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The emergence of MDR-TB and XDR-TB has complicated TB treatment success. Among many factors that contribute to the development of resistance, low drug exposure is not the least important. This review summarizes the available information on pharmacokinetic properties of levofloxacin in relation to microbial susceptibilities, in order to optimize the dose and make general treatment recommendations. A total of 37 studies on adult (32 studies) and paediatric (5 studies) MDR-TB patients were included. Among the 32 adult studies, 19 were on susceptibility of Mycobacterium tuberculosis isolates to levofloxacin by MIC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by MBC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by mutant prevention concentration and 4 were on pharmacokinetics of levofloxacin, and 7 others were included. Likewise, out of five studies on children, two dealt with levofloxacin pharmacokinetic parameters, one reviewed CSF concentrations and two dealt with background information. In adult MDR-TB patients, standard dosing of once-daily 1000 mg levofloxacin in TB treatment did not consistently attain the target concentration (i.e. fAUC/MIC >100 and fAUC/MBC >100) in 80% of the patients with MIC and MBC of 1 mg/L, leaving them at risk of developing drug resistance. However, with an MIC of 0.5 mg/L, 100% of the patients achieved the target concentration. Similarly, paediatric patients failed consistently in achieving given pharmacokinetic/pharmacodynamic targets due to age-related differences, demanding a shift towards once daily dosing of 15-20 mg/kg. Therefore, we recommend therapeutic drug monitoring for patients with strains having MICs of ≥0.5 mg/L and suggest revising the cut-off value from 2 to 1 mg/L., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Few innovative anti-microbial products have been brought to market in recent years to combat the global multidrug resistant-tuberculosis (MDR-TB) epidemic. Bedaquiline, a novel oral diarylquinoline, was approved by the US FDA as a part of combination therapy in adults with pulmonary MDR-TB based on phase II trials., Area Covered: Pubmed searches were conducted using search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included World Health Organization, Clinicaltrial.gov, US Food and Drug Administration. Bedaquiline is an ATP synthase inhibitor specific for M. tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4 and it's drug exposure can be influenced by inducers and inhibitors of this enzyme. Phase II studies showed promising results on efficacy of bedaquiline when being used in combination with a background regimen for MDR-TB. Main safety concerns include QTc prolongation and hepatotoxicity. Phase III trials are ongoing to confirm efficacy findings from phase II studies and provide additional evidence of safety and efficacy. Expert commentary: Critical data for long-term efficacy and safety are incomplete and scarce, supporting the cautious use of bedaquiline.

For treatment of multidrug-resistant tuberculosis (MDR-TB), there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for TB-HIV-coinfected patients. However, only limited data are available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate the PK parameters and in vitro PD data on the effective part of co-trimoxazole: sulfamethoxazole. In a prospective PK study in patients infected with drug-susceptible Mycobacterium tuberculosis (drug-susceptible TB patients) (age, >18), sulfamethoxazole-trimethoprim (SXT) was administered orally at a dose of 960 mg once daily. One-compartment population pharmacokinetic modeling was performed using MW\Pharm 3.81 (Mediware, Groningen, The Netherlands). The area under the concentration-time curve for the free, unbound fraction of a drug (ƒAUC)/MIC ratio and the period in which the free concentration exceeded the MIC (fT > MIC) were calculated. Twelve patients received 960 mg co-trimoxazole in addition to first-line drugs. The pharmacokinetic parameters of the population model were as follows (geometric mean ± standard deviation [SD]): metabolic clearance (CLm), 1.57 ± 3.71 liters/h; volume of distribution (V), 0.30 ± 0.05 liters · kg lean body mass(-1); drug clearance/creatinine clearance ratio (fr), 0.02 ± 0.13; gamma distribution rate constant (ktr_po), 2.18 ± 1.14; gamma distribution shape factor (n_po), 2.15 ± 0.39. The free fraction of sulfamethoxazole was 0.3, but ranged between 0.2 and 0.4. The median value of the MICs was 9.5 mg/liter (interquartile range [IQR], 4.75 to 9.5), and that of theƒAUC/MIC ratio was 14.3 (IQR, 13.0 to 17.5). The percentage of ƒT > MIC ranged between 43 and 100% of the dosing interval. The PK and PD data from this study are useful to explore a future dosing regimen of co-trimoxazole for MDR-TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01832987.)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, p<0.0001) and higher XDR-TB prevalence (67.9% versus 49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60-428) versus 85 (49-156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7% versus 94.8%, p=0.02 and 71.9% versus 94.8%, p<0.0001, respectively) and on success rates (59.7% versus 77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients., (Copyright ©ERS 2016.)

Introduction: The current refugee crisis emphasizes the need for information on infectious diseases and resistant microorganisms in asylum seekers with possible consequences for public health and infection control., Methods: We collected data from asylum seekers admitted to our university hospital or who presented at the Emergency Department (n = 273). We collected general and demographic characteristics including country of origin, the reason of presentation, and the screening results of multi-drug resistant organisms., Results: 67% of the patients were male with a median age of the study group of 24 years (IQR 15-33); 48% of the patients had an infectious disease-predominantly malaria with P. vivax or tuberculosis. Patients also reported with diseases which are less common-e.g. leishmaniasis, or even conditions rarely diagnosed in Europe-e.g. louse borne relapsing fever. A carriage rate of 31% for multi-drug resistant microorganisms (MDRO) was observed, with ESBL-expressing E.coli (n = 20) being the most common MDRO. No carriage of Carbapenemase Producing Enterobacteriaceae was found., Conclusion: The current refugee crisis in Europe challenges hospitals to quickly identify and respond to communicable diseases and the carriage of MDRO. A rapid response is necessary to optimize the treatment of infectious diseases amongst asylum seekers to maximize infection control.

Treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is becoming more challenging because of increased levels of drug resistance against second-line TB drugs. One promising group of antimicrobial drugs is carbapenems. Ertapenem is an attractive carbapenem for the treatment of MDR- and XDR-TB because its relatively long half-life enables once-daily dosing.A retrospective study was performed for all patients with suspected MDR-TB at the Tuberculosis Center Beatrixoord of the University Medical Center Groningen (Haren, the Netherlands) who received ertapenem as part of their treatment regimen between December 1, 2010 and March 1, 2013. Safety and pharmacokinetics were evaluated.18 patients were treated with 1000 mg ertapenem for a mean (range) of 77 (5-210) days. Sputum smear and culture were converted in all patients. Drug exposure was evaluated in 12 patients. The mean (range) area under the concentration-time curve up to 24 h was 544.9 (309-1130) h·mg·L(-1) The mean (range) maximum observed plasma concentration was 127.5 (73.9-277.9) mg·L(-1)In general, ertapenem treatment was well tolerated during MDR-TB treatment and showed a favourable pharmacokinetic/pharmacodynamic profile in MDR-TB patients. We conclude that ertapenem is a highly promising drug for the treatment of MDR-TB that warrants further investigation., (Copyright ©ERS 2016.)

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6-9)versus 5 (4-6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49-156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases., (Copyright ©ERS 2016.)

Rationale: Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics., Objectives: To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose., Methods: Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation., Results and Discussion: Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways-i.e., at the site of infection., Conclusions: In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population.

Treatment of mycobacterial diseases such as tuberculosis (TB) entails long and intense antimicrobial therapy. TB patients are at risk of coinfection with other multidrug-resistant bacteria, such as those from Enterobacteriaceae family, because of antimicrobial selection pressure and nosocomial transmission during prolonged hospital admission. Here, we report on two patients treated for multidrug-resistant TB, who developed severe sepsis due to an extended spectrum β-lactamase producing organism. Diagnostic culture identified the venous access port as source, and upon surgical removal and antimicrobial therapy rapid clinical improvement was achieved. Increased awareness and knowledge on the prevalence of multi-resistant Enterobacteriaceae is needed, notably in TB centers, to provide a safe hospital environment to our patients., (© The American Society of Tropical Medicine and Hygiene.)

A 29-year-old pregnant woman from Syria was screened for tuberculosis upon arrival in the Netherlands. The chest X-ray showed a smooth sharply demarcated mass in her left upper lobe. A low-dose CT showed that the mass was lobulated and surrounded by a hyperlucent pulmonary segment. To protect the foetus from further exposure to radiation, an MRI was performed, which confirmed bronchial atresia with a mucocele of the distal bronchus.

Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration-time curve (AUC0-24h) was 77.2 mg h/L [interquartile range (IQR) 64.7-96.2 mg h/L] for amikacin and 64.1 mg h/L (IQR 55.6-92.1 mg h/L) for kanamycin. The PPK model was developed and validated using n-1 cross-validation. A robust population model was developed that is suitable for predicting the AUC0-24h of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0-24h in phase 3 studies., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen., (Copyright ©ERS 2015.)

Patients infected with pathogenic bacteria have to be treated with antibiotics. When the infection is in the lungs, as for instance in cystic fibrosis, bronchiectasis and tuberculosis, inhaled antibiotics have certain advantages over systemically administered antibiotics. In this study, it is shown that re-designing the Twincer™ high dose disposable inhaler into a device named Cyclops enables effective dispersion of up to 50mg of pure spray dried tobramycin. This proves that spray dried tobramycin powders in the preferred size range for inhalation can be administered without applying complex particle engineering techniques and/or using excipients. Only some coarse sweeper crystals added separately are desired to minimise the inhaler losses to less than 20% at 4 kPa. The fine particle fractions <5 μm of the aerosol obtained from the Cyclops closely resemble the primary particle size distribution of the spray dried tobramycin powder. Moreover, without any further optimisation the Cyclops performs good with other spray dried aminoglycosides such as kanamycin and amikacin too. Therefore, the results of this study show that with an appropriate inhaler design, adapted to the physico-chemical properties of a particular drug or drug class, excellent dispersion can be achieved for high doses of pure (spray dried) drug., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Respiratory tract infections are among the most common infections in men. We reviewed literature to document their pharmacological treatments, and the extent to which therapeutic drug monitoring (TDM) is needed during treatment. We subsequently examined potential use of dried blood spots as sample procedure for TDM. TDM was found to be an important component of clinical care for many (but not all) pulmonary infections. For gentamicin, linezolid, voriconazole and posaconazole dried blood spot methods and their use in TDM were already evident in literature. For glycopeptides, β-lactam antibiotics and fluoroquinolones it was determined that development of a dried blood spot (DBS) method could be useful. This review identifies specific antibiotics for which development of DBS methods could support the optimization of treatment of pulmonary infections.

The incidence of tuberculosis in the Netherlands has dropped dramatically over the past 50 years. With declining experience of tuberculosis, misdiagnosis can easily happen. Laryngeal tuberculosis often presents as a tumorous mass that may initially be mistaken for cancer. As laryngeal tuberculosis is usually highly infectious, this poses a risk to the patient as well as his/her contacts including healthcare providers. We describe three patients with (suspected) laryngeal tuberculosis and discuss potential pitfalls. Pivotal for a correct diagnosis are thorough history-taking, physical examination and relatively simple radiological and laboratory tests. Risk groups have been identified for tuberculosis and this can provide a clue. Differentiation between tuberculosis and cancer can be difficult, and the two diseases may concur. Even in low-incidence settings for tuberculosis, knowledge of the disease remains necessary as it is curable and further spread can be prevented with simple measures.

Variable-number tandem-repeat (VNTR) typing with a panel of 24 loci is the current gold standard in the molecular typing of Mycobacterium tuberculosis complex isolates. However, because of technical problems, a part of the loci often cannot be amplified by multiplex PCRs. Therefore, a considerable number of single-locus PCRs have to be performed for the loci with missing results, which impairs the laboratory work flow. Therefore, the original in-house method described by Supply et al. in 2006 was reevaluated. We modified seven primers and the PCR master mixture and obtained a strongly optimized in-house 24-locus VNTR typing method. The percentage of instantly complete 24-locus VNTR patterns detected in the routine flow of typing activities increased to 84.7% from the 72.3% obtained with the typing conducted with the commercially available Genoscreen MIRU-VNTR typing kit. The analytical sensitivity of the optimized in-house method was assessed by serial dilutions of M. tuberculosis in bronchoalveolar lavage fluid. A 1:10 dilution of the different strains tested was the lowest dilution for the detection of a complete 24-locus VNTR pattern. The optimized in-house 24-locus VNTR typing method will reduce the turnaround time of typing significantly and also the financial burden of these activities.

An animal keeper was diagnosed with pulmonary tuberculosis (TB) after bi-annual screening for latent TB infection in zoo employees. In the same period, several bonobos of the zoo were suffering from TB as well. The Mycobacterium tuberculosis strains from both the animal keeper and the bonobos appeared identical. We provide evidence that the animals infected their keeper.

We compared 14 molecular assays for their ability to detect the Mycobacterium tuberculosis complex in bronchoalveolar lavage fluid samples. Three approaches were followed. First, by using DNA from Mycobacterium bovis BCG, we determined the detection limits of the assays using routine molecular methods. Second, in order to determine the analytical sensitivities of the assays, we added one of four M. tuberculosis isolates with various numbers of the insertion sequence IS6110 to N-acetyl-l-cysteine (NALC)-NaOH-treated bronchoalveolar lavage fluid samples in dilutions of 1:10 to 1:10,000,000. Third, intertest variabilities were measured and defined by the standard deviations for the quantitation cycle (Cq) values of three positive test results per dilution per assay. The 14 assays tested had similar analytical sensitivities, except for GeneXpert, which had an analytical sensitivity that was 10- to 100-fold lower than that of the other assays. The MP MTB/NTM test and the in-house TaqMan-10 revealed the best performances for the detection limit and had the highest analytical sensitivities. Most of the tests performed well regarding detection limit and analytical sensitivity for the detection of the M. tuberculosis complex in serial dilutions, and the differences were small. The MP MTB/NTM and the in-house TaqMan-10 assays revealed the best, and GeneXpert the worst, overall performances.