In December 2022, based on the assessment of new evidence, the World Health Organization (WHO) updated its guidelines for the treatment of drug-resistant tuberculosis (TB). The evaluation of both, these recommendations, and the latest study data, makes it necessary to update the existing guidelines on the treatment of at least rifampicin-resistant tuberculosis for the German-speaking region, hereby replacing the respective chapters. A shortened MDR-TB treatment of at least 6 month using the fixed and non-modifiable drug combination of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) is now also recommended for Germany, Austria, and Switzerland under certain conditions. This recommendation applies to TB cases with proven rifampicin resistance, including rifampicin monoresistance. For treatment of pre-extensively drug resistant TB (pre-XDR-TB), an individualized treatment for 18 months adjusted to resistance data continues to be the primary recommendation. The non-modifiable drug combination of bedaquiline, pretomanid, and linezolid (BPaL) may be used alternatively in pre-XDR TB if all prerequisites are met. The necessary prerequisites for the use of BPaLM and BPaL are presented in this amendment to the S2k guideline for \'Tuberculosis in adulthood\'.
Im Dezember 2022 hat die Weltgesundheitsorganisation (WHO) die Empfehlungen für die Behandlung der medikamentenresistenten Tuberkulose (TB) aktualisiert. Die Bewertung dieser Empfehlungen und der neuen Studiendaten macht auch für den deutschsprachigen Raum eine Aktualisierung der Leitlinienempfehlungen zur Therapie der mindestens Rifampicin-resistenten Tuberkulose notwendig, welche die entsprechenden Kapitel ersetzt. Auch für Deutschland, Österreich und die Schweiz wird nun eine verkürzte, mindestens 6-monatige MDR-TB-Therapie unter Einsatz der festgelegten und nicht veränderbaren Medikamentenkombination Bedaquilin, Pretomanid, Linezolid und Moxifloxacin (BPaLM) empfohlen, wenn alle hierfür notwendigen Voraussetzungen erfüllt sind. Diese Empfehlung gilt für TB-Fälle mit nachgewiesener Rifampicin-Resistenz einschließlich der Rifampicin-Monoresistenz. Zur Behandlung der präextensiven (prä-XDR) TB wird weiterhin in erster Linie eine individualisierte, an die Resistenzdaten angepasste Therapie über 18 Monate empfohlen. Die nicht veränderbare Medikamentenkombination Bedaquilin, Pretomanid und Linezolid (BPaL) kann bei prä-XDR alternativ angewendet werden, wenn alle Voraussetzungen dafür erfüllt sind. Die notwendigen Voraussetzungen für den Einsatz von BPaLM und BPaL werden in diesem Amendment zur S2k-Leitlinie „Tuberkulose im Erwachsenenalter“ begründet dargestellt.

New evidence and knowledge about the clinical management of drug-resistant tuberculosis (TB) in the last 3 years, makes it necessary to update the recent guideline published by SEPAR in 2017, mainly in relation to new diagnostic methods, drug classification, and regimens of treatment recommended to treat patients with isoniazid-resistance TB, rifampicin resistance TB and multidrug-resistant TB. With respect to tuberculosis diagnosis, we recommend the use of rapid molecular assays that also help to detect mutations associated with resistance. In relation to the treatment of multidrug-resistant TB we prioritize effective all-oral shorter treatment regimens including bedaquiline, a fluoroquinolone (levofloxacin or moxifloxacin), bedaquiline and linezolid, instead of the previously recommended short-course treatment with aminoglycosides and other less effective and more toxic drugs. The design of these regimens (initial schedule and changes in the regimen if necessary) should be made in accordance with drug-resistant TB experts; the treatment should be the responsibility of personnel with experience in the treatment of TB and in TB units guaranteeing the follow-up of the treatment and the management of drugs adverse effects.

The 2018 World Health Organization (WHO) treatment guidelines for multidrug-/rifampicin-resistant tuberculosis (MDR/RR-TB) give preference to all-oral long regimens lasting for 18-20 months. The guidelines strongly recommend combining bedaquiline, levofloxacin (or moxifloxacin) and linezolid, supplemented by cycloserine and/or clofazimine. The effectiveness of this combination in a long regimen has not been tested in any study to date, with corresponding uncertainty. The guidelines indicate that, ideally, all MDR-TB patients should have - as a minimum - the isolate tested for fluoroquinolones, bedaquiline and linezolid susceptibility before the start of treatment. Unfortunately, the capacity for drug susceptibility testing is insufficient in resource-limited settings. The risk of acquired bedaquiline resistance cannot be ignored, especially in patients with undetected resistance to fluoroquinolones. Both linezolid and cycloserine are known for their high frequency of serious adverse events. The combination of bedaquiline, moxifloxacin and clofazimine in the same regimen may excessively increase the QT interval. These expected adverse effects are difficult to monitor and manage in resource-limited settings, and may result in frequent modifications and a less effective regimen. The final STREAM results have confirmed the non-inferiority of the short regimen compared with the long regimen. Before evidence on the all-oral long and modified all-oral short treatment regimens is available, the WHO-recommended short MDR-TB regimens, with monitoring for ototoxicity, remain a better treatment option for the management of MDR/RR-TB patients who are eligible for short regimens in low- and middle-income countries. National tuberculosis programmes should also strengthen their capacity in the detection and management of fluoroquinolone-resistant MDR-TB following the WHO guidelines.

For effective antibacterial therapy, physicians require qualitative test results using susceptibility breakpoints provided by clinical microbiology laboratories. This article summarizes the key components used to establish the Clinical Laboratory Standards Institute (CLSI) breakpoints for tedizolid. First, in vitro studies using recent surveillance and clinical trial isolates ascertained minimal inhibitory concentration (MIC) distributions against pertinent organisms, including staphylococci, streptococci, and enterococci. Studies in animal models of infection determined rates of antibacterial efficacy and survival following administration of tedizolid phosphate at doses equivalent to those in humans. Pharmacokinetic and pharmacodynamic analyses examined the relationship between plasma concentrations and MICs against the target organism. Finally, clinical trials assessed clinical and microbiologic outcomes by MIC. All these data were evaluated and combined to obtain the ratified CLSI susceptibility criteria for tedizolid of ≤0.5μg/mL for Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Enterococcus faecalis and ≤0.25μg/mL for Streptococcus anginosus group.

BACKGROUND: Linezolid has been directly compared to vancomycin in pneumonia; however, most clinical trials have not compared outcomes specifically in the healthcare-associated pneumonia (HCAP) population. The objective of this study was to compare the effectiveness of vancomycin and linezolid in a national cohort of hospitalized veterans with HCAP.
METHODS: This was a retrospective cohort study of Veterans Health Administration patients admitted to >150 hospitals across the United States between 2002 and 2007. Patients were included if they were at least 65 years old, had an ICD-9-CM code for pneumonia, had one or more HCAP risk factors, and received guideline-concordant antibiotic therapy with linezolid or vancomycin within 48 h of admission. Critically ill patients were excluded. Multivariable logistic regression models and propensity scores were used to examine the association between linezolid or vancomycin therapy and 30-day mortality.
RESULTS: A total of 1211 patients met study criteria; 946 received vancomycin and 265 received linezolid. Thirty-day mortality was higher in patients treated with vancomycin (n = 243; 25.7 %) as compared to linezolid (n = 33; 12.5 %) (adjusted OR 2.56; 95 % CI 1.67-4.04). Vancomycin use (n = 945) was also predictive of 30-day mortality compared to linezolid use (n = 264) in the propensity score analysis (adjusted OR 2.55; 95 % CI 1.66-4.02).
CONCLUSIONS: Linezolid was associated with decreased patient mortality compared to vancomycin in a national cohort of non-critically ill, hospitalized veterans with HCAP.

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The accuracy of the published disk diffusion quality control (QC) range for linezolid for Staphylococcus aureus ATCC 25923 has been reported to be problematic, prompting a multicenter study to determine if revision was necessary. Five out of seven laboratories reported values outside the current QC range. Three participants had significant (13.3-60.0%) \'unacceptable\' results with zones smaller than the established range. Overall, a range of 21-32 mm was shown (82.4% within the NCCLS published range). A revision (25-31 mm; 95.7% of results) of the QC range is necessary when testing S. aureus ATCC 25923 against linezolid.

Quality control guidelines for standardized antimicrobial susceptibility test methods are critical to the continuing accuracy of the tests. In this report, quality control limits were proposed for 22 organism-antimicrobial combinations with minimum inhibitory concentration (MIC) ranges of three or four log2 dilution steps. Disk diffusion zone diameter ranges were proposed for azithromycin compared with Neisseria gonorrhoeae ATCC 49226 and ticarcillin with and without clavulanic acid tested against Staphylococcus aureus ATCC 25923. The data from five or six participating laboratories produced > or = 94.7% of results within proposed MIC limits, and 94.3%-99.0% of zones were found within suggested zone guidelines. These proposed quality control ranges should be validated by in-use results from clinical laboratories.