Global antibacterial resistance: The never-ending story

New resistance mechanisms evolve, resistant bacteria are spreading quickly in some parts of the world. The topic of resistance finds increasingly interest as physicians are confronted with infections caused by multi-drug resistant, extensively- drug resistant and even pan-drug resistant bacteria without any therapeutic option.

The new Journal of Global Antimicrobial Resistance focuses on the global spread of antibiotic-resistant microbes. It has received its first Impact Factor despite not being indexed yet by PubMed. My paper, published 2 years ago, is the most-cited paper from this new journal: Global antibacterial resistance: The never-ending story.

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

In memoriam Bill Craig

The PK/PD world has lost a leader and pioneer. Dr. William A. Craig has passed away Wednesday March 11, 2015. Bill Craig was instrumental in founding the International Society of Anti-InfectivePharmacology (ISAP). As current president of ISAP, I published an editorial in AAC with all past presidents and the president-elect of ISAP as coauthors. This orbituary has been recently published.

 

G7 summit June 2015

The leaders of the G7 agreed on concrete steps with regard to antimicrobial drug resistsance to respond to some of the most pressing issues in the world:

“Antimicrobials play a crucial role for the current and future success of human and veterinary medicine. We fully support the recently adopted WHO Global Action Plan on Antimicrobial Resistance. We will develop or review and effectively implement our national action plans and support other countries as they develop their own national action plans.

We are strongly committed to the One Health approach, encompassing all areas — human, and animal health as well as agriculture and the environment. We will foster the prudent use of antibiotics and will engage in stimulating basic research, research on epidemiology, infection prevention and control, and the development of new antibiotics, alternative therapies, vaccines and rapid point-of-care diagnostics. We commit to taking into account the annex (Joint Efforts to Combat Antimicrobial Resistance) as we develop or review and share our national action plans.”

Let’s hope that real action will follow the nice words.

Antibiotic research and development: business as usual?

My recent publication in the Journal of Antimicrobial Chemotherapy describes the problem of global resistance, the dry antibacterial R&D pipelines and the new IMI-funded, multistakeholder, €9.4 million DRIVE-AB (Driving Re-InVEstment in R&D and responsible AntiBiotic use) project with a consortium, composed of 14 public and 9 private partners from 12 countries.

New approved antibiotics

Which antibiotics has the FDA approved in the last year? Will they help combat antibiotic resistance?

In a blog published on the CDDEP website I give an overview of how the six new approvals will help treat resistant bacteria in certain patient populations. I summarise each antibiotic, give expert detail and context for these new drugs that have been in development for years and even decades. Though we will have six new antibiotics available based on known antibacterial drug classes or approaches, they will not provide a solution to the treatment of infections caused by extensively or pan drug-resistant bacteria.

COMBACTE-MAGNET launched

I am partner of the newly launched project COMBACTE-MAGNET. The European Innovative Medicines Initiative’s (IMI) program New Drugs for Bad Bugs (ND4BB) leads the efforts to  combat antibiotic resistance in Europe by tackling the scientific, regulatory, and business challenges that are hampering the development of new antibiotics. The 7 year, €167 million project will investigate a new approach to preventing respiratory infections in patients in intensive care units and new treatment options for patients with life-threatening infections caused by multi-drug resistant bacteria.

It will be exciting to be part of this important project that will perform clinical trials and describe the epidemiology of antibiotic resistance and healthcare associated infections.

DRIVE-AB launched

DRIVE-AB (Driving Reinvestment in R&D and Responsible Antibiotic Use), a public-private consortium funded by the EU Innovative Medicines Initiative (IMI), hold its inaugural meeting which announced the launch of a €9.3million project to tackle the dual crisis of antimicrobial resistance and re-stimulate Pharma interest in antibiotic research and development. We will develop new economic models to incentivise antibiotic discovery and development activities while safeguarding the efficacy of antibiotics by researching and advocating their appropriate use.

I am responsible for  communication, engagement of all involved stakeholder groups, and dissemination of results of this multinational project. My partners are the British Society of Antimicrobial Chemotherapy (BSAC) and the Chatham House (Royal Institute of International Affairs, London).

Progress on colistin

The European Medicines Agency recommended updating and harmonising the Summary of Product Characteristics of nationally approved colistin products throughout the EU to reflect what is currently known. The recommendations focus mainly on optimising dosing schedules but will also review the quality of the products and the way the potency of colistimethate sodium is measured and tested. Details here. This is a great success given the administrative challenges as the products have not been approved under the EU regulatory framework and knowledge is still evolving about how to use this drug.

In spring 2013 an expert conference in Prato summarised the current knowledge on polymyxin drugs and laid the ground for awareness and the need to update the information: The Lancet Infectious Diseases, 21 October 2014

R.L. Nation, J. Li, O. Cars, W. Couet, M.N. Dudley, K.S. Kaye, J.W. Mouton, D. L. Paterson, V. H. Tam, U. Theuretzbacher, B.T. Tsuji, J.D. Turnidge: Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus.