A four-drug standardized short regimen for highly resistant TB in South-West Nigeria.

BACKGROUND: Patients with TB resistant to rifampicin (Rr-TB), and those with additional resistance to fluoroquinolones (pre-XDR-TB), should be treated with bedaquiline-pretomanid-linezolid-moxifloxacin and bedaquiline-pretomanid-linezolid, respectively. However, pretomanid is not yet widely available. METHODS: This is a pragmatic prospective single-arm study investigating the efficacy and safety of 9 mo of bedaquiline-delamanid-linezolid-clofazimine in patients with pre-XDR-TB or Rr-TB unresponsive to Rr-TB treatment in Nigeria. RESULTS: From January 2020 to June 2022, 14 of 20 patients (70%) successfully completed treatment, five died and one was lost-to-follow-up. No one experienced a treatment-emergent grade three/four event. Treatment success was higher compared with global pre-XDR-TB treatment outcomes. CONCLUSIONS: While pretomanid is unavailable, highly resistant TB can be treated with bedaquiline-delamanid-linezolid-clofazimine.

Tratamiento de la tuberculosis drogorresistente en adultos y niños. Revisión narrativa / Treatment of drug-resistant tuberculosis in adults and children. A narrative review

Resumen Desde 2018 han surgido a la luz de la evidencia importantes cambios en el tratamiento de la tuberculosis drogorresistente. El descubrimiento de nuevas drogas antituberculosis, como la bedaquilina y los derivados de nitroimidazopiranos, así como la utilización de drogas repropuestas, llevó a la recomendación de organismos internacionales de nuevos esquemas de tratamiento de la tuberculosis monorresistente y multidro gorresistente que son totalmente orales y así dejan de lado el uso prolongado de inyectables, con su inherente toxicidad e incomodidad. Algunas de las definiciones de tuberculosis drogorresistente han cambiado. También está en revisión el tiempo de su tratamiento y con algunos nuevos esquemas en estudio, como el BpaL (bedaquilina, pretomanid y linezolid), se ha logrado una duración similar a la del tratamiento de la tuberculosis pansensible. En esta revisión bibliográfica narrativa describimos las nuevas definiciones, algunos aspectos diagnósticos básicos, los aspectos farmacológicos y la nueva clasificación de las drogas a utilizar en el tratamiento de la tuberculosis drogorresistente, así como los esquemas actualmente propuestos para tratarla, contextualizados con la realidad nacional. Finalizamos con una breve reseña de los estudios clínicos en curso de nuevos esquemas acortados de tratamiento.

Abstract Since 2018, important changes in the treatment of drug-resistant tuberculosis have been produced in the light of new evidence. The discovery of new anti-tuberculosis drugs, such as bedaquiline and nitroimidazopirane derivatives, as well as the use of repurposed drugs, led to international organizations to recommend new, totally oral, treatment regimens for mono-resistant and multidrug-resistant tuberculosis, leaving aside the prolonged use of injectables, with their inherent toxicity and discomfort. Some definitions of drug-resistant tuberculosis have changed. The duration of treatment is also under review, leading some new regimens under study, such as BPaL (bedaquiline, pretomanid and linezolid), to a duration similar to that for treating susceptible tuberculosis. In this narrative review, we describe the new definitions, some basic diagnostic aspects, the pharmacological aspects, and the new classification of drugs to be used in the treatment of drug-resistant tuberculosis as well as the cur rently proposed schemes to treat it available within the Argentinean context. Finally, we include a brief review of ongoing clinical trials on new shortened treatments.

[Treatment of drug-resistant tuberculosis in adults and children. A narrative review]. / Tratamiento de la tuberculosis drogorresistente en adultos y niños. Revisión narrativa.

Since 2018, important changes in the treatment of drug-resistant tuberculosis have been produced in the light of new evidence. The discovery of new anti-tuberculosis drugs, such as bedaquiline and nitroimidazopirane derivatives, as well as the use of repurposed drugs, led to international organizations to recommend new, totally oral, treatment regimens for mono-resistant and multidrug-resistant tuberculosis, leaving aside the prolonged use of injectables, with their inherent toxicity and discomfort. Some definitions of drug-resistant tuberculosis have changed. The duration of treatment is also under review, leading some new regimens under study, such as BPaL (bedaquiline, pretomanid and linezolid), to a duration similar to that for treating susceptible tuberculosis. In this narrative review, we describe the new definitions, some basic diagnostic aspects, the pharmacological aspects, and the new classification of drugs to be used in the treatment of drug-resistant tuberculosis as well as the currently proposed schemes to treat it available within the Argentinean context. Finally, we include a brief review of ongoing clinical trials on new shortened treatments.

Desde 2018 han surgido a la luz de la evidencia importantes cambios en el tratamiento de la tuberculosis drogorresistente. El descubrimiento de nuevas drogas antituberculosis, como la bedaquilina y los derivados de nitroimidazopiranos, así como la utilización de drogas repropuestas, llevó a la recomendación de organismos internacionales de nuevos esquemas de tratamiento de la tuberculosis monorresistente y multidrogorresistente que son totalmente orales y así dejan de lado el uso prolongado de inyectables, con su inherente toxicidad e incomodidad. Algunas de las definiciones de tuberculosis drogorresistente han cambiado. También está en revisión el tiempo de su tratamiento y con algunos nuevos esquemas en estudio, como el BpaL (bedaquilina, pretomanid y linezolid), se ha logrado una duración similar a la del tratamiento de la tuberculosis pansensible. En esta revisión bibliográfica narrativa describimos las nuevas definiciones, algunos aspectos diagnósticos básicos, los aspectos farmacológicos y la nueva clasificación de las drogas a utilizar en el tratamiento de la tuberculosis drogorresistente, así como los esquemas actualmente propuestos para tratarla, contextualizados con la realidad nacional. Finalizamos con una breve reseña de los estudios clínicos en curso de nuevos esquemas acortados de tratamiento.

[Establishment of recombinase polymerase amplification assay for drug resistance gene bla_(NDM) coding metallo-beta-lactamase].

OBJECTIVE: To establish a recombinase polymerase amplification(RPA) method for extensively resistant pathogen screening and rapid detection in the field for rapid amplification of the metallo-beta-lactamase gene bla_(NDM). METHODS: Specific conservative sequence had been selected as target genes by sequence comparative analysis. The primers and probes for RPA assays were designed according to the principle of RPA amplification requirements. A descending gradient diluted template genes were used for RPA detection to determine the sensitivity. Reference templates of other resistant types of bacteria were used to analysis the specificity of amplification reaction systems. The amplification reaction systems were also conducted repeatedly for verifying the repeatability. RESULTS: Three of the RPA reaction systems could effectively amplify the target genes, the sensitivities reach 2×10~2 copies. No one cross reaction existed with the other drug-resistant bacteria DNA. All the reactions can be completed between two to seven minutes. CONCLUSION: The RPA assays of the metallo-beta-lactamase gene bla_(NDM) are established, which may amply target genes fast and have a lower detection limit, and be potentially useful for in field pathogens detection.

In vitro activity of ceftazidime-avibactam combined with colistin against extensively drug-resistant Pseudomonas aeruginosa / 中华危重病急救医学

Objective@#To evaluate the in vitro activity of ceftazidime-avibactam (CAZ-AVI) alone or in combination with colistin (COL) against clinically isolated extensively drug-resistant Pseudomonas aeruginosa (XDR-PA).@*Methods@#Minimum inhibitory concentration (MIC) of 16 clinical XDR-PA isolates was determined by broth dilution method and chessboard design when CAZ-AVI and COL were used alone or in combination, then the combined inhibitory concentration index (FICI) was calculated. Class A [Klebsiella pneumoniae carbapenemase β-lactamase (blaKPC), Guiana extended-spectrum β-lactamase (blaGES)], Class B [imipenemase β-lactamase (blaIMP), Verona-Integronmetallo β-lactamase (blaVIM), New Delhi metallo β-lactamase (blaNDM), German imipenemase β-lactamase (blaGIM), Sao Paulo metallo -β- lactamase (blaSPM)], Class C [AmpC β-lactamase (blaAmpC)], Class D [oxacillinase β-lactamase (blaOXA)] β- lactamase-related resistance genes were detected by polymerase chain reaction. Drug-resistant mutation frequencies of each strain were determined on a drug-containing plate. The time kill curves of three XDR-PA were plotted by colony counting method. A biofilm model was established in vitro, and the synergistic effect of CAZ-AVI and COL on biofilm inhibition was detected by methythiazolyl tetrazolium assay (MTT).@*Results@#The MICs of 16 XDR-PA for CAZ-AVI ranged from 1 mg/L to 128 mg/L, and three of the isolates showed resistance (MIC > 8 mg/L). The FICI range of CAZ-AVI combined with COL was 0.312-1.000. Four isolates were synergistic, while the other 12 isolates were additive. Three isolates resistant to CAZ-AVI contained Class B resistance genes such as blaIMP and blaVIM, while 13 susceptible isolates carried resistance genes belonging to Class A, C or D. The logarithm values of mutation frequencies of drug resistance in CAZ-AVI group, COL group and combination group were -4.81±0.88, -7.06±0.69 and -9.70 (-9.78, -9.53), respectively. There were significant differences among the three groups (H = 33.601, P < 0.001), and between every two groups (adjusted P < 0.05). In time kill curves, the phytoplankton load of three XDR-PA decreased more than 6 log CFU/L when these two drugs were used together, and number of PA1819 planktonic bacteria decreased more than 5.1 log CFU/L compared with monotherapy group. Viable quantity in biofilm (A490) of normal saline group, CAZ-AVI group, COL group and CAZ-AVI-COL group were 0.665±0.068, 0.540±0.072, 0.494±0.642 and 0.317±0.080, respectively. There was significant difference between the other two groups (all P < 0.001), except for that between CAZ-AVI group and COL group (P = 0.109).@*Conclusions@#CAZ-AVI combined with COL can effectively improve the bactericidal effect of each drug alone on XDR-PA. The regimen can also reduce the production of drug-resistant bacteria and inhibit the formation of biofilm. Therefore, it is a potential treatment for XDR-PA infection.

In vitro activity of ceftazidime-avibactam combined with colistin against extensively drug-resistant Pseudomonas aeruginosa / 中华危重病急救医学

Objective To evaluate the in vitro activity of ceftazidime-avibactam (CAZ-AVI) alone or in combination with colistin (COL) against clinically isolated extensively drug-resistant Pseudomonas aeruginosa (XDR-PA). Methods Minimum inhibitory concentration (MIC) of 16 clinical XDR-PA isolates was determined by broth dilution method and chessboard design when CAZ-AVI and COL were used alone or in combination, then the combined inhibitory concentration index (FICI) was calculated. Class A [Klebsiella pneumoniae carbapenemase β-lactamase (blaKPC), Guiana extended-spectrum β-lactamase (blaGES)], Class B [imipenemase β-lactamase (blaIMP), Verona-Integronmetallo β-lactamase (blaVIM), New Delhi metallo β-lactamase (blaNDM), German imipenemase β-lactamase (blaGIM), Sao Paulo metallo -β- lactamase (blaSPM)], Class C [AmpC β-lactamase (blaAmpC)], Class D [oxacillinase β-lactamase (blaOXA)] β- lactamase-related resistance genes were detected by polymerase chain reaction. Drug-resistant mutation frequencies of each strain were determined on a drug-containing plate. The time kill curves of three XDR-PA were plotted by colony counting method. A biofilm model was established in vitro, and the synergistic effect of CAZ-AVI and COL on biofilm inhibition was detected by methythiazolyl tetrazolium assay (MTT). Results The MICs of 16 XDR-PA for CAZ-AVI ranged from 1 mg/L to 128 mg/L, and three of the isolates showed resistance (MIC > 8 mg/L). The FICI range of CAZ-AVI combined with COL was 0.312-1.000. Four isolates were synergistic, while the other 12 isolates were additive. Three isolates resistant to CAZ-AVI contained Class B resistance genes such as blaIMP and blaVIM, while 13 susceptible isolates carried resistance genes belonging to Class A, C or D. The logarithm values of mutation frequencies of drug resistance in CAZ-AVI group, COL group and combination group were -4.81±0.88, -7.06±0.69 and -9.70 (-9.78, -9.53), respectively. There were significant differences among the three groups (H = 33.601, P < 0.001), and between every two groups (adjusted P < 0.05). In time kill curves, the phytoplankton load of three XDR-PA decreased more than 6 log CFU/L when these two drugs were used together, and number of PA1819 planktonic bacteria decreased more than 5.1 log CFU/L compared with monotherapy group. Viable quantity in biofilm (A490) of normal saline group, CAZ-AVI group, COL group and CAZ-AVI-COL group were 0.665±0.068, 0.540±0.072, 0.494±0.642 and 0.317±0.080, respectively. There was significant difference between the other two groups (all P < 0.001), except for that between CAZ-AVI group and COL group (P = 0.109). Conclusions CAZ-AVI combined with COL can effectively improve the bactericidal effect of each drug alone on XDR-PA. The regimen can also reduce the production of drug-resistant bacteria and inhibit the formation of biofilm. Therefore, it is a potential treatment for XDR-PA infection.

In vitro activity of ceftazidime-avibactam combined with colistin against extensively drug-resistant Pseudomonas aeruginosa / 中华危重病急救医学

Objective To evaluate the in vitro activity of ceftazidime-avibactam (CAZ-AVI) alone or in combination with colistin (COL) against clinically isolated extensively drug-resistant Pseudomonas aeruginosa (XDR-PA). Methods Minimum inhibitory concentration (MIC) of 16 clinical XDR-PA isolates was determined by broth dilution method and chessboard design when CAZ-AVI and COL were used alone or in combination, then the combined inhibitory concentration index (FICI) was calculated. Class A [Klebsiella pneumoniae carbapenemase β-lactamase (blaKPC), Guiana extended-spectrum β-lactamase (blaGES)], Class B [imipenemase β-lactamase (blaIMP), Verona-Integronmetallo β-lactamase (blaVIM), New Delhi metallo β-lactamase (blaNDM), German imipenemase β-lactamase (blaGIM), Sao Paulo metallo -β- lactamase (blaSPM)], Class C [AmpC β-lactamase (blaAmpC)], Class D [oxacillinase β-lactamase (blaOXA)] β- lactamase-related resistance genes were detected by polymerase chain reaction. Drug-resistant mutation frequencies of each strain were determined on a drug-containing plate. The time kill curves of three XDR-PA were plotted by colony counting method. A biofilm model was established in vitro, and the synergistic effect of CAZ-AVI and COL on biofilm inhibition was detected by methythiazolyl tetrazolium assay (MTT). Results The MICs of 16 XDR-PA for CAZ-AVI ranged from 1 mg/L to 128 mg/L, and three of the isolates showed resistance (MIC > 8 mg/L). The FICI range of CAZ-AVI combined with COL was 0.312-1.000. Four isolates were synergistic, while the other 12 isolates were additive. Three isolates resistant to CAZ-AVI contained Class B resistance genes such as blaIMP and blaVIM, while 13 susceptible isolates carried resistance genes belonging to Class A, C or D. The logarithm values of mutation frequencies of drug resistance in CAZ-AVI group, COL group and combination group were -4.81±0.88, -7.06±0.69 and -9.70 (-9.78, -9.53), respectively. There were significant differences among the three groups (H = 33.601, P < 0.001), and between every two groups (adjusted P < 0.05). In time kill curves, the phytoplankton load of three XDR-PA decreased more than 6 log CFU/L when these two drugs were used together, and number of PA1819 planktonic bacteria decreased more than 5.1 log CFU/L compared with monotherapy group. Viable quantity in biofilm (A490) of normal saline group, CAZ-AVI group, COL group and CAZ-AVI-COL group were 0.665±0.068, 0.540±0.072, 0.494±0.642 and 0.317±0.080, respectively. There was significant difference between the other two groups (all P < 0.001), except for that between CAZ-AVI group and COL group (P = 0.109). Conclusions CAZ-AVI combined with COL can effectively improve the bactericidal effect of each drug alone on XDR-PA. The regimen can also reduce the production of drug-resistant bacteria and inhibit the formation of biofilm. Therefore, it is a potential treatment for XDR-PA infection.

Identification and characterization of potential druggable targets among hypothetical proteins of extensively drug resistant Mycobacterium tuberculosis (XDR KZN 605) through subtractive genomics approach.

Among the resistant isolates of tuberculosis (TB), the multidrug resistance tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) are the areas of growing concern for which the front-line antibiotics are no more effective. As a result, the search of new therapeutic targets against TB is an imperative need of time. On the other hand, the target identification is an a priori step in drug discovery based research. Furthermore, the availability of the complete proteomic data of extensively drug resistant Mycobacterium tuberculosis (XDR-MTB) made it possible to carry out in silico analysis for the discovery of new drug targets. In the current study, we aimed to prioritize the potential drug targets among the hypothetical proteins of XDR-TB via subtractive genomics approach. In the subtractive genomics, we stepwise reduced the complete proteome of XDR-MTB to only two hypothetical proteins and evidently proposed them as new therapeutic targets. The 3D structure of one of the two target proteins was predicted via homology modeling and later on, validated by various analysis tools. Our study suggested that the domains identified and the motif hits found in the sequences of the shortlisted drug targets are crucial for the survival of the XDR-MTB. To the best of our knowledge, the current study is the first attempt in which the complete proteomic data of XDR-MTB was subjected to the computational subtractive genomics approach and therefore, would provide an opportunity to identify the unique therapeutic targets against deadly XDR-MTB.

Comparison of efficacy and safety among individualized regimens containing clofazimine, linezolid or meropenem-clavulanic acid in treatment of multidrug/extensively resistant tuberculosis: a network meta-analysis / 中华临床感染病杂志

Objective To compare the efficacy and safety among individualized regimens ( IR ) containing clofazimine ( Cfz ) , linezolid ( Lzd ) or meropenem-clavulanic acid ( MC ) in treatment of multidrug/extensively resistant tuberculosis (MDR/XDR-TB) by using network meta-analysis.Methods Randomized controlled trials ( RCTs) and observational studies of Cfz-IR, Lzd-IR and MC-IR regimens in the treatment of MDR/XDR-TB published from January 2000 to August 2017 at home and abroad were retrieved.The literature was screened according to inclusion and exclusion criteria.The quality of the literature was evaluated and valid data were extracted.The efficacy and safety of Cfz-IR, Lzd-IR and MC-IR in the treatment of MDR/XDR-TB were directly and indirectly compared by network meta-analysis.Relative risk ( RR) or relative comparative effect ( Mean) or adverse reaction rate and 95％confidence interval ( CI) were used as indicators of systematic evaluation , and Berg' s funnel plot was used for the existing publication bias.Results A total of 20 papers and 21 studies were included.There were 2490 cases in the study group and 2303 cases in the control group included.According to the direct comparison of the network meta-analysis, the efficacy for treatment of MDR/XDR-TB of Lzd-IR ( RR=1.18, 95％ CI 1.02-1.36, Z=2.28, P <0.05) and MC-IR(RR=1.23,95％CI 1.01-1.50,Z=2.10,P<0.05)was better than that of IR in control group.The rates of adverse reactions of Lzd-IR, Cfz-IR and MC-IR were 29％(95％CI 0.24-0.35), 21％(95％CI 0.13-0.28) and 7％ (95％ CI 0.03-0.10), respectively.The top-down efficacy outcomes of the 4 individualized chemotherapy regimens were MC-IR (66.4％), Lzd-IR(22.6％), Cfz-IR (10.0％) and IR without Cfz, Lzd or MC (1.0％).The fitting model showed that MC-IR (Z=3.04, P<0.05) and Lzd-IR (Z=2.31, P<0.05) significantly shortened the "off"time compared with IR without Cfz, Lzd or MC.Conclusion The network meta-analysis shows that the efficacy and safety of regimen MC-IR are significantly higher than those of Lzd-IR and Cfz-IR in treatment of MDR/XDR-TB.

Tuberculosis extensamente resistente (XDR-TB) en Argentina: aspectos destacables epidemiológicos, bacteriológicos, terapéuticos y evolutivos / Extensively resistant tuberculosis (XDR-TB) in Argentina: epidemiology, bacteriology, therapy and outcome

La XDR-TB (resistente a isoniazida, rifampicina, alguna fluoroquinolona y al menos una entre kanamicina, amikacina o capreomicina), ha causado efectos devastadores en pacientes con SIDA y es prácticamente incurable. Se presentan 12 casos de localización pulmonar en pacientes no SIDA. Se trataron con esquemas que incluyeron en todos linezolid y en 9 moxifloxacino, todos negativizaron el examen directo y cultivo del esputo. Nueve pacientes cumplieron criterios de curación, 1 está aún en tratamiento y 2 abandonaron. Ocho pacientes presentaron efectos adversos, en solo 1 caso debió suspenderse la tioridazina. La utilización de linezolid, moxifloxacina y tioridazina han contribuido a la evolución satisfactoria de estos pacientes. Estos fármacos son considerados de utilidad en la serie reportada, debiendo ser utilizados en centros especializados con experiencia en el manejo de la TB MR y XDR-TB.

The XDR-TB (resistant to isoniazid, rifampiN, fluorquinolone and at least of the following: kanamycina, amikacyna or capreomycin), has caused devastating effects in patients with AIDS and is practically incurable. Twelve cases of pulmonary XDR-TB in non AIDS are described. All were treated with schemes that included linezolid in all and moxifloxacin in 9, all respiratory specimens became negative. Nine patients fulfilled healing criteria, 1 is still under treatment and 2 abandoned the therapy. Eight patients presented adverse effects, thioridazine was stopped in only one patient. Linezolid, moxifloxacin and tioridazin contributed to the satisfactory evolution of these patients. These drugs were considered useful in the reported series of cases and should be used in specialized centres with experience in the management of MR TB and XDR-TB.