Revived old antibiotics: Nitrofurantoin

Bacterial resistance increases and old antibiotics are being revived to expand therapy options or ease the selection pressure for commonly used drugs. Nitrofurantoin was commercialized in an era predating requirements for robust methodology in drug development. Despite the drug’s resurgence and widespread consumption, uncertainties persist regarding PK/PD relationships, dosing, efficacy and toxicity. The re-developing process of a revived antibiotic in an academic setting starts with a systematic review to identify knowledge gaps and select the most important non-clinical and clinical studies.

The EU-funded AIDA project (FP7 HEALTH.2011.2.3.1-1—Preserving Old Antibiotics for the Future) is systematically “re-developing” some old antibiotics and includes vital PK, PD studies and PK/PD analysis as well as 3 randomized controlled clinical trials.

One of the studied drugs in nitrofurantoin for uncomplicated lower urinary tract infections caused by multi-drug resistant bacteria. The current body of clinical knowledge is unclear. For this reason we performed a structured, systematic review and meta-analysis of controlled clinical trials to evaluate nitrofurantoin’s efficacy and toxicity when given short term (≤14 days) for the treatment of UTI.

This study has just been published in the Journal of Antimicrobial Chemotherapy.

Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW: Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015 Jun 11.

OBJECTIVES: Nitrofurantoin’s use has increased exponentially since recent guidelines repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review and meta-analysis to assess nitrofurantoin’s efficacy and toxicity in the treatment of lower UTI.
METHODS: We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials.
RESULTS: Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89-0.97). If given for only 3 days, nitrofurantoin’s clinical efficacy was diminished (61%-70%). Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare.
CONCLUSIONS: When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.

Re-development of old antibiotics

In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents. Strategies are urgently needed to ‘re-develop’ these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigorously testing them according to today’s standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance.

The recently published paper REVIVING OLD ANTIBIOTICS describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections.

Theuretzbacher U, Van Bambeke F, Cantón R, Giske CG, Mouton JW, Nation RL, Paul M, Turnidge JD, Kahlmeter G: Reviving old antibiotics. J Antimicrob Chemother. 2015 Jun 10. pii: dkv157

Gram-negative R&D pipelines dry up

Gram-negative R&D pipelines dry up

GSK has pressed the “pause” button and halted collaboration on one of the few promising novel anti-Gram-negative compounds that had progressed beyond Phase 1. Here is yet another warning sign that antibacterial pipelines are under close scrutiny and may dry up quickly and completely.

My recent review article “Accelerating resistance, inadequate antibacterial drug pipelines and international responses” in the International Journal of Antimicrobial Agents details the critical health problem of growing multidrug resistance in the face of slim prospects for novel treatments. However there is hope, as the threat of untreatable infectious diseases has spurred national and international government responses. Read more in my new publication.

EU strategy to combat resistance

Concerned over the rapidly worsening global health care crisis caused by multi-drug resistant bacteria and the lack of robust drug pipelines, several multinational campaigns have issued policy recommendations and have initiated broad discussion with a goal of stimulating the development of novel antibacterial drugs and technologies. These activities have resulted in intensified cooperation between the US and the EU. The recently announced extensive “Action plan against the rising threats from antimicrobial resistance” substantially ramps up action within the EU. The European Commission decided on an unprecedented approach to drive the search for novel antibiotics by integrating the pharmaceutical industry, the research capacities of universities and small companies supported by public funding along with pricing/reimbursement and regulatory bodies. The European Commission has shown leadership and put action plans in place. Only the future will tell if these initiatives will help curb the impact of the multi-drug resistance pandemic.

Public Research should benefit Society

In an open letter sent today to the President and Members of the European Commission as well as the European Parliament and the EU Member states, 98 civil society and research organisations from across Europe warn that the Commission’s draft proposals for the next Research funding framework (2014-2020) fail to address the real challenges faced by European societies and call for a research agenda geared towards the needs of society and the environment rather than those of big business.

Our recent React meeting in Brussels to discuss the challenges in discovery and development of new antibiotics “Collaboration for Innovation – The Urgent Need for New Antibiotics”  provided strong input for the upcoming action plan from the EU commission. Among invited key stakeholders were representatives from the European Commission, the European Medicines Agency, the World Health Organization, academia, the pharmaceutical industry as well as several civil society organizations. Key issues discussed at the meeting were put in the perspective of the upcoming action plan from the EU commission and included the nature of the scientific challenges, possibilities for open source solutions, and the need for a new business logic for antibiotic discovery and development where the return of investment is decoupled from sales to the extent possible.

We hope that our ideas and analysis will find their way into the next Research funding framework (2014-2020).

European Commissions’ FP7 call

The EU’s 2012 FP7 call places a strong emphasis on the participation of small and medium enterprises (SMEs). To put it plainly, the FP7 selection criteria favor or require projects that incorporate SME providers.  Another area where FP7 extends previous expectations regards the dissemination and communication of project results. Recognizing the importance of effective communication of the project results, the FP7 selection criteria look for a well-developed dissemination plan.

I partly bring these FP7 areas of emphasis to your attention because as both a scientific dissemination expert and a small enterprise, I offer high value with my participation as a WP leader. In conjunction with an experienced consortium of European researchers, my experience with dissemination and communication in the field of infectious diseases creates a strong and proven element in a successful proposal.

A few examples of new topics related to my interests and abilities:

FP7-HEALTH-2012-INNOVATION-1,2 (September/October 2011)

  • HEALTH.2012.2.2.2.-2: Investigator-driven clinical trials for optimisation of management of elderly patients with multiple diseases.
  • HEALTH.2012.2.3.0-1: Diagnostics for infectious diseases in humans.
  • HEALTH.2012.2.3.0-2: ERA-NET on infectious diseases.

Topics for the IMI 4th call for  proposals (mid-June 2011):

EU Medical Information System

  • Building up a European Medical Information Framework to improve healthcare and facilitate research
  • eTRIKS: European Translational Research Infrastructure & Knowledge Management Services