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.

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.

 

Reviving old antibiotics: Colistin terminology

Multidrug resistance is a growing health crisis and old antibiotics such as colistin  are being used increasingly as a last-line therapy against infections caused by Gram-negative bacteria that are resistant to other available antibiotics. Colistin was never developed according to current regulatory standards and regional differences in approved product characteristics and labeling is confounding the appropriate clinical use of colistin worldwide. A serious problem is the confusing terminology of describing the contents of parenteral vials and corresponding doses of the administered prodrug  colistin colistin methanesulfonate (CMS) that may lead to lethal dosing errors.

The experts of The Prato Polymyxin Consensus recently published a letter to the editor of Clinical Infectious Diseases that recommends a consistent global approach on reporting of colistin doses and labeling.

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.

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.

Our article on PK/PD for old antibiotics has been published

Drug Resist Updat. 2011 Mar 25. [Epub ahead of print]
Conserving antibiotics for the future: New ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective.
Mouton JW, Ambrose PG, Canton R, Drusano GL, Harbarth S, Macgowan A, Theuretzbacher U, Turnidge J.

Abstract

There is a growing need to optimize the use of old and new antibiotics to treat serious as well as less serious infections. The topic of how to use pharmacokinetic and pharmacodynamic (PK/PD) knowledge to conserve antibiotics for the future was elaborated on in a workshop of the conference (The conference “The Global Need for Effective Antibiotics – moving towards concerted action”, ReAct, Uppsala, Sweden, 2010). The optimization of dosing regimens is accomplished by choosing the dose and schedule that results in the antimicrobial exposure that will achieve the microbiological and clinical outcome desired while simultaneously suppressing emergence of resistance. PK/PD of antimicrobial agents describe how the therapeutic drug effect is dependent on the potency of a drug against a microorganism and the exposure (the concentration of antimicrobial available for effect over time). The description and modeling of these relationships quantitatively then allow for a rational approach to dose optimization and several strategies to that purpose are described. These strategies include not only the dosing regimen itself but also the duration of therapy, preventing collateral damage through inappropriate use and the application of PK/PD in drug development. Furthermore, PK/PD relationships of older antibiotics need to be urgently established. The need for global harmonization of breakpoints is also suggested and would add efficacy to antibiotic therapy. For each of the strategies, a number of priority actions are provided.