Nitroimidazole Resistance Research Articles

Unnoticed antimicrobial resistance risk in Tibetan cities unveiled by sewage metagenomic surveillance: Compared to the eastern Chinese cities

Sewage surveillance is a cost-effective tool for assessing antimicrobial resistance (AMR) in urban populations. However, research on sewage AMR in remote areas is still limited. Here, we used shotgun metagenomic sequencing to profile antibiotic resistance genes (ARGs) and ARG-carrying pathogens (APs) across 15 cities in Tibetan Plateau (TP) and the major cities in eastern China. Notable regional disparities in sewage ARG composition were found, with a significantly higher ARG abundance in TP (2.97 copies/cell). A total of 542 and 545 APs were identified in sewage from TP and the East, respectively, while more than 40 % carried mobile genetic elements (MGEs). Moreover, 65 MGEs-carrying APs were identified as World Health Organization (WHO) priority-like bacterial and fungal pathogens. Notably, a fungal zoonotic pathogen, Enterocytozoon bieneusi, was found for the first time to carry a nitroimidazole resistance gene (nimJ). Although distinct in AP compositions, the relative abundances of APs were comparable in these two regions. Furthermore, sewage in TP was found to be comparable to the cities in eastern China in terms of ARG mobility and AMR risks. These findings provide insights into ARGs and APs distribution in Chinese sewage and stress the importance of AMR surveillance and management strategies in remote regions.

Molecular study on metronidazole resistance in Bacteroides fragilis group isolates from a South Indian tertiary care center

ObjectiveBacteroides species are an important part of human intestinal microbiota. They can cause infections of significant mortality and morbidity when moved out of their niche in the gut. The cornerstone drug for prophylaxis and therapy, metronidazole, is exhibiting signs of resistance, which are frequently attributed to nitroimidazole (nim) resistance genes. The aim of this study was to use Epsilometer test (E-test) to assess the metronidazole susceptibility and conventional PCR methodology to map the distribution of nim genes in Bacteroides fragilis group (BFG) isolates. MethodsMALDI-TOF MS was used to identify BFG isolates. Using the E-test methodology, metronidazole minimum inhibitory concentrations (MICs) were determined. The presence of nim genes in these isolates were checked by conventional PCR methodology. Sequencing was done on selected amplicons for determining the nim gene types. ResultsBacteroides fragilis accounted for 55.3% of the total 273 BFG members identified. Of these, 196 (71.8%) were susceptible, 43 (15.8%) intermediate and 34 (12.5%) resistant to metronidazole as determined by the E-test. nim gene was present in 101 (37%) of the total 273 isolates. Out of the 34 phenotypically resistant isolates (MIC ≥32 μg/ml), 29 harboured nim gene (Chi-square test, p < 0.0000001) but nim gene was absent in 5 (14.7%) isolates. Also, nim gene was detected in 72 (30.1%) of the 239 isolates with susceptible and intermediate metronidazole MIC. Sequencing of 20 amplicons gave a nimE gene type. ConclusionsIn view of the rising metronidazole resistance among BFG and its close association with nim genes, there is a need for implementing routine metronidazole susceptibility testing and more researches are needed to find the molecular basis of these nim genes.

Molecular dynamic assisted investigation on impact of mutations in deazaflavin dependent nitroreductase against pretomanid: a computational study

In the past decade, TB drugs belonging to the nitroimidazole class, pretomanid and delamanid, have been authorised to treat MDR-TB and XDR-TB. With a novel inhibition mechanism and a reduction in the span of treatment, it is now being administered in various combinations. This approach is not the ultimate remedy since the target protein Deazaflavin dependent nitroreductase (Ddn) has a high mutation frequency, and already pretomanid resistant clinical isolates are reported in various studies. Ddn is essential for M.tuberculosis to emerge from hypoxia, and point mutations in critical residues confer resistance to Nitro-imidazoles. Among the pool of available mutants, we have selected seven mutants viz DdnL49P, DdnY65S, DdnS78Y, DdnK79Q, DdnW88R, DdnY133C, and DdnY136S, all of which exhibited resistance to pretomanid. To address this issue, through computational study primarily by MD simulation, we attempted to elucidate these point mutations’ impact and investigate the resistance mechanism. Hence, the DdnWT and mutant (MT) complexes were subjected to all-atom molecular dynamics (MD) simulations for 100 ns. Interestingly, we observed the escalation of the distance between cofactor and ligand in some mutants, along with a significant change in ligand conformation relative to the DdnWT. Moreover, we confirmed that mutations rendered ligand instability and were ejected from the binding pocket as a result. In conclusion, the results obtained provide a new structural insight and vital clues for designing novel inhibitors to combat nitroimidazole resistance Communicated by Ramaswamy H. Sarma

New insight into the In-Silico prediction and molecular docking of Giardia intestinalis protease resistance to nitroimidazole

Background/Objective. Giardia intestinalis is a flagella protozoan residing in human intestine causing diarrhea that affecting most common among the children. Usually metronidazole and nitroimidazole were used for the treatment of giardiasis worldwide. Pyruvate Ferredoxin oxidoreductase (PFeO) protease enzyme may play a role inactivation of these drugs that may lead to resistance. Studies regarding drug resistance are very less. Therefore, present study was carried out to predict the structure and characterize them structurally as well as functionally by using appropriate in-silico methods. Methods: The proteins sequences of wild type and mutant strain i.e. Pyruvate Ferredoxin oxidoreductase (PFeO) and Pyruvate flavodoxin oxidoreductase (PFIO) were retracted from the NCBI and aligned using ClustalW. Bioinformatic tools were carried out like molecular dynamics simulations and docking to understand the three-dimensional (3D) conformational structure and interaction behavior of mutant and wild types with the ligand. Findings: The wild complex maintained an approximate 4H-bonds during simulation while the mutant complex could hardly maintain single H-bond by the end of the simulation, suggesting that 4-nitroimidazole is highly stable in the wild complex. Since the compound occupies this binding site by making stable H-bond with key interacting residues, the function of mutant may be affected. For the very reason, the mutant may be resistant to the nitroimidazole. Applications: Molecular dynamic simulation and docking results have increased our understanding of resistance mechanisms and may also help for the design derivatives of nitroimidazole that inhibit protein function more efficiently. Keywords: Molecular dynamic simulation; Nitroimidazole resistance; Pyruvate Ferredoxin Oxidoreductase (PFeO) mutant type; Pyruvate Flavodoxin Oxidoreductase (PFIO) wild type; Giardia intestinalis

Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis.

The nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10-5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid.

Improved genetic understanding of Mycobacterium tuberculosis (MTB) resistance to novel and repurposed anti-tubercular agents can aid the development of rapid molecular diagnostics. Adhering to PRISMA guidelines, in March 2018, we performed a systematic review of studies implicating mutations in resistance through sequencing and phenotyping before and/or after spontaneous resistance evolution, as well as allelic exchange experiments. We focused on the novel drugs bedaquiline, delamanid, pretomanid and the repurposed drugs clofazimine and linezolid. A database of 1373 diverse control MTB whole genomes, isolated from patients not exposed to these drugs, was used to further assess genotype-phenotype associations. Of 2112 papers, 54 met the inclusion criteria. These studies characterized 277 mutations in the genes atpE, mmpR, pepQ, Rv1979c, fgd1, fbiABC and ddn and their association with resistance to one or more of the five drugs. The most frequent mutations for bedaquiline, clofazimine, linezolid, delamanid and pretomanid resistance were atpE A63P, mmpR frameshifts at nucleotides 192-198, rplC C154R, ddn W88* and ddn S11*, respectively. Frameshifts in the mmpR homopolymer region nucleotides 192-198 were identified in 52/1373 (4%) of the control isolates without prior exposure to bedaquiline or clofazimine. Of isolates resistant to one or more of the five drugs, 59/519 (11%) lacked a mutation explaining phenotypic resistance. This systematic review supports the use of molecular methods for linezolid resistance detection. Resistance mechanisms involving non-essential genes show a diversity of mutations that will challenge molecular diagnosis of bedaquiline and nitroimidazole resistance. Combined phenotypic and genotypic surveillance is needed for these drugs in the short term.

Emerging metronidazole resistance in Bacteroides spp. and its association with the nim gene: a study from North India.

Bacteroides spp. are anaerobic resident intestinal flora but are also known to cause severe morbidity. They are resistant to a wide variety of antimicrobial agents, including metronidazole, which has been shown to be associated with specific nitroimidazole (nim) resistance genes. Metronidazole resistance is emerging worldwide, although presently it remains at ca. 5%. This study aimed to determine the metronidazole susceptibility and distribution of nim genes in Bacteroides spp. clinical isolates in India. The relationship among strains harbouring nim genes and their susceptibility to metronidazole was also analysed. A total of 42 Bacteroides spp. clinical isolates were identified using an advanced MALDI-TOF system. Minimum inhibitory concentrations (MICs) for metronidazole were determined by the agar dilution method. Bacterial DNA was extracted and was subjected to nim gene PCR and the amplified PCR products were sequenced to determine the prevalent nim types. Bacteroides fragilis was the most common isolate (64%) among all Bacteroides spp. isolates. Among the total 42 clinical Bacteroides spp. isolates, 29 (69%) were susceptible and 13 (31%) were resistant to metronidazole by the agar dilution method. nim gene PCR performed on 38 isolates showed positivity in 20 isolates (53%), of which 12 had high metronidazole MICs (χ2 test, P<0.005). On sequencing, these nim genes were most closely related to nimE type. Resistance to metronidazole is consistently emerging worldwide. There is a significant association of the nim gene with metronidazole resistance. Periodic surveillance is needed to detect geographic and temporal trends in nim gene prevalence.

NimH, a novel nitroimidazole resistance gene contributing to metronidazole resistance in Bacteroides fragilis.

nimH, a novel nitroimidazole resistance gene contributing to metronidazole resistance in Bacteroides fragilis.

Increased incidence of nitroimidazole-refractory giardiasis at the Hospital for Tropical Diseases, London: 2008–2013

Giardia intestinalis is the commonest gastrointestinal protozoal pathogen worldwide, and causes acute and chronic diarrhoea with malabsorption. First-line treatment is with a nitroimidazole, with a reported efficacy rate of 89%. Failure of treatment can occur in patients with hypogammaglobulinaemia or human immunodeficiency virus (HIV), or be due to nitroimidazole-resistant organisms. There is little evidence to guide the clinical management of nitroimidazole-refractory disease. We performed a retrospective audit of nitroimidazole-refractory giardiasis in returned travellers at the Hospital for Tropical Diseases, London between 2011 and 2013. Seventy-three patients with microscopy-proven or PCR-proven giardiasis in whom nitroimidazole treatment had failed were identified, and their management was investigated. In 2008, nitroimidazole treatment failed in 15.1% of patients. This increased to 20.6% in 2011 and to 40.2% in 2013. Patient demographics remained stable during this period, as did routes of referral. Of patients with giardiasis, 39.0% had travelled to India; this rose to 69.9% in patients with nitroimidazole-refractory disease. Of the patients with refractory disease, 44.6% had HIV serological investigations performed and 36.5% had immunoglobulin levels determined. Patients with refractory disease were treated with various agents, including albendazole, nitazoxanide, and mepacrine, alone or in combination. All 20 patients who received a mepacrine-containing regimen were cured. This data shows a worrying increase in refractory disease, predominantly in travellers from India, which is likely to represent increasing nitroimidazole resistance. Improved tools for the diagnosis of resistant G. intestinalis are urgently needed to establish the true prevalence of nitroimidazole-resistant giardiasis, together with clinical trials to establish the most effective second-line agent for empirical treatment regimens.

Trichomonas vaginalisAntimicrobial Drug Resistance in 6 US Cities, STD Surveillance Network, 2009–2010

Nitroimidazoles (metronidazole and tinidazole) are the only recommended drugs for treating Trichomonas vaginalis infection, and previous samples that assessed resistance of such isolates have been limited in geographic scope. We assessed the prevalence of in vitro aerobic metronidazole and tinidazole resistance among T. vaginalis isolates from multiple geographic sites in the United States. Swab specimens were obtained from women who underwent routine pelvic examinations at sexually transmitted disease clinics in 6 US cities. Cultured T. vaginalis isolates were tested for nitroimidazole resistance (aerobic minimum lethal concentration [MLC] >50 µg/mL). Of 538 T. vaginalis isolates, 23 (4.3%) exhibited low-level in vitro metronidazole resistance (minimum lethal concentrations 50-100 µg/mL). No isolates exhibited moderate- to high-level metronidazole resistance or tinidazole resistance. Results highlight the possibility that reliance on a single class of antimicrobial drugs for treating T. vaginalis infections may heighten vulnerability to emergence of resistance. Thus, novel treatment options are needed.

Metronidazole Resistance in Prevotella spp. and Description of a New nim Gene in Prevotella baroniae

Nonduplicate clinical isolates of Prevotella spp. recovered from patients hospitalized between 2003 and 2006 in two French tertiary-care teaching hospitals were investigated for their susceptibility to metronidazole and the presence of nim genes. Of the 188 strains tested, 3 isolates displayed reduced susceptibility to metronidazole after 48 h of incubation, while 27 additional isolates exhibited heterogeneous resistance after prolonged incubation; all 30 of the isolates were nim negative. Among the remaining 158 isolates, 7 nim-positive isolates were detected. All of these strains were identified as Prevotella baroniae by 16S rRNA gene sequence analysis and contained a new nim gene, named nimI, as determined by DNA sequence analysis. Chromosomal localization of this single-copy gene was demonstrated in all clinical isolates as well as in type strain P. baroniae DSM 16972 by using Southern hybridization. No known associated insertion sequence elements were detected upstream of the nimI gene in any of the nim-positive strains by PCR mapping. After prolonged exposure to metronidazole, stable resistant subpopulations could be selected in nimI-positive Prevotella isolates (n = 6) as well as in nim-negative Prevotella isolates (n = 6), irrespective of their initial susceptibility to this antibiotic. This study is the first description of a new nitroimidazole resistance gene in P. baroniae which seems to be silent and which might be intrinsic in this species. Moreover, our findings highlight the fact that high-level resistance to metronidazole may be easily induced in both nim-positive and nim-negative Prevotella sp. strains.

Meta‐analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first‐line therapies for Helicobacter pylori

Information regarding the effects of drug resistance on therapies for Helicobacter pylori is limited. To determine the effect of drug resistance on the efficacy of first-line treatment regimens for H. pylori and identify the most efficacious treatments in the presence of drug resistance. We searched for studies using the keywords: 'Helicobacter pylori','resistance' and 'treatment' or 'therapy'. Multilevel meta-regression models were used to determine the effect of drug resistance on treatment efficacy. We analysed data from 93 studies with 10,178 participants. For triple therapies, clarithromycin resistance had a greater effect on treatment efficacy than nitroimidazole resistance. Metronidazole resistance reduced efficacy by 26% in triple therapies containing a nitroimidazole, tetracycline and bismuth, while efficacy was reduced by only 14% when a gastric acid inhibitor was added to the regimen. Quadruple therapies containing both clarithromycin and metronidazole were the most efficacious; >80% of H. pylori infections were consistently eradicated with these regimens. Drug resistance was a strong predictor of efficacy across triple therapies for the eradication of H. pylori in adults. Resistance to either clarithromycin or metronidazole, but not both simultaneously, may be overcome by using quadruple therapies, especially those containing both clarithromycin and metronidazole.

Dissemination of nim-class genes, encoding nitroimidazole resistance, among different species of Gram-negative anaerobic bacteria isolated in Athens, Greece

Dissemination of nim-class genes, encoding nitroimidazole resistance, among different species of Gram-negative anaerobic bacteria isolated in Athens, Greece

Trichomoniasis and its treatment

Trichomonas vaginalis has long been recognized as a cause of infectious vaginitis in women. More recently, studies have demonstrated a significant burden of disease in men with urethritis or men at high risk for sexually transmitted diseases. There is increasing interest in this pathogen as more data accumulates linking it to HIV transmission and perinatal morbidity. New diagnostic methods have emerged that may increase sensitivity of diagnosis or improve point-of-care access to testing. Nitroimidazoles remain the mainstay of therapy. Metronidazole and tinidazole are highly effective as single-dose therapy. Unfortunately, despite the link between T. vaginalis infection and perinatal morbidity, nitroimidazole therapy during pregnancy remains controversial. Although metronidazole resistance is currently uncommon, pharmacological features and nitroimidazole resistance patterns suggest that tinidazole may be more effective in treating patients with metronidazole treatment failure. Alternatives to nitroimidazole therapy are few, and most have limited efficacy and significant toxicity.

What constitutes failure for Helicobacter pylori eradication therapy?

Apart from patients with peptic ulcer disease, the use of eradication therapy for Helicobacter pylori infection has been extended to patients with H pylori-positive dyspepsia and conditions at risk for gastric cancer. Standard treatments comprise a proton pump inhibitor plus two antibiotics for at least one week. The main factors leading to treatment failure are noncompliance and antibiotic resistance. Provided the patient is sufficiently informed about possible side effects, discontinuation of the newer triple therapies has become rare. The prevalence of antibiotic resistance varies considerably among different geographic regions, reflecting the habits of prescription of these antibiotics for other indications. Largely, it ranges from 1% to 15% for macrolides, and from 7% to 60% for nitroimidazoles. With nitroimidazole resistance, treatment failure occurs in only less than 50%; with macrolide resistance, by contrast, in more than 50% of the cases. Furthermore, bacterial and host-related factors (Cag A virulence factor, grade of inflammation) contribute to eradication success. In case of treatment failure, post-therapeutic resistance is frequent. Important principles for the choice of second-line treatment are: not to repeat an antibiotic with potential post-therapeutic resistance, and to ensure sufficient acid suppression.

Reply

SIRS, The purpose of testing for nitroimidazole resistance in Helicobacter pylori is that in vitro resistance is significantly related to reduced efficacy of nitroimidazole-containing eradication regimens1234 – these data have been obtained from microaerophilic incubation of samples. Furthermore, a recent study compared the effects of microaerophilic incubation with anaerobic incubation followed by microaerophilic incubation on the assessment of metronidazole resistance in 102 isolates and found little difference in the evaluation of resistance prevalence.5 In addition, alterations in the H. pylori gene rdxA have been identified as responsible for the vast majority of metronidazole resistance.6 Failure to produce the protein product of this gene can be assessed by immunoblotting with antisera to RdxA. This was confirmed in 25 out of 27 microaerophilically cultured metronidazole-resistant isolates7 supporting the currently recommended culture condition as being able to identify correctly metronidazole resistance in H. pylori. Current methods of sensitivity testing of H. pylori have been validated in the identification of resistance. Resistance to antimicrobials is a frequent cause of eradication failure. Specific resistance profiles of individual patients' samples will aid in the selection of effective and microbiologically sound eradication regimens.

Review article: nitroimidazole resistance in Helicobacter pylori

The efficacy of a nitroimidazole-containing regimen for the treatment of Helicobacter pylori infection is decreased by nitroimidazole resistance. Nitroimidazoles are meta- bolized by H. pylori by several nitro-reductases of which an oxygen-insensitive NADPH nitroreductase encoded by the rdxA gene is the most important. Null mutations in this gene are associated with resistance. Susceptibility testing to nitroimidazoles may give variable results. This is not only related to the slow growth under specific conditions, but also to variability in the activity of the other nitroreductases and the ability to deactivate toxic metabolites of an NI and to repair DNA damage. Moreover, co-infections with resistant and susceptible bacteria are frequently found. The presence of nitroimidazole resistance is related to the previous use of this drug. The prevalence of resistance is rising and nowadays 10-50% of the isolates are resistant. Resistance reduces the efficacy of a treatment regimen to a variable degree. This is related to efficacy of the other components of the regimen and the treatment duration. Whether a nitroimidazole is still effective in resistant strains remains unresolved. When nitroimidazole resistance is present, a nitro-imidazole-containing regimen should be avoided or a regimen with other highly effective components should be used.

PCR-restriction fragment length polymorphism analysis for identification of Bacteroides spp. and characterization of nitroimidazole resistance genes.

Bacteroides spp. are opportunist pathogens that cause blood and soft tissue infections and are often resistant to antimicrobial agents. We have developed a combined PCR-restriction fragment length polymorphism (RFLP) technique to characterize the 16S rRNA gene for identification purposes and the nitroimidazole resistance (nim) gene for detection of resistance to the major antimicrobial agent used to treat Bacteroides infections: metronidazole (MTZ). PCR-RFLP analysis of 16S ribosomal (rDNA) with HpaII and TaqI produced profiles that enabled discrimination of type strains and identification of 70 test strains to the species level. The 16S rDNA PCR-RFLP identification results agreed with routine phenotypic testing for 62 of the strains. The discrepancies between phenotypic and PCR-RFLP methods for eight strains were resolved by 16S rDNA sequencing in three cases, but five strains remain unidentified. The presence of nim genes was indicated by PCR in 25 of 28 strains that exhibited reduced sensitivity to MTZ. PCR-RFLP of the nim gene products identified the four reported genes (nimA, -B, -C, and -D) and indicated the presence of a previously unreported nim gene in 5 strains. This novel nim gene exhibited 75% DNA sequence similarity with nimB. These rapid, accurate, and inexpensive methods should enable improved identification of Bacteroides spp. and the detection of MTZ resistance determinants.

A systematic review of Helicobacter pylori eradication therapy--the impact of antimicrobial resistance on eradication rates.

We systematically reviewed all available data in the literature to determine the overall eradication rates of currently advised Helicobacter pylori eradication regimens and to resolve conflicting evidence on the impact of antimicrobial resistance on the eradication rates. A comprehensive search of all published trials on H. pylori eradication therapy was carried out via an electronic database search, hand-searching and checking reference lists of pharmaceutical companies and other reviews. Full papers and abstracts in the English language which study currently advised eradication regimes were included. 770 study-arms were analysed. Mean eradication rates for bismuth based triple, proton pump inhibitor triple, quadruple and ranitidine bismuth citrate combination therapies vary from 65 to 92%. In case of nitroimidazole resistance, a drop in efficacy of up to 50% was found for bismuth-based triple and proton pump inhibitor-based triple therapies. For quadruple therapy, a significant difference in efficacy was found in the equal-effects analysis; however, this could not be confirmed in the random-effects analysis. In case of clarithromycin resistance, a mean drop in efficacy of 56% was found for one- and two-week clarithromycin containing proton pump inhibitor-triple therapies and of 58% for two-week ranitidine bismuth citrate combined with clarithromycin therapies. For ranitidine bismuth citrate combined with clarithromycin and nitroimidazole, no difference in efficacy was found in case of nitroimidazole or clarithromycin resistance, but data are still scarce. The cure rate with most regimens dropped significantly, in case of nitroimidazole-resistant strains, compared to nitroimidazole-susceptible strains. In case of clarithromycin resistance, the efficacy of most regimens is also decreased; however, data are still scarce. These data should allow physicians to make a better choice of an appropriate therapy for their patients.

The influence of in vitro nitroimidazole resistance on the efficacy of nitroimidazole-containing anti-Helicobacter pylori regimens: a meta-analysis.

The aim of this study was to determine the influence of nitroimidazole resistance (NIR) on the efficacy of treatment for Helicobacter pylori (H. pylori) infections by meta-analysis of the world literature. A MEDLINE search, a manual search of all major gastroenterological journals from 1993 to 1997, and abstracts of gastroenterological and H. pylori meetings from 1993 to 1997 were performed. All treatment studies using a nitroimidazole and providing data about the medication used, dose frequency, total daily dose, duration of treatment, and eradication results in relation to NIR were included. Eradication had to be assessed by two biopsy-based tests or a urea breath test > or = 4 wk after treatment. Individual studies were pooled into groups according to the medication used and the duration of treatment. The pooled estimate of the odds ratio (OR) of NIR for treatment failure and its 95% confidence interval (95% CI) were calculated for each group using the logit method. To detect any possible bias, funnel plots (plots of effect estimates against sample size) were constructed. A total of 91 treatment arms, including a total of 4823 patients, were evaluated. The pooled ORs of NIR for treatment failure (95% CI) of proton pump inhibitors, bismuth, and quadruple regimens were 5.2 (3.8-7.1), 5.9 (4.1-8.3), and 7.0 (3.1-16.0), respectively. Eradication rates were 90% in susceptible strains but <75% in resistant strains. In susceptible strains, neither treatment duration nor the choice of the second antibiotic influenced efficacy. In resistant strains, tetracycline was more effective than amoxicillin (bismuth regimens), and the longer the duration of regimens (bismuth-amoxicillin regimens) the more effective they were. Only quadruple regimens given for > or = 1 wk were effective in resistant strains. NIR decreases treatment efficacy. Treatment duration and choice of other drugs influence the impact of NIR on treatment efficacy. If NIR is present, a nitroimidazole-containing regimen should be avoided or a quadruple regimen should be given for > 1 wk.