Revival of old antibiotics: needs, the state of evidence and expectations

ARTICLE IN PRESS International Journal of Antimicrobial Agents ■■ (2017) ■■–■■

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International Journal of Antimicrobial Agents j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j a n t i m i c a g

Themed Issue: Resurrection of old antibiotics

Revival of old antibiotics: needs, the state of evidence and expectations Hiba Zayyad a, Noa Eliakim-Raz b,c, Leonard Leibovici b,c, Mical Paul a,d,*,1 a

Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel c Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel d The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel b

A R T I C L E

I N F O

Keywords: Evidence-based medicine Polymyxins Carbapenem-resistant Gram-negative bacteria Carbapenem-resistant Enterobacteriaceae MRSA

A B S T R A C T

The gap between the emergence of antibiotic resistance and new antibiotic development has drawn attention to old antibiotics whose spectrum of coverage frequently comprises highly resistant bacteria. However, these antibiotics have frequently not undergone the structured process of antibiotic development of modern antibiotics, from pharmacokinetic/pharmacodynamic (PK/PD) studies establishing safe and effective dosing, establishment of susceptibility breakpoints, to clinical trials establishing clinical safety and effectiveness. In this review, we highlight the gaps for which we need old antibiotics in community- and hospital-acquired infections. Reviewing recently published and ongoing randomised controlled trials (RCTs) shows advances in our understanding of the efficacy and effectiveness of oral fosfomycin, mecillinam and nitrofurantoin for cystitis, and of trimethoprim/sulfamethoxazole for complicated skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in the community. Summarising older evidence shows the inferiority of chloramphenicol versus modern antibiotics for severe infections. We lack studies on severe infections caused by carbapenem-resistant Gram-negative bacteria and other multidrug-resistant (MDR) bacteria in hospitalised and critically ill patients; ongoing studies assessing colistin and intravenous fosfomycin might fill in some gaps. In the re-development process of old antibiotics, we mandate modern PK/PD studies comprising special populations as well as RCTs addressing the target population of patients in need of these antibiotics powered to examine patient-relevant outcomes. Structured antibiotic re-development from the laboratory to evidencebased treatment recommendations requires public funding, multidisciplinary collaboration, international coordination, and methods to streamline the recruitment of critically ill patients infected by MDR bacteria. © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

1. Introduction The growing burden of antibiotic resistance worldwide imposes challenges to our antibiotic armamentarium. We are running out of effective treatment options for infections caused by multidrugresistant (MDR) bacteria. While developing new and hopefully effective drugs (a process that is time consuming and costly), ‘old antibiotics’ that were developed decades ago and were abandoned for different reasons have become appealing [1]. These agents are cheap, frequently broad-spectrum, with no regulatory restrictions on their use. However, we cannot use old antibiotics for any infection based only on their spectrum of coverage. We have sparse data on the appropriate dose for different types of infections and on their efficacy. These drugs entered clinical use before contemporary drug approval processes were established, starting from pharmacokinetic/pharmacodynamic (PK/PD) studies to appropriately

* Corresponding author. Infectious Diseases Institute, Rambam Health Care Campus, Haifa 3109601, Israel. Fax: +972 4 777 1620. E-mail address: [email protected] (M. Paul). 1 Present address: Infectious Diseases Institute, Rambam Health Care Campus, Haifa 3109601, Israel.

conducted clinical studies. Mostly, they were not intended for the types of infections we now need them for. 2. What do we need old antibiotics for? The niche for old antibiotics spans the community and hospitals. Among community-acquired infections, we need antibiotics to treat urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-producing micro-organisms that are resistant to quinolones. These infections affect young healthy and active women who should not be hospitalised for cystitis or uncomplicated pyelonephritis. Furthermore, we need oral antibiotics for pregnant women with asymptomatic bacteriuria caused by ESBLproducing organisms in order to avoid hospitalisation for intravenous (i.v.) antibiotic administration and exposure to broad-spectrum β-lactams. Nitrofurantoin, fosfomycin or mecillinam can fulfil this niche [2]. In locations where community-acquired methicillinresistant Staphylococcus aureus (MRSA) is prevalent, simple antibiotics for skin and soft-tissue infections (SSTIs) are needed; trimethoprim/ sulfamethoxazole (SXT) is a relevant option. In hospitals, we need new (or new-old) antibiotics to save lives rather than for convenience. The mortality of infections caused by

http://dx.doi.org/10.1016/j.ijantimicag.2016.11.021 0924-8579/© 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Please cite this article in press as: Hiba Zayyad, Noa Eliakim-Raz, Leonard Leibovici, Mical Paul, Revival of old antibiotics: needs, the state of evidence and expectations, International Journal of Antimicrobial Agents (2017), doi: 10.1016/j.ijantimicag.2016.11.021

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Table 1 Bacteria and clinical scenarios for which old antibiotics might be needed. Bacteria

Settings and clinical scenarios

Potentially useful old antibiotic (susceptibility ranges reported in contemporary literature)

Carbapenem-resistant Gram-negative bacteria (CR-GNB) Carbapenem-resistant Healthcare-associated and hospital-acquired infections, including Enterobacteriaceae (CRE) bacteraemia, pneumonia and other severe infections

Carbapenem-resistant Pseudomonas aeruginosa Carbapenem-resistant Acinetobacter baumannii (CRAB)

ESBL-producing Enterobacteriaceae

Outpatients: mainly uncomplicated UTIs (cystitis), asymptomatic bacteriuria in pregnancy and prostatitis Inpatients, carbapenem-sparing regimens for complicated UTIs, pneumonia and other infections

MRSA

VRE

Initial treatment or step-down to oral treatment for several infections mainly SSTIs

Healthcare-associated and hospital-acquired infections, as glycopeptide-sparing agents or for polymicrobial infections involving enterococci or Gram-negatives and MRSA Healthcare-associated and hospital-acquired infections, including bacteraemia, pneumonia and abdominal infections

Polymyxins (colistin/polymyxin B) (50–100%) i.v. fosfomycin (39–100%) Temocillin (3–91% of KPC-producers) Aminoglycosides (locally variable) Polymyxins (colistin/polymyxin B) (98–99.4%) i.v. fosfomycin (30–80%) Aminoglycosides (locally variable) Polymyxins (colistin/polymyxin B) (92–100%) i.v. minocycline (68–79%) SXT (locally variable) Aminoglycosides (15–57%) Nitrofurantoin (40–96%) Oral fosfomycin (15–97%) Pivmecillinam (93–100%) i.v. fosfomycin (83–97%) Temocillin (76–87%) Mecillinam (93–100%) Aminoglycosides (locally variable) Minocycline (97–100%) Fusidic acid (93–98.2%) SXT (0–99%, locally variable) i.v. fosfomycin (33–100%) Chloramphenicol (52–87%) i.v. fosfomycin (33–100%) SXT (0–99%, locally variable) Chloramphenicol (80%) i.v. fosfomycin (30–100%)

i.v., intravenous; SXT, trimethoprim/sulfamethoxazole; ESBL, extended-spectrum β-lactamase; UTI, urinary tract infection; MRSA, methicillin-resistant Staphylococcus aureus; SSTI, skin and soft-tissue infection; VRE, vancomycin-resistant enterococci.

carbapenem-resistant Gram-negative bacteria (CR-GNB) acquired in the hospital is ca. 30–40% worldwide. New antibiotics are in the pipeline or have been recently approved. However, the activities of ceftazidime/avibactam, meropenem/vaborbactam and imipenem/ relebactam are limited to CR-GNB whose resistance is mediated through KPC (serine) carbapenemases; they are not active against isolated producing class B metallo-β-lactamases (MBLs) [3]. The activity of polymyxins, 60-year-old antibiotics, is not carbapenemaseselective and their spectrum of coverage comprises all carbapenemases and non-carbapenemase-producing CR-GNB as well as carbapenem-resistant Acinetobacter and Pseudomonas spp. None of the β-lactam-based combination therapies currently approved or in the pipeline have this spectrum of coverage. A new aminoglycoside, plazomicin, is in the pipeline. Before adopting it, we must make the best use of available aminoglycosides. A variable percentage of carbapenem-resistant Acinetobacter baumannii are susceptible to SXT, minocycline and chloramphenicol; their use could spare polymyxin treatment and delay the emergence of polymyxin resistance that has been observed in high-consumption hospitals [4]. Fosfomycin has a very broad spectrum of coverage against Gram-positive and Gram-negative MDR bacteria and, when administered intravenously, might be effective against systemic infections [2,5]. Fosfomycin can serve as a carbapenem- or polymyxin-sparing agent or for polymicrobial Gram-positive/Gram-negative infections. These and other scenarios for which old drugs might be useful are detailed in Table 1. 3. Pharmacokinetic/pharmacodynamic knowledge gaps PK/PD knowledge gaps are most obvious and indeed are being addressed in current research [1,6,7]. Colistin is a good example of recent progress. Previous dosing recommendations varied across countries and were not based on adequate studies; the product information recommended much lower dosing in Europe than in the USA [8]. Contemporary studies showed that the European dosing of 3–6 million international units (MIU) colistimethate per day did not reach optimal active colistin levels [peak concentration/minimum inhibitory

concentration (Cmax/MIC) ratio]. Furthermore, the time to reach steadystate therapeutic concentrations of colistin was unacceptable for severe sepsis, suggesting the need for a loading dose strategy in critically ill patients [9]. A recent study, however, showed somewhat contradictory results, and much higher than expected levels were observed after the initial colistin methanesulphonate dose with rapid attainment of steady-state, challenging the need for a loading dose [10]. Large unexplained variability in colistin concentrations between patients suggests the need for therapeutic drug monitoring (TDM). Dose reductions according to creatinine clearance have been established. Colistin is subject to extensive removal by haemodialysis, suggesting that intermittent haemodialysis be performed at the end of the dosing interval with supplemental dosing after each session. In patients receiving renal replacement therapy by continuous haemodialysis, the high extent of removal requires a higher dose than for patients with normal renal function, and TDM is advised. Studies of colistin in the last decade resulted in a formal change of recommendations to standardise its use worldwide [11]. Similar developments are needed in the PK/PD study of other old antibiotics. Clinical studies assessing dosing strategies of old antibiotics are largely missing. Again, the largest advances have occurred with colistin. A recent observational study showed no difference in mortality for a low (median 4 MIU/day) versus a high (median 9 MIU/day) dose colistin [12]. However, more clinical studies are needed combining clinical with PK assessment [13], as well as studies comparing colistin with polymyxin B, which has a longer half-life than colistin and might be safer. For other old antibiotics, no clinical studies assessing dosing regimens are available and these are needed if we are to adopt them for the treatment of severe infections. 4. Clinical evidence missing, available and accumulating The available evidence from contemporary randomised controlled trials (RCTs) and systematic reviews (published in the last decade) and the evidence we hope to have in the near future from ongoing RCTs is summarised in Table 2. It is clear that well-conducted

Please cite this article in press as: Hiba Zayyad, Noa Eliakim-Raz, Leonard Leibovici, Mical Paul, Revival of old antibiotics: needs, the state of evidence and expectations, International Journal of Antimicrobial Agents (2017), doi: 10.1016/j.ijantimicag.2016.11.021

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Table 2 Existing and accumulating evidence of old antibiotics for acute bacterial infections: randomised controlled trials (RCTs) and systematic reviews of RCTs published in the last decade, or ongoing RCTsa. Antibiotic

Study design

Results or ongoing studies

Systemic colistin/ polymyxin B vs. other antibiotics

RCTs

Small quasi-randomised trial comparing colistin vs. ampicillin/sulbactam for Acinetobacter baumannii VAP showed comparable safety and effectiveness [14] None

Polymyxin monotherapy vs. polymyxin-based combination therapy

Minocycline vs. other

Chloramphenicol vs. other

i.v. fosfomycin vs. other

Oral fosfomycin vs. no or other antibiotics

Systematic review of RCTs Ongoing RCTs RCTs

Systematic review of RCTs Ongoing RCTs RCTs Systematic review of RCTs Ongoing RCTs RCTs Systematic review of RCTs Ongoing RCTs RCTs Ongoing RCTs

Systematic review of RCTs RCTs

Systematic review of RCTs Ongoing RCTs

Mecillinam/ pivmecillinam vs. no or other antibiotics

Temocillin

Nitrofurantoin vs. no or other antibiotics

RCTs

Systematic review of RCTs Ongoing RCTs RCTs Systematic review of RCTs Ongoing RCTs RCTs

Systematic review of RCTs Ongoing RCTs

Colistin vs. meropenem as empirical treatment for VAP in high MDR-GNB prevalence hospitals—completed, not published [15] Colistin loading dose vs. no loading dose for CR-GNB infections among critically ill patients [16] Two RCTs evaluating colistin monotherapy vs. colistin/rifampicin combination therapy for A. baumannii—no difference in mortality or clinical failure, combination resulted in lower microbiological failure rates [17,18] Colistin vs. colistin plus fosfomycin for CRAB—no significant difference in mortality or clinical failure, combination resulted in lower microbiological failure rates [19] No benefit of combination therapy vs. monotherapy when analysis limited to RCTs [20] Two RCTs evaluating colistin monotherapy vs. colistin/meropenem combination therapy for invasive infections caused by CR-GNB [21,22] None None RCT evaluating oral minocycline plus rifampicin vs. linezolid for MRSA SSTIs [23] Chloramphenicol vs. ampicillin plus gentamicin for severe community-acquired pneumonia among children. Chloramphenicol inferior to comparator [24] Higher mortality with chloramphenicol vs. comparators in respiratory tract infections and meningitis, but similar for enteric fever. Evidence lacking on MDR bacteria [25] None See above under polymyxins, colistin + fosfomycin Fosfomycin vs. meropenem for bacteraemic UTI caused by ESBL-positive Escherichia coli [26] Daptomycin/fosfomycin combination vs. daptomycin alone for MRSA bacteraemia [27] Fosfomycin (ZTI-01) vs. TZP for complicated UTI and pyelonephritis [28] None Single-dose fosfomycin vs. 3-day ibuprofen for uncomplicated UTI in women. Large reduction in antibiotic use and significantly higher symptom burden with ibuprofen. No significant difference in pyelonephritis [29] Single-dose fosfomycin vs. 5-day ciprofloxacin for uncomplicated UTI in women. Similar effectiveness [30] Two-dose fosfomycin vs. 3-day ciprofloxacin for uncomplicated UTI among post-menopausal women. Similar effectiveness [31] Single-dose fosfomycin vs. 5-day amoxicillin/clavulanate or cefuroxime axetil for symptomatic cystitis among pregnant women. Similar effectiveness [32] Single-dose fosfomycin vs. 7-days amoxicillin/clavulanate for asymptomatic bacteriuria in pregnancy. Similar effectives and lower rate of secondary UTI with fosfomycin [33] Similar rate of clinical success, microbiological success, relapse and re-infection for fosfomycin vs. comparators [34] Single-dose fosfomycin vs. 5-day nitrofurantoin for uncomplicated UTI in women [35] Single-dose fosfomycin vs. 3-day SXT for acute cystitis among women [36] Single-dose fosfomycin vs. 7-day herbal drug for acute cystitis among women [37] Fosfomycin vs. nitrofurantoin for patients with complicated lower UTI [38] Different regimens of pivmecillinam vs. placebo for uncomplicated UTI among women. Pivmecillinam significantly more effective than placebo, with no significant different between different dosing regimens [39] Pivmecillinam vs. sulfamethizole for uncomplicated UTI among women. Similar effectiveness [40] None Mecillinam vs. ibuprofen for acute cystitis among women [41] 3-day vs. 5-day pivmecillinam for uncomplicated UTI among women [42] Temocillin 6 g daily as continuous infusion vs. every 8 h for critically ill patients with abdominal or pulmonary infections. Exposure better with continuous dosing [43] None None Nitrofurantoin vs. placebo for asymptomatic bacteriuria in pregnancy. No significant difference in the development of pyelonephritis or preterm birth [44] 1-day vs. 7-day nitrofurantoin for asymptomatic bacteriuria in pregnancy. Significantly higher microbiological failure rates and lower mean gestational age at delivery with the 1-day regimen [45] 5-day nitrofurantoin vs. 3-day SXT for uncomplicated UTI. Equivalent clinical and microbiological cure rates [46] Pilot study evaluation of 3-day nitrofurantoin vs. 3-day ciprofloxacin for acute cystitis in an emergency department. Similar clinical cure and adverse events [47] No difference between nitrofurantoin and comparators for uncomplicated UTI in clinical failure and adverse events. Slightly increase microbiological failure with nitrofurantoin [48] No difference between nitrofurantoin vs. SXT for uncomplicated UTI among women [49] See above, two RCTs on nitrofurantoin vs. fosfomycin [35,38] (continued on next page)

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Table 2 (continued) Antibiotic

Study design

Results or ongoing studies

Trimethoprim/ sulfamethoxazole (SXT) vs. no or other antibiotics

RCTs

Oral SXT vs. placebo for uncomplicated wound infections among emergency department patients treated as outpatients in a region endemic for community-acquired MRSA. Higher cure rates with SXT [50] Oral SXT vs. placebo for uncomplicated skin abscesses receiving drainage. Similar cure rates but fewer recurrences with SXT [51] 3-day vs. 10-day oral SXT for children with uncomplicated skin abscesses receiving drainage. Higher cure rates with 10 days of treatment for MRSA infections [52] Oral SXT vs. clindamycin for skin abscesses receiving drainage among emergency department patients treated as outpatients in a region endemic for community-acquired MRSA. Similar effectiveness [53] Oral SXT vs. clindamycin for uncomplicated skin infections among outpatients in a region endemic for community-acquired MRSA. Similar effectiveness [54] Small RCT comparing oral SXT vs. doxycycline for uncomplicated skin abscesses receiving drainage among outpatients in a region endemic for community-acquired MRSA [55] Oral SXT (two dosing regimens) vs. intramuscular benzathine benzylpenicillin for children with impetigo. Non-inferiority shown and once-daily SXT equivalent to twice-daily regimen [56] SXT/rifampicin vs. linezolid for various MRSA infections among adult inpatients. Non-inferiority shown [57] High-dose i.v. SXT vs. vancomycin for severe MRSA infections among inpatients. SXT did not achieve non-inferiority to vancomycin, the difference especially marked among bacteraemic patients [58] See above on SXT vs. nitrofurantoin [46] Oral SXT vs. ceftibuten for children with febrile UTI. Higher cure rates with ceftibuten, with similar microbiological cure [59] 3-day oral SXT vs. 5-day amoxicillin among children treated in the community for non-severe pneumonia in rural India. Similar effectiveness [60] SXT vs. quinolones, β-lactams and nitrofurantoin for uncomplicated UTI among women. Similar clinical cure rates [49]

Systematic review of RCTs Ongoing RCTs

Early switch from i.v. to oral antibiotics for S. aureus bacteraemia, with SXT first option for MRSA bacteraemia [61] See above on SXT vs. fosfomycin for acute cystitis among women [36]

VAP, ventilator-associated pneumonia; MDR, multidrug-resistant; GNB Gram-negative bacteria; CR, carbapenem-resistant; CRAB, carbapenem-resistant A. baumannii; MRSA, methicillin-resistant Staphylococcus aureus; SSTI, skin and soft tissue infection; i.v., intravenous; UTI, urinary tract infection; ESBL, extended-spectrum β-lactamase; TZP, piperacillin/tazobactam; SXT, trimethoprim/sulfamethoxazole. a The search included PubMed, The Cochrane Library, the National Institutes of Health (NIH) clinical trials registry and EUDRA-CT; excluding endemic infections (e.g. typhoid, malaria, melioidosis, rickettsial infections), sexually-transmitted diseases and prophylaxis.

RCTs are lacking, especially for hospitalised patients with severe infections. Observational studies assessing treatment regimens against MDR bacteria are problematic since selection bias is inherent to these comparisons. For example, studies that attempt to assess the effectiveness of colistin compared with modern β-lactams always compared patients with infections caused by carbapenem-resistant bacteria to patients with infections caused by β-lactam-susceptible bacteria, since polymyxins are reserved in clinical practice for the treatment of carbapenem-resistant bacteria. Adjusting for the differences between patients infected by drug-resistant and drug-susceptible bacteria is difficult to impossible. There are no RCTs to date informing us as to the efficacy of colistin versus no antibiotics, effectiveness versus other antibiotics, or effectiveness as monotherapy compared with combination therapy. Bias is unavoidable in observational studies comparing colistin monotherapy with colistin-based combination therapy. Nearly all of these studies performed to date claim an advantage to combination therapy. However, a systematic review showed that the quality of evidence of these studies was very low, allowing no confidence in the results [20]. Therefore, well-conducted RCTs addressing the patient population in need of these antibiotics and assessing patient-relevant outcomes are sorely needed. RCTs showed that oral fosfomycin and mecillinam are more effective than symptombased treatment for cystitis and that oral fosfomycin, nitrofurantoin and mecillinam are as effective as comparator antibiotics (Table 2). As for other antibiotics, 1-day nitrofurantoin was less effective than 3–7-day regimens for uncomplicated UTIs [62]. Single-dose fosfomycin was as effective as 7-day amoxicillin/clavulanate for the treatment of asymptomatic bacteriuria in pregnancy [33]. There is no evidence to date on the effectiveness of i.v. fosfomycin for systemic infections. RCTs suggest that chloramphenicol is less effective than comparator antibiotics for severe bacterial infections (such as pneumonia and meningitis), with the exception of typhoid fever [25]. Whether this is a drug-specific effect or reflects outcomes in general of antibiotics whose bacteriological activity is primarily bacteriostatic is unknown; however, a systematic review showed that overall bacteriostatic antibiotics are as effective as those that are bactericidal [63]. The efficacy and effectiveness of SXT have been established for

the treatment of skin infections and abscesses following drainage in locations endemic for MRSA (Table 2). But for severe MRSA infections, especially bacteraemia, SXT might not be as effective as vancomycin [58]. Few relatively large RCTs funded by the European commission, the National Institutes of Health (NIH) or national academic grants are ongoing (Table 2). There are several ongoing trials assessing the efficacy and effectiveness of nitrofurantoin, fosfomycin and mecillinam for uncomplicated UTIs. One trial is comparing minocycline/rifampicin versus linezolid for MRSA complicated SSTIs. Intravenous fosfomycin is currently being assessed versus meropenem and piperacillin/tazobactam for complicated UTIs and pyelonephritis in two RCTs, and its addition to daptomycin is being assessed for MRSA bacteria. Targeting CR-GNB, there are two ongoing RCTs comparing colistin monotherapy versus colistin + meropenem combination therapy for CR-GNB, and one trial assessing the effectiveness of colistin versus meropenem as empirical treatment for ventilator-associated pneumonia in CR-GNB-endemic hospitals. To our knowledge, no RCTs are currently ongoing to examine chloramphenicol, temocillin or the older aminoglycosides for the treatment of MDR bacteria. 5. Orchestrating the re-development of old antibiotics What should we mandate in the re-development process of an old antibiotic? First, we should decide that a drug is ‘worth’ redeveloping given what is known about its spectrum of coverage, its safety and based on the likelihood of resistance development [64]. Then, dosing and breakpoints need to be re-established, addressing the site of infection, severity of infection, protein binding, clearance and adjustments [6]. Finally, the clock should be set back and the efficacy and effectiveness of these antibiotics should be assessed. Summarising the experience to date with these drugs can probably replace phase 1 and 2 studies [65]. But appropriately conducted RCTs are needed. Trials should be designed for the new indications for which the antibiotic is needed, target the relevant MDR pathogens, and be compared versus the best available

Please cite this article in press as: Hiba Zayyad, Noa Eliakim-Raz, Leonard Leibovici, Mical Paul, Revival of old antibiotics: needs, the state of evidence and expectations, International Journal of Antimicrobial Agents (2017), doi: 10.1016/j.ijantimicag.2016.11.021

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treatment. Best available treatment should be based on judicious summary of the in vitro and clinical evidence. Trials should be pragmatic in terms of including patients who would be treated in real life. While drug approval trials frequently exclude patients previously treated with other antibiotics, pragmatic trials can be more flexible, mimicking real-life patient management. Daunting lists of exclusion criteria can be relinquished in studies assessing patients with CR-GNB infections in the hospital. These are patients dying from untreatable infections and regardless of the creatinine or liver function we treat them in clinical practice and we want to know which antibiotic is effective for them. A major exclusion criterion slowing patient recruitment into new antibiotic trials, e.g. the plazomicin trial [66], is the presence of a polymicrobial infection. Investigators should consider carefully whether and which polymicrobial infections introduce bias into the comparison. But as much as possible these patients should be included; adjustments to the treatment protocol can be made and such patients can be excluded for ‘cleaner’ comparisons at the end of the trial. No less important is the selection of an appropriate outcome. Regulatory agencies define endpoints for clinical trials that will qualify for drug registration. These endpoints can serve as a basis but are frequently irrelevant to the types of infections and patients we need to address in the revival of old antibiotics. Thus, investigators need to devise outcomes that are deemed patientrelevant for the trial. For severe infections among critically ill patients, survival should be always be evaluated. For infections in stable patients, the outcome should still be meaningful to the individual in the community or in the hospital, and not determined mainly by antibiotic modifications [67]. All trials should report on the safety of treatments, and the development of resistance needs to be addressed through active surveillance. Streamlining the informed consent process for old antibiotics compared with best available treatment can optimise patient recruitment, as suggested for similar comparative effectiveness research [68]. We witness the paradox of slow recruitment into antibiotic trials targeting CR-GNB but large cohorts being published in observational studies of old antibiotics. Obviously, some of these patients cannot provide informed consent and it is in the patients’ best interest to include them in RCTs rather than in observational studies from which we learn very little. 6. The future of old antibiotics There is no incentive for pharmaceutical companies/industry to invest in the re-development of old antibiotics. Studies of old antibiotics are based on public funding. A large number of academic clinical trials do not achieve their goals owing to limitations in design, slow patient recruitment, missing data and funding issues [69]. Hence, we need to raise awareness among governments and stakeholders to form collaborative groups with extensive knowledge and skills needed for the re-developing process, sharing new information based on recent studies, monitoring resistance development, and assuring access to old antibiotics thorough communication with pharmaceutical producers [70]. Using old antibiotics as last resort for some infections and without updated knowledge about pharmacokinetics/pharmacodynamics, dosing efficacy and safety, their use might cause harm to patients as well as enhance the development of resistance to these old antibiotics. Thus, re-developing old antibiotics in a co-ordinated process is critical. Funding: Part of this work was funded by the EU-project AIDA [grant Health-F3-2011-278348 to MP and LL] and by The Israeli Ministry of Science, Space and Technology [grant no. 3–12075 to MP and NE-R]. Competing interests: None declared. Ethical approval: Not required.

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Please cite this article in press as: Hiba Zayyad, Noa Eliakim-Raz, Leonard Leibovici, Mical Paul, Revival of old antibiotics: needs, the state of evidence and expectations, International Journal of Antimicrobial Agents (2017), doi: 10.1016/j.ijantimicag.2016.11.021