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The emergence of plasmid-mediated resistance threatens the efficacy of polymyxins as the last line of defense against pan-drug-resistant infections. However, we have found that using Mueller-Hinton II (MHII), the standard minimum inhibitory concentration (MIC) medium, results in MIC data that are disconnected from in vivo treatment outcomes. We found that culturing putative colistin-resistant Acinetobacter baumannii clinical isolates, as defined by MICs of >2 mg/L in standard MHII testing conditions, in bicarbonate-containing media reduced MICs to the susceptible range by preventing colistin resistance-conferring lipopolysaccharide modifications from occurring. Furthermore, the lower MICs in bicarbonate-containing media accurately predicted in vivo efficacy of a human-simulated dosing strategy of colistin and polymyxin B in a lethal murine infection model for some polymyxin-resistant A. baumannii strains. Thus, current polymyxin susceptibility testing methods overestimate the contribution of polymyxin resistance-conferring mutations and incorrectly predict antibiotic activity in vivo . Polymyxins may remain a viable therapeutic option against Acinetobacter baumannii strains heretofore determined to be "pan-resistant.", Competing Interests: The authors declare no conflict of interest.

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background: Based on multiple randomized-controlled clinical trials, shorter antibiotic courses are equally effective as traditional longer courses for many types of infections. However, longer courses are still being used widely in the clinical practice., Objectives: To describe four components involved in the successful implementation of shorter antibiotic courses in our health care institutions, including an academic, public hospital and a community hospital staffed primarily by private practitioners., Sources: Clinical trials and peer-reviewed publications., Content: We provide practical advice on how to support the change in clinical practice to shorten antibiotic duration. Specifically, we list the steps that we have successfully used to develop and implement an institutional practice change regarding the duration of antibiotic therapy: (a) establishing consensus documents outlining a data-driven expected practice for using antibiotics, (b) antibiotic stewardship programme support, (c) provider education, and (d) reinforcing behaviour through psychological and other tools. The implementation of these processes has successfully led to shorter antibiotic courses and decreased antibiotic use in our diverse practice settings., Implications: Intentional improvement in decreasing the duration of antibiotic therapy can be achieved by a specific antibiotic stewardship programme strategy and tactics. The implementation of shorter antibiotic courses has effects at individual and societal levels in an era of increasing antibacterial resistance and health care costs., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Polymyxin B is a "last-line-of-defense" antibiotic approved in the 1960s. However, the population pharmacokinetics (PK) of its four main components has not been reported in infected mice. We aimed to determine the PK of polymyxin B1, B1-Ile, B2, and B3 in a murine bloodstream and lung infection model of Acinetobacter baumannii and develop humanized dosage regimens. A linear 1-compartment model, plus an epithelial lining fluid (ELF) compartment for the lung model, best described the PK. Clearance and volume of distribution were similar among the four components. The bioavailability fractions were 72.6% for polymyxin B1, 12.0% for B1-Ile, 11.5% for B2, and 3.81% for B3 for the lung model and were similar for the bloodstream model. While the volume of distribution was comparable between both models (17.3 mL for the lung and ~27 mL for the bloodstream model), clearance was considerably smaller for the lung (2.85 mL/h) compared to that of the bloodstream model (5.59 mL/h). The total drug exposure (AUC) in ELF was high due to the saturable binding of polymyxin B presumably to bacterial lipopolysaccharides. However, the modeled unbound AUC in ELF was ~16.7% compared to the total drug AUC in plasma. The long elimination half-life (~4 h) of polymyxin B enabled humanized dosage regimens with every 12 h dosing in mice. Daily doses that optimally matched the range of drug concentrations observed in patients were 21 mg/kg for the bloodstream and 13 mg/kg for the lung model. These dosage regimens and population PK models support translational studies for polymyxin B at clinically relevant drug exposures., Competing Interests: The authors declare no conflict of interest.

Industry screens of large chemical libraries have traditionally relied on rich media to ensure rapid bacterial growth in high-throughput testing. We used eukaryotic, nutrient-limited growth media in a compound screen that unmasked a previously unknown hyperactivity of the old antibiotic, rifabutin (RBT), against highly resistant Acinetobacter baumannii. In nutrient-limited, but not rich, media, RBT was 200-fold more potent than rifampin. RBT was also substantially more effective in vivo. The mechanism of enhanced efficacy was a Trojan horse-like import of RBT, but not rifampin, through fhuE, only in nutrient-limited conditions. These results are of fundamental importance to efforts to discover antibacterial agents.

Importance: The requirement of prolonged intravenous antibiotic courses to treat infective endocarditis (IE) is a time-honored dogma of medicine. However, numerous antibiotics are now available that achieve adequate levels in the blood after oral administration to kill bacteria. Moreover, prolonged intravenous antibiotic regimens are associated with high rates of adverse events. Accordingly, recent studies of oral step-down antibiotic treatment have stimulated a reevaluation of the need for intravenous-only therapy for IE., Observations: PubMed was reviewed in October 2019, with an update in February 2020, to determine whether evidence supports the notion that oral step-down antibiotic therapy for IE is associated with inferior outcomes compared with intravenous-only therapy. The search identified 21 observational studies evaluating the effectiveness of oral antibiotics for treating IE, typically after an initial course of intravenous therapy; none found such oral step-down therapy to be inferior to intravenous-only therapy. Multiple studies described an improved clinical cure rate and an improved mortality rate among patients treated with oral step-down vs intravenous-only antibiotic therapy. Three randomized clinical trials also demonstrated that oral step-down antibiotic therapy is at least as effective as intravenous-only therapy in right-sided, left-sided, or prosthetic valve IE. In the largest trial, at 3.5 years of follow-up, patients randomized to receive oral step-down antibiotic therapy had a significantly improved cure rate and mortality rate compared with those who received intravenous-only therapy., Conclusions and Relevance: This review found ample data demonstrating the therapeutic effectiveness of oral step-down vs intravenous-only antibiotic therapy for IE, and no contrary data were identified. The use of highly orally bioavailable antibiotics as step-down therapy for IE, after clearing bacteremia and achieving clinical stability with intravenous regimens, should be incorporated into clinical practice.

Importance: Among patients diagnosed with diabetes, the lifetime incidence of foot ulcers is 15%. Infection is a common complication of foot ulcers, and 20% to 60% of infections result in diabetic foot osteomyelitis (DFO). Current treatment guidelines do not endorse any specific antibiotic agent for DFO, but small clinical trials suggest the addition of rifampin to antimicrobial regimens results in improved cure rates for osteomyelitis., Objective: To compare the clinical outcomes of patients treated for DFO in the Veterans Health Administration (VHA) with and without adjunctive rifampin., Design, Setting, and Participants: This observational cohort study used VHA databases to identify index DFO cases from January 1, 2009, through December 31, 2013, and analyzed patients alive and without high-level amputation at 90 days after diagnosis in whom antibiotic therapy was initiated within 6 weeks of diagnosis. Patients with death or major amputation within 90 days of diagnosis, who were not treated with systemic antibiotics dispensed by the VHA within 6 weeks of diagnosis, or who were treated at facilities where rifampin was not dispensed for DFO were excluded. The retrospective cohort to inform the planning of a multisite randomized clinical trial was first investigated in spring 2015; retrospective analysis was performed from February 2017 through September 2019., Exposures: Patients initiating rifampin therapy within 6 weeks of the DFO diagnosis and receiving the drug for at least 14 days within 90 days of diagnosis were considered treated with rifampin. Patients not administered rifampin within 90 days of diagnosis served as the comparator group., Main Outcomes and Measures: A combined end point of mortality or amputation within 2 years of diagnosis was analyzed. Differences in times to event were evaluated using log-rank tests. Differences in event rates were compared using χ2 tests and multivariable logistic regression., Results: The analysis population included 130 patients treated with rifampin and 6044 treated without rifampin (total of 6174; 6085 men [98.6%]; mean [SD] age, 64.9 [9.7] years). Lower event rates were observed among the rifampin group (35 of 130 [26.9%] vs 2250 of 6044 [37.2%]; P = .02). Patients treated with rifampin were younger (mean [SD] age, 62.2 [9.4] vs 64.9 [9.6] years), had fewer comorbidities (mean [SD] Charlson comorbidity index score, 3.5 [1.8] vs 4.0 [2.2]), had more infectious disease specialty consultations (63 of 130 [48.5%] vs 1960 of 6044 [32.4%]), and more often had Staphylococcus aureus identified in cultures (55 of 130 [42.3%] vs 1755 of 6044 [29.0%]) than patients not treated with rifampin. A logistic regression estimating the odds of events and controlling for these and other covariates yielded a significant association of rifampin (odds ratio, 0.65; 95% CI, 0.43-0.96; P = .04)., Conclusions and Relevance: In this cohort study, patients administered rifampin experienced lower rates of death and amputation than patients not treated with rifampin, which remained significant after adjustment for confounders. These results coupled with existing evidence from small clinical trials suggest the addition of rifampin to current treatment regimens may be a useful antimicrobial option in the treatment of DFO.

Background: New strategies are needed to slow the emergence of antibiotic resistance among bacterial pathogens. In particular, society is experiencing a crisis of antibiotic-resistant infections caused by Gram-negative bacterial pathogens and novel therapeutics are desperately needed to combat such diseases. Acquisition of iron from the host is a nearly universal requirement for microbial pathogens-including Gram-negative bacteria-to cause infection. We have previously reported that apo-transferrin (lacking iron) can inhibit the growth of Staphylococcus aureus in culture and diminish emergence of resistance to rifampicin., Objectives: To define the potential of apo-transferrin to inhibit in vitro growth of Klebsiella pneumoniae and Acinetobacter baumannii, key Gram-negative pathogens, and to reduce emergence of resistance to antibiotics., Methods: The efficacy of apo-transferrin alone or in combination with meropenem or ciprofloxacin against K. pneumoniae and A. baumannii clinical isolates was tested by MIC assay, time-kill assay and assays for the selection of resistant mutants., Results: We confirmed that apo-transferrin had detectable MICs for all strains tested of both pathogens. Apo-transferrin mediated an additive antimicrobial effect for both antibiotics against multiple strains in time-kill assays. Finally, adding apo-transferrin to ciprofloxacin or meropenem reduced the emergence of resistant mutants during 20 day serial passaging of both species., Conclusions: These results suggest that apo-transferrin may have promise to suppress the emergence of antibiotic-resistant mutants when treating infections caused by Gram-negative bacteria., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

There has been renewed interest in combining traditional small-molecule antimicrobial agents with nontraditional therapies to potentiate antimicrobial effects. Apotransferrin, which decreases iron availability to microbes, is one such approach. We conducted a 48-h one-compartment in vitro infection model to explore the impact of apotransferrin on the bactericidal activity of ciprofloxacin. The challenge panel included four Klebsiella pneumoniae isolates with ciprofloxacin MIC values ranging from 0.08 to 32 mg/liter. Each challenge isolate was subjected to an ineffective ciprofloxacin monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio] ranging from 0.19 to 96.6) with and without apotransferrin. As expected, the no-treatment and apotransferrin control arms showed unaltered prototypical logarithmic bacterial growth. We identified relationships between exposure and change in bacterial density for ciprofloxacin alone ( R 2 = 0.64) and ciprofloxacin in combination with apotransferrin ( R 2 = 0.84). Addition of apotransferrin to ciprofloxacin enabled a remarkable reduction in bacterial density across a wide range of ciprofloxacin exposures. For instance, at a ciprofloxacin AUC/MIC ratio of 20, ciprofloxacin monotherapy resulted in nearly 2 log 10 CFU increase in bacterial density, while the combination of apotransferrin and ciprofloxacin resulted in 2 log 10 CFU reduction in bacterial density. Furthermore, addition of apotransferrin significantly reduced the emergence of ciprofloxacin-resistant subpopulations compared to monotherapy. These data demonstrate that decreasing the rate of bacterial replication with apotransferrin in combination with antimicrobial therapy represents an opportunity to increase the magnitude of the bactericidal effect and to suppress the growth rate of drug-resistant subpopulations., (Copyright © 2019 American Society for Microbiology.)

The treatment of osteomyelitis in patients with stage IV sacral pressure ulcers is controversial. We conducted a systematic literature review and did not find evidence of benefit of antibacterial therapy in this setting without concomitant surgical debridement and wound coverage. Furthermore, many patients with chronically exposed bone do not have evidence of osteomyelitis when biopsied, and magnetic resonance imaging may not accurately distinguish osteomyelitis from bone remodeling. The goal of therapy should be local wound care and assessment for the potential of wound closure. If the wound can be closed and osteomyelitis is present on bone biopsy, appropriate antibiotic therapy is reasonable. We find no data to support antibiotic durations of >6 weeks in this setting, and some authors recommend 2 weeks of therapy if the osteomyelitis is limited to cortical bone. If the wound will not be closed, we find no clear evidence supporting a role for antibiotic therapy.

We sought to determine if clinical data validate the dogma that bactericidal antibiotics are more clinically effective than bacteriostatic agents. We performed a systematic literature review of published, randomized, controlled trials (RCTs) that compared a bacteriostatic agent to a bactericidal agent in the treatment of clinical, bacterial infections. Of 56 identified trials published since 1985, 49 found no significant difference in efficacy between bacteriostatic and bactericidal agents. In 6 trials it was found that the bacteriostatic agent was superior to the bactericidal agent in efficacy. Only 1 trial found that the bactericidal agent was superior; in that case, the inferiority of the static agent was explainable by underdosing of the drug based on pharmacokinetic-pharmacodynamic analysis. Thus, virtually all available data from high-quality, RCTs demonstrate no intrinsic superiority of bactericidal compared to bacteriostatic agents. Other drug characteristics such as optimal dosing, pharmacokinetics, and tissue penetration may be more important efficacy drivers.

The emergence of Klebsiella pneumoniae carbapenemases (KPCs), β-lactamases that inactivate "last-line" antibiotics such as imipenem, represents a major challenge to contemporary antibiotic therapies. The combination of ceftazidime (CAZ) and avibactam (AVI), a potent β-lactamase inhibitor, represents an attempt to overcome this formidable threat and to restore the efficacy of the antibiotic against Gram-negative bacteria bearing KPCs. CAZ-AVI-resistant clinical strains expressing KPC variants with substitutions in the Ω-loop are emerging. We engineered 19 KPC-2 variants bearing targeted mutations at amino acid residue Ambler position 179 in Escherichia coli and identified a unique antibiotic resistance phenotype. We focus particularly on the CAZ-AVI resistance of the clinically relevant Asp179Asn variant. Although this variant demonstrated less hydrolytic activity, we demonstrated that there was a prolonged period during which an acyl-enzyme intermediate was present. Using mass spectrometry and transient kinetic analysis, we demonstrated that Asp179Asn "traps" β-lactams, preferentially binding β-lactams longer than AVI owing to a decreased rate of deacylation. Molecular dynamics simulations predict that (i) the Asp179Asn variant confers more flexibility to the Ω-loop and expands the active site significantly; (ii) the catalytic nucleophile, S70, is shifted more than 1.5 Å and rotated more than 90°, altering the hydrogen bond networks; and (iii) E166 is displaced by 2 Å when complexed with ceftazidime. These analyses explain the increased hydrolytic profile of KPC-2 and suggest that the Asp179Asn substitution results in an alternative complex mechanism leading to CAZ-AVI resistance. The future design of novel β-lactams and β-lactamase inhibitors must consider the mechanistic basis of resistance of this and other threatening carbapenemases. IMPORTANCE Antibiotic resistance is emerging at unprecedented rates and threatens to reach crisis levels. One key mechanism of resistance is the breakdown of β-lactam antibiotics by β-lactamase enzymes. KPC-2 is a β-lactamase that inactivates carbapenems and β-lactamase inhibitors (e.g., clavulanate) and is prevalent around the world, including in the United States. Resistance to the new antibiotic ceftazidime-avibactam, which was designed to overcome KPC resistance, had already emerged within a year. Using protein engineering, we uncovered a mechanism by which resistance to this new drug emerges, which could arm scientists with the ability to forestall such resistance to future drugs., (Copyright © 2017 Barnes et al.)

Carbapenem-resistant Enterobacteriaceae (CRE) are among the most critical threats facing our healthcare system and account for significant patient mortality. There is considerable interest in the development of new treatment strategies. However, less attention has been paid to reducing CRE infection rates. Antibiotic stewardship programs can be uniquely empowered to reduce widespread pathogen resistance and by extension, optimize patient care and lower healthcare costs.

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included bla IMP , bla NDM , bla OXA-48 , bla CTX-M , bla AmpC , and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log 10 -CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log 10 -CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae ., (Copyright © 2017 American Society for Microbiology.)

Use of antivirulence therapy has assumed that inhibition of bacterial fitness at the site of infection without directly affecting viability will minimize the development of resistance. However, selection for resistant strains is much more likely to occur at sites of colonization or in the environment following excretion of the therapeutic agent. Data are needed regarding whether the drug's target promotes fitness among bacteria in (drug-exposed) niches other than sites of infection. Furthermore, in vivo studies of resistance selection should assess off-target selection for resistance (eg, within the microbiome). Only when such data are available can the risk for development of resistance be gauged appropriately., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Society faces a crisis of rising antibiotic resistance even as the pipeline of new antibiotics has been drying up. Antibiotics are a public trust; every individual's use of antibiotics affects their efficacy for everyone else. As such, responses to the antibiotic crisis must take a societal perspective. The market failure of antibiotics is due to a combination of scientific challenges to discovering and developing new antibiotics, unfavorable economics, and a hostile regulatory environment. Scientific solutions include changing the way we screen for new antibiotics. More transformationally, developing new treatments that seek to disarm pathogens without killing them, or that modulate the host inflammatory response to infection, will reduce selective pressure and hence minimize resistance emergence. Economic transformation will require new business models to support antibiotic development. Finally, regulatory reform is needed so that clinical development programs are feasible, rigorous, and clinically relevant. Pulmonary and critical care specialists can have tremendous impact on the continued availability of effective antibiotics. Encouraging use of molecular diagnostic tests to allow pathogen-targeted, narrow-spectrum antibiotic therapy, using short rather than unnecessarily long course therapy, reducing inappropriate antibiotic use for probable viral infections, and reducing infection rates will help preserve the antibiotics we have for future generations.

The ways we have developed, used, and protected antibiotics have led, predictably, to our current crisis of rising antibiotic resistance and declining new treatments. If we want to stave off a postantibiotic era, we need to fundamentally change our approach. We need to challenge long-standing assumptions and cherished beliefs. We need to push through the reflexive resistance and excuses (eg, "that's not how we do things" and "that can't be done") that result from challenging established ways. Excuses abound. Action is needed. Ultimately, we need a coordinated national action plan to combat resistance. Herein we discuss 7 tasks and 3 common themes that cut across those tasks, which are necessary to achieve long-term success in dealing with antibiotics and resistance. These principles derive from many years of dialogue with Dr John Bartlett. The field of infectious diseases, and indeed medicine in general, has benefited immeasurably from his remarkable leadership., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

As a result of declining new antibacterial approvals and rising antibiotic resistance, society clearly needs new treatments for bacterial infections. Specific areas of unmet need evolve over time owing to changes in resistance patterns and treatment strategies. Our goal here is to describe and prioritize the current areas of greatest unmet need for new antibacterial development based on an understanding of the most serious treatment challenges facing patients and their providers today.

Antibiotic resistance continues to spread even as society is experiencing a market failure of new antibiotic research and development (R&D). Scientific, economic, and regulatory barriers all contribute to the antibiotic market failure. Scientific solutions to rekindle R&D include finding new screening strategies to identify novel antibiotic scaffolds and transforming the way we think about treating infections, such that the goal is to disarm the pathogen without killing it or modulate the host response to the organism without targeting the organism for destruction. Future economic strategies are likely to focus on 'push' incentives offered by public-private partnerships as well as increasing pricing by focusing development on areas of high unmet need. Such strategies can also help protect new antibiotics from overuse after marketing. Regulatory reform is needed to re-establish feasible and meaningful traditional antibiotic pathways, to create novel limited-use pathways that focus on highly resistant infections, and to harmonize regulatory standards across nations. We need new antibiotics with which to treat our patients. But we also need to protect those new antibiotics from misuse when they become available. If we want to break the cycle of resistance and change the current landscape, disruptive approaches that challenge long-standing dogma will be needed.

Funded by the National Institute of Allergy and Infectious Diseases, the Antibacterial Resistance Leadership Group (ARLG) is tasked with developing a clinical research agenda and conducting clinical studies to address the growing public health threat of antibacterial resistance. The ARLG has identified 4 high-priority areas of research: infections caused by gram-negative bacteria, infections caused by gram-positive bacteria, antimicrobial stewardship and infection prevention, and diagnostics. The ARLG will be accepting proposals from the scientific community for clinical research that addresses 1 or more of these high-priority areas. These studies should have the potential to transform medical practice and be unlikely to occur without ARLG support. The purpose of this article is to make interested parties aware of clinical research opportunities made available by ARLG and to encourage submission of clinical research proposals that address the problem of antibacterial resistance.

Iron acquisition is a virulence factor for Staphylococcus aureus. We assessed the efficacy of the iron chelator, deferasirox (Def), alone or in combination with vancomycin (Van) against two methicillin-resistant S. aureus (MRSA) strains in vitro and in a murine bacteremia model. In vitro time-kill assays were carried out against MRSA or vancomycin-intermediate S. aureus (VISA) strains. The impact of Def on Van binding to the surface of S. aureus was measured by flow cytometry. Furthermore, we compared the efficacy of Def, Van, or both drugs in treating S. aureus bacteremia in a murine model. Combination therapy reduced MRSA and VISA viability in vitro versus either drug alone or untreated controls (p < 0.005); this outcome was correlated with enhanced Van surface binding to S. aureus cells. In vivo, Def + Van combination therapy significantly reduced the bacterial burden in mice kidneys (p = 0.005) and spleen (p < 0.001), and reduced the severity of infection with MRSA or VISA strains compared to placebo-treated mice. Our results show that Def enhances the in vitro and in vivo capacity of Van-mediated MRSA killing via a mechanism that appears to involve increased binding of Van to the staphylococcal surface. Iron chelation is a promising, novel adjunctive therapeutic strategy for MRSA and VISA infections.

Antibiotic resistance is a well-acknowledged crisis with no clearly defined comprehensive, national corrective plan. We propose a number of interventions that, collectively, could make a large difference. These include collection of data to inform decisions, efforts to reduce antibiotic abuse in people and animals, great emphasis on antibiotic stewardship, performance incentives, optimal use of newer diagnostics, better support for clinical and basic resistance-related research, and novel methods to foster new antibiotic development.

In order to meet the challenges of our current medical need to address infections caused by highly resistant pathogens, we propose the use of superiority trial designs. The proposed trials may or may not be statistically powered. All require extensive preclinical justification. The designs could use either historical or active controls. For historically controlled trials we propose two approaches for defining the control response rate to therapy; (1) the use of pharmacometrics from modern trials and (2) the use of a concurrent observational study. Designs for active controlled trials could be (1) standard of care+test vs. standard of care alone or (2) standard of care vs. test article. The second approach requires extensive justification to show that the test article will be of sufficient efficacy to allow ethical use as a single agent., (Copyright © 2012. Published by Elsevier Ltd.)

Objectives: Extremely drug-resistant (XDR; i.e. resistant to all antibiotics except colistin or tigecycline) Acinetobacter baumannii has emerged as one of the most common and highly antibiotic-resistant causes of infection. Diabetes is a risk factor for acquisition of and worse outcomes from A. baumannii infection. We sought to develop diabetic mouse models of A. baumannii bacteraemia and pneumonia and validate these models by comparing the efficacy of antibiotic treatment in these models with the established neutropenic mouse models., Methods: Diabetic or neutropenic mice were infected via intravenous inoculation or inhalation in an aerosol chamber with an XDR A. baumannii. Treatment with colistin started 24 h after infection and continued daily for 7 days. Survival served as the primary endpoint while tissue bacterial burden and histopathological examination served as secondary endpoints., Results: Lethal infection was achieved for the neutropenic and diabetic mice when infected intravenously or via inhalation. Neutropenic mice were more susceptible to infection than diabetic mice in the pneumonia model and equally susceptible in the bacteraemia model. Both models of bacteraemia were sensitive enough to detect virulence differences among different clinical strains of A. baumannii. In the pneumonia model, colistin treatment was effective in improving survival, reducing lung bacterial burden and histologically resolving the infection compared with placebo only in diabetic mice., Conclusions: We developed novel models of A. baumannii bacteraemia and pneumonia in diabetic mice. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies and evaluate drug efficacies against highly lethal A. baumannii infections.

The standard recommendation for treating chronic osteomyelitis is 6 weeks of parenteral antibiotic therapy. However, oral antibiotics are available that achieve adequate levels in bone, and there are now more published studies of oral than parenteral antibiotic therapy for patients with chronic osteomyelitis. Oral and parenteral therapies achieve similar cure rates; however, oral therapy avoids risks associated with intravenous catheters and is generally less expensive, making it a reasonable choice for osteomyelitis caused by susceptible organisms. Addition of adjunctive rifampin to other antibiotics may improve cure rates. The optimal duration of therapy for chronic osteomyelitis remains uncertain. There is no evidence that antibiotic therapy for >4-6 weeks improves outcomes compared with shorter regimens. In view of concerns about encouraging antibiotic resistance to unnecessarily prolonged treatment, defining the optimal route and duration of antibiotic therapy and the role of surgical debridement in treating chronic osteomyelitis are important, unmet needs.