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.


Bedside Dosing

Since the introduction of antibacterial drugs, dosing concepts have evolved considerably. Distinct refinements of dosing strategy have been incorporated into practice over time to deal more effectively with different patient groups and to retain the utility of particular drugs. In recent years, individualized dosing in critically ill patients based on software programs that calculate individual PK factors and required doses proved to be an essential part of the antibacterial treatment strategy.

We recently published a review on individualised dosing for critically ill patients in Lancet Infectious Diseases. In this review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients.

Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions

Jason A Roberts, Mohd H Abdul-Aziz, Jeff rey Lipman, Johan W Mouton, Alexander A Vinks, Timothy W Felton, William W Hope, Andras Farkas, Michael N Neely, Jerome J Schentag, George Drusano, Otto R Frey, Ursula Theuretzbacher, Joseph L Kuti, on behalf of The International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases

Reviving old antibiotics: Colistin SPCs

Colistin is arguably the first case in the antibacterial field where substantial “re-development” activities have been driven by academic and clinical investigators, rather than a sponsoring company. As a result of these activities, there is rapidly evolving new non-clinical and clinical knowledge on colistin. My recently published study investigated the variation and accuracy of information in the summary of product characteristics (SPCs) of intravenous colistin products approved in the European Union. This study highlights the challenges of integrating new rapidly evolving scientific knowledge into approved SPCs in Europe.

More information on regulatory issues of colistin:

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

The new book on antimicrobial pharmacokinetics and pharmacodynamics has just been published. Editors: A.V. Vinks, H. Derendorf, JW Mouton. ISBN: 978-0-387-75612-7 (Print) 978-0-387-75613-4 (Online)

It describes the basic concepts and prinicples as well as clinical aspects of PK/PD. I contributed the chapter of PK/PD of oxazolidinones with linezolid as the first drug of this group but more to come.


1st international polymyxin conference

As a member of the organizing committee I would like to invite you to attend the first international polymyxin conference that is held in beautiful Prato, Italy, on 2 – 4 May, 2013, to learn of the latest findings on the polymyxin antibiotics.

Colistin and polymyxin B became available in the clinic in the 1950s but soon fell out of favor, mainly due to concerns about their potential to cause kidney toxicity. They have now come back into use as ‘last line’ antibiotics for the treatment of infections caused by Gram-negative pathogens that are resistant to other available antibiotics. During the first several decades after they began to be used, there was little information on how to use them most effectively. Over the last several years, substantial progress has been made in understanding how to optimize their clinical use.

Early bird registrations close on December 7, 2012 and spaces at this opinion leader conference are strictly limited.

ISAP symposium

International Society for Anti-Infective Pharmacology (ISAP)

This year’s ISAP post ICAAC Symposium will take place on Wednesday, September 12th, 2-6 pm.

Location: San Francisco, Fort Mason Center, Marina Blvd & Buchanan St, Golden Gate Room

As in previous years, the symposium has two segments:

1. Main topic: Jason Roberts: Translational aspects of PK/PD tools for personalized dosing in the ICU. The presentation is followed by some prepared comments regarding online PK/PD tools to support dosing decisions as well as a lively discussion.

2. Forum for Young Investigators: Brief presentations on PK/PD topics related to old and new anti-infectives.
Young Investigators – this is an unique opportunity for insightful and motivating feedback regarding your research!

During the ICAAC, ISAP organizes four workshops as well as several symposia dedicated to PK/PD.

Anti-Infectives: Special issue in Current Opinion in Pharmacology

The special issue on anti-infectives in Current Opinion in Pharmacology has been recently published. Together with my colleague J. Mouton I developed the concept of this issue that focuses on the global resistance problem and includes important aspects of resistance, from R&D of  novel antibiotics to improved usage of existing antibacterial as well as antifungal drugs to minimize the emergence of resistance.

Our Editorial Overview concludes:

For decades clinicians have overused antibiotics and thus exploited apparently exhaustible resources. Abuse in livestock, agriculture, aquaculture, consumer industry, as well as persistence of antibacterial drugs in the environment all contribute to high selection pressure on bacteria including, of course, pathogenic ones. Nearly dry antibacterial and antifungal R&D pipelines will fall short of addressing currently untreatable infections caused by MDR bacteria and fungi. That meticulous infection control, consistent stewardship programs, and restrictive usage in all fields can and do work is beyond dispute. To drive antibacterial drug R&D forward and to improve clinical practice, we must effectively use recently gained insights into the mechanisms of emergence, into the spread of resistance and into drug exposure-resistance relationships. We have much to lose if we do not work in concert. All members of society and, most critically, stakeholders including researchers, clinicians, drug developers, health care managers, regulatory agencies, policy makers and, yes, patients must collaborate in sustainably managing our critically limited and invaluably precious cache of antibacterial and antifungal drugs.

Antibacterial Distribution and Drug–Drug Interactions in Cancer Patients

I am always surprised again how variable and unpredictable pharmacokinetic parameters of antibacterial drugs in severely ill cancer patients are.  With approved antibacterial drug dosages the probability of attaining the required drug exposure and PK/PD target is quite low. In other words, the risk for the individual patient to be insufficiently treated is very high. Though strategies for optimized dosage regimens exist the only way of improving results is applying individualized dosing regimens based on therapeutic drug monitoring.

In collaboration with my colleague Markus Zeitlinger (University of Vienna) I reviewed the topic “Antibacterial Distribution and Drug–Drug Interactions in Cancer Patients”. The book chapter of  the renowned text book series Principles and Practice of Cancer Infectious Diseases has just been published.