisome about non-inferiority designs is absent in this context means that non-inferiority designs may be acceptable.
But the question remains: is it justified to ask patients facing serious infection to risk treatment with an investigational product in a non-inferiority trial when they likely would be adequately treated by a reliable drug in the UDR setting and are therefore not likely to be made better off by participation?
In other words, is equipoise—which focuses on the avoidance of inferior treatment—sufficient? The short answer is yes. This is because there is no ethical requirement that research have the potential to make participants better off compared to how they might fare outside a study, or even to offer them any possibility of direct benefit at all.
If trials posing risks in the absence of the potential for superior or direct benefit were necessarily unethical, it would be impossible to conduct Phase I trials in healthy participants—or any non-therapeutic research.
Instead, ethical obligations to study participants demand minimizing the risks to which they may be exposed, ensuring that remaining risks are justified by potential benefits, and protecting participant autonomy by securing adequate informed consent 45 , Each responsibility could be satisfied in this context.
First, if a non-inferiority study was designed so that a the dose of the novel agent is chosen to maximize its likely efficacy based on preclinical data and b individuals failing either study arm are promptly moved to a salvage therapy, the risk of inadequately treated infection or rapid progression would be addressed and the risk of serious harm to study subjects minimized.
Thus, it would be possible to comply with the ethical standard espoused in the Good Clinical Practice guidelines Point 2. Second, risks to individual trial participants are often justified by the prospect of benefit that would accrue only or primarily to future patients 44 , Moreover, U.
Of course, this can be a challenging calculation for research ethics review committees, especially considering that there is no well-accepted upper threshold of permissible research risk 48 and reasonableness standards are notoriously fuzzy.
In the context of a non-inferiority trial of a novel antibiotic, infected participants are offered the prospect of direct benefit and expected to fare as well as they would in standard care, while the risk that they will not—if minimized as described above—is likely justified by potential public benefits of having a new effective therapy available in the armamentarium against resistant bacteria.
Thus, we anticipate that this type of research can easily satisfy required risk—benefit analysis. Finally, it is important to explain to potential participants that they could be treated outside the trial with an agent predicted to be safe and effective, absent resistance, and that by enrolling they would face risk predominantly for the benefit of others 41 , 50 , 51 , Some may be willing to do this altruistically and some may need financial incentives, but both can be acceptable motivations 53 , Assuming there is reason to believe there would be enough willing participants to adequately enroll a trial—an essential ethical assumption, as otherwise the risks to participants could not be outweighed by potential social benefits because it would not be possible to answer the study questions—non-inferiority designs to develop new interventions to gird the future stock of available therapeutics can satisfy essential ethical criteria.
It is essential to note, however, that the social benefit that is ethically required of research is not guaranteed simply by developing a theoretically useful novel antibiotic. If patients would not have adequate reason to take that product once approved, the potential for social benefit will be dramatically limited, raising a range of practical and ethical concerns preliminary to any questions regarding appropriate regulatory pathways for approval.
Consider again the hypothetical product Z-3, theorized to prevent human acquisition of non-pathogenic MBL-producing bacteria. Prevention typically depends on patients reasonably anticipating the implications for them of clinical infection by a pathogen.
For example, unless they are required to be vaccinated by their employer, people are likely to receive the influenza vaccine because they anticipate they are likely to be exposed to the virus and do not wish to suffer from infection. From the individual perspective, it is often only an incidental benefit that their contacts may also be protected by their vaccination.
For a product like Z-3 to be taken up in practice, individuals would have to anticipate a sufficient individual benefit stemming from a reasonable likelihood of clinical infection due to MBL-producing bacteria. Otherwise, they are not likely to use a product to prevent such infection simply for the public health benefit to others.
Although state governments have the authority to impose public health measures e. Therefore, use of the product will have to be motivated by patients themselves rather than some external mandate. Perhaps individuals living in or visiting certain countries in which bacteria susceptible to Z-3 are more prevalent would have adequate concerns to motivate its use for their own benefit, but they would have to be convinced that the risks are sufficiently great that they will become infected and suffer clinical sequelae from such bacteria, which is not something that can be taken for granted.
Clinical trials to evaluate a product like Z-3 would be ethically acceptable only if there is an adequate population likely to utilize the product once approved and marketed. As described above, such trials would otherwise subject participants to risks and burdens that could not be justified by their ostensible social value.
Note that this stands in contrast to novel antibiotics intended to treat individual patients when they lack other options for quelling a current infection with resistant bacteria; these patients would clearly have reason to take such a drug for their own benefit, if approved.
Assuming there is a plausible patient population and path to approval for Z-3, along with sufficient numbers of willing participants for adequate clinical trials, the primary ethical considerations arising for trial participants would be risk minimization, adequate balance of risks and potential benefits to subjects and society, and informed consent, as discussed above with regard to non-inferiority design.
However, the questionable clinical utility and acceptability of a product like Z-3 is likely to be the most substantial hurdle to its development, due to the modest direct benefits to the patient and difficulties creating a market for more diffuse benefits to public health.
Designing a trial that can capture both the direct and population-level benefits of a product like Z-3 will not be simple and may require techniques such as cluster randomization to allow measurement of the population benefits of lower resistance rates in, for example, hospitals using vs.
not using the product. Approval pathways could also be challenging given measurable benefits primarily at the population rather than individual level, but this is a secondary concern behind the development issues related to an uncertain market for these products and associated ethical concerns for justifying clinical trials.
The idea of non-traditional antibiotic products has generated substantial interest because of the potential for radically different mechanisms of action that could address unmet needs. These products have potential value for society, but investment in these products may be suboptimal if the regulatory requirements for demonstrating safety and efficacy are not clear.
Developers of non-traditional antibacterial agents should not expect to bypass established regulatory and ethical standards.
Rather, most non-traditional products fall readily into one of the four arms of the STAR paradigm, and can be tested using existing non-inferiority- or superiority-based trial designs under existing regulations applicable to traditional small-molecule products.
While most antibiotics are currently approved based on non-inferiority designs 27 , 31 , some non-traditional products can best or must show their value via a demonstration of superiority over existing products. This challenge is most evident in the case of products in the Augment category where a partner therapy or the antibacterial standard of care has retained its activity, but where it is hoped that efficacy can be improved.
Here, the core test is of the combination vs. the existing product alone, and the combination will be required to be superior. The existing product must be fully dosed and expected to yield its baseline level of efficacy. Given the good efficacy of current tools, superiority is predicted to be difficult to demonstrate.
It thus seems unlikely that this pathway will be routinely feasible and there is no obvious solution for this problem — if the partner compound is highly efficacious, then simply showing similar efficacy in combination with an Augment agent does not provide a reason to use the new product in the absence of other information.
Turning to the question of non-traditional goals, the primary benefit in all the trials just discussed will be observable at the level of the individual treated with the new agent, in some cases based on newly validated surrogate endpoints. A challenge remains, however, for products with the primary potential for population-based benefits, including benefits to future generations.
Although these may be important products from a public health perspective, if they are insufficiently attractive to the patients who would need to take them because they are insufficiently relevant to their individual health, development is likely to be stymied by practical and ethical issues even before the challenges of regulatory approval arise.
For these products, it will be important to identify an appropriate clinical market in which individual benefit is sufficiently large to motivate use.
In summary, the idea of a non-traditional product has only limited relevance to regulatory decision-making as most products classified as non-traditional can and should be developed within the existing regulatory framework. That said, innovative product types with primarily population-level and future benefits can be envisioned and these would seem to warrant further discussion regarding how such benefits can best be incorporated into the drug evaluation paradigm.
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Antibacterials that inhibit protein synthesis J01A , J01B , J01F , J01G , QJ01XQ. Gentamicin Netilmicin Sisomicin Micronomicin Plazomicin Isepamicin Verdamicin Astromicin.
Eperezolid Linezolid Posizolid Radezolid Ranbezolid Sutezolid Tedizolid. Chloramphenicol Azidamfenicol Thiamphenicol Florfenicol. Azamulin Lefamulin Retapamulin Tiamulin Valnemulin.
Azithromycin Boromycin Carbomycin Clarithromycin Dirithromycin Erythromycin Flurithromycin Gamithromycin Josamycin Kitasamycin Midecamycin Miocamycin Oleandomycin Rokitamycin Roxithromycin Solithromycin Spiramycin Telithromycin Tildipirosin Tilmicosin Troleandomycin Tulathromycin Tylosin Tylvalosin.
Clindamycin Lincomycin Pirlimycin. Fusidic acid. Antibacterials active on the cell wall and envelope J01C - J01D. Ceftaroline fosamil Ceftolozane Ceftobiprole. Ceftiofur Cefquinome Cefovecin. Penam Sulbactam Tazobactam Clavam Clavulanic acid non-β-lactam Avibactam Durlobactam Relebactam Vaborbactam.
Insert into bacterial cell wall causing perforation and depolarization: Daptomycin Surfactin. Bind to LPS in the outer bacterial membrane, acting in detergent-like fashion: Colistin Polymyxin B. Inhibits PG elongation and crosslinking: Ramoplanin §. Hydrolyze NAM-NAG lysozyme Tyrothricin Gramicidin Tyrocidine Isoniazid Teixobactin.
Antibacterials that inhibit nucleic acid J01E , J01M. Sulfaisodimidine Sulfamethizole Sulfadimidine Sulfapyridine Sulfasalazine Sulfafurazole Acetyl sulfisoxazole Sulfanilamide Prontosil Sulfathiazole Phthalylsulfathiazole , Succinylsulfathiazole Sulfathiourea.
Sulfamethoxazole Sulfadiazine Sulfamoxole. Sulfadimethoxine Sulfadoxine Sulfalene Sulfametomidine Sulfametoxydiazine Sulfamethoxypyridazine Sulfaperin Sulfamerazine Sulfaphenazole Sulfamazone. Mafenide Sulfacetamide Sulfaclozine Sulfadicramide Sulfaguanidine Sulfametrole Sulfanitran.
Acediasulfone Dapsone Solasulfone Sulfoxone. Nemonoxacin Ozenoxacin. Aminocoumarins : Novobiocin. Metronidazole Ornidazole Secnidazole Tinidazole. Rifampicin Rifabutin Rifapentine Rifaximin Rifalazil §. Antibacterials : others J01X , D06AX. Antifungals D01 and J Topical: naftifine terbinafine Systemic: terbinafine.
Topical: butenafine. Topical: amorolfine. Systemic: echinocandins anidulafungin caspofungin cilofungin micafungin rezafungin ibrexafungerp. Systemic: flucytosine. Systemic: griseofulvin. Topical: tavaborole. Antimycobacterials , including tuberculosis treatment and leprostatic agents J Rifampicin Rifabutin Rifapentine Rifalazil §.
Dapsone Acedapsone Diucifon Promin Solasulfone Sulfoxone. Gatifloxacin Moxifloxacin. Amikacin Kanamycin Streptomycin. Linezolid Sutezolid.
Alanine analogue: Cycloserine. Phenazine Clofazimine Pyrazine Pyrazinamide , Morinamide Isoxazole Terizidone Bedaquiline Nitroimidazole Delamanid , Pretomanid. Immune sera and immunoglobulins J Anthrax immune globulin Rho D immune globulin Hepatitis B immune globulin Zoster-immune globulin.
Adjuvants Vaccine ingredients list Mathematical modelling Storage Timeline Trials. Global: GAVI Alliance NITAG SAGE Vaccine wastage Policy Schedule Vaccine injury US: ACIP Vaccine court Vaccines for Children Program VAERS VSD.
Malaria RTS,S research: Trypanosomiasis. research: Hookworm Schistosomiasis. Edward Jenner Louis Pasteur Hilary Koprowski Jonas Salk John Franklin Enders Maurice Hilleman Stanley Plotkin H.
Fred Clark Paul Offit Katalin Karikó Drew Weissman. General MMR Lancet MMR autism fraud NCVIA Pox party Thiomersal Vaccines and SIDS Cedillo v.
Secretary of Health and Human Services Alternative vaccination schedule. Epidemiology Eradication of infectious diseases Vaccinate Your Family List of vaccine topics.
Antiparasitics — Anthelmintics P02 and endectocides QP benzimidazole Triclabendazole. benzimidazole Albendazole. quinoline Praziquantel salicylanilide Niclosamide aminoacridine Quinacrine butyrophenone Desaspidin chlorophenol Dichlorophen.
BMC Microbiology volume antibactterial Effective antibacterial agents, Article number: Cite this Effective antibacterial agents. Metrics details. Agens tonsillitis is anfibacterial of the most common Colon cleanse for digestive system support disorders caused by cell-invading bacteria, such as Streptococcus pyogenes S. pyogenes and Haemophilus influenzae. The aim of this study was to investigate the effect of antibacterial agents against cell-invading bacteria. The intracellular invasion of Detroit cells by five strains of nontypeable Haemophilus influenzae NTHi and four strains of S. pyogenes was investigated.
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