Systematic review: Would susceptibility-guided treatment achieve acceptable cure rates for second-line Helicobacter pylori therapy as currently practiced?

BACKGROUND: Susceptibility-guided treatment has been proposed as a way to improve Helicobacter pylori eradication rates. Evidence on its efficacy for rescue therapy is very scarce. The aim of this study was to indirectly assess the applicability and effectiveness of susceptibility-guided treatment by evaluating (a) the rate of acceptance of endoscopy, (b) its success in detecting resistances, and (c) infection cure rates in patients harboring strains found to be susceptible to the antibiotics administered in clinical trials in which the efficacy of second-line treatments was reported. METHODS: A systematic review of studies evaluating second-line H pylori treatment was carried out in multiple databases. Studies reporting antibiotic susceptibility evaluation and/or cure rates in patients harboring sensitive and resistant strains were selected. Data were extracted in duplicate. RESULTS: The systematic review identified 36 eligible studies. Acceptance was evaluated in only one study of 60 patients, of whom only 38 agreed to endoscopy. Among the 2890 patients who received endoscopy and culture, resistances were finally determined in 86.5%. Cure rate was 72.5% in the 113 patients harboring a clarithromycin-susceptible strain after previous clarithromycin treatment, 93.5% in the 765 patients harboring a metronidazole-susceptible strain, and 83.8% in the 192 patients harboring a levofloxacin-susceptible strain. No studies with repeated administration of levofloxacin or metronidazole were found. CONCLUSION: Even if the culture shows a clarithromycin-sensitive strain, repeating clarithromycin after a first failure should be discouraged. Susceptibility-guided treatment alone did not achieve adequate cure rates for rescue therapies. Additional measures are needed to design rescue treatments that consistently achieve excellent cure rates.

Prevalencia de las resistencias de Helicobacter pylori tras el fracaso de una primera línea de tratamiento. Revisión sistemática / Prevalence of Helicobacter pylori resistance after failure of first-line therapy. A systematic review

No hay datos sistemáticos sobre cuáles son las tasas de resistencia a antibióticos tras el fracaso de un primer tratamiento erradicador. El objetivo del estudio es determinar la prevalencia de las resistencias secundarias a los antibióticos mediante una revisión sistemática de estudios que evaluaban las resistencias secundarias de Helicobacter pylori. Se identificaron 31 estudios (2.787 pacientes). Se determinaron resistencias en 1.764 pacientes. El 99,1% de los pacientes recibieron claritromicina como tratamiento de primera línea, y un 58,7% desarrollaron resistencias. El 24,3% de los pacientes recibieron metronidazol, desarrollando resistencias el 89,7%. La resistencia secundaria a amoxicilina fue excepcional. Las resistencias secundarias tras un primer tratamiento son muy elevadas. Estos hallazgos dan soporte a la recomendación de no repetir claritromicina o metronidazol tras el fracaso de un primer tratamiento erradicador

There are no systematic data on the rates of antibiotic resistance after the failure of a first eradication treatment. The objective of this study was to determine the prevalence of secondary resistance to antibiotics by conducting a systematic review of studies evaluating the secondary resistance of Helicobacter pylori. We identified 31 studies (2,787 patients). Resistance was determined in 1,764 patients. A percentage of 99.1 of patients received clarithromycin as first-line treatment and 58.7% developed resistance. A percentage of 24.3 received metronidazole and 89.7% developed resistance. Secondary resistance to amoxicillin was extremely rare. Secondary resistance after first-line treatment was very common. These findings support the recommendation not to repeat clarithromycin or metronidazole after the failure of a first eradication treatment

Prevalence of Helicobacter pylori resistance after failure of first-line therapy. A systematic review. / Prevalencia de las resistencias de Helicobacter pylori tras el fracaso de una primera línea de tratamiento. Revisión sistemática.

There are no systematic data on the rates of antibiotic resistance after the failure of a first eradication treatment. The objective of this study was to determine the prevalence of secondary resistance to antibiotics by conducting a systematic review of studies evaluating the secondary resistance of Helicobacter pylori. We identified 31 studies (2,787 patients). Resistance was determined in 1,764 patients. A percentage of 99.1 of patients received clarithromycin as first-line treatment and 58.7% developed resistance. A percentage of 24.3 received metronidazole and 89.7% developed resistance. Secondary resistance to amoxicillin was extremely rare. Secondary resistance after first-line treatment was very common. These findings support the recommendation not to repeat clarithromycin or metronidazole after the failure of a first eradication treatment.

Systematic review, meta-analysis, and meta-regression: Successful second-line treatment for Helicobacter pylori.

BACKGROUND: Multiple Helicobacter pylori second-line schedules have been described as potentially useful. It remains unclear, however, which are the best combinations, and which features of second-line treatments are related to better cure rates. The aim of this study was to determine that second-line treatments achieved excellent (>90%) cure rates by performing a systematic review and when possible a meta-analysis. A meta-regression was planned to determine the characteristics of treatments achieving excellent cure rates. METHODS: A systematic review for studies evaluating second-line Helicobacter pylori treatment was carried out in multiple databases. A formal meta-analysis was performed when an adequate number of comparative studies was found, using RevMan5.3. A meta-regression for evaluating factors predicting cure rates >90% was performed using Stata Statistical Software. RESULTS: The systematic review identified 115 eligible studies, including 203 evaluable treatment arms. The results were extremely heterogeneous, with 61 treatment arms (30%) achieving optimal (>90%) cure rates. The meta-analysis favored quadruple therapies over triple (83.2% vs 76.1%, OR: 0.59:0.38-0.93; P = .02) and 14-day quadruple treatments over 7-day treatments (91.2% vs 81.5%, OR; 95% CI: 0.42:0.24-0.73; P = .002), although the differences were significant only in the per-protocol analysis. The meta-regression did not find any particular characteristics of the studies to be associated with excellent cure rates. CONCLUSION: Second-line Helicobacter pylori treatments achieving>90% cure rates are extremely heterogeneous. Quadruple therapy and 14-day treatments seem better than triple therapies and 7-day ones. No single characteristic of the treatments was related to excellent cure rates. Future approaches suitable for infectious diseases-thus considering antibiotic resistances-are needed to design rescue treatments that consistently achieve excellent cure rates.

Systematic review: third-line susceptibility-guided treatment for Helicobacter pylori infection.

BACKGROUND: Susceptibility-guided therapies (SGTs) have been proposed as preferable to empirical rescue treatments after two treatment failures. The aim of this study was to perform a systematic review and meta-analysis evaluating the effectiveness and efficacy of SGT as third-line therapy. METHODS: A systematic search was performed in multiple databases. Studies reporting cure rates of Helicobacter pylori with SGT in third-line therapy were selected. A qualitative analysis describing the current evidence and a pooled mean analysis summarizing the cure rates of SGT in third-line therapy was performed. RESULTS: No randomized controlled trials or comparative studies were found. Four observational studies reported cure rates with SGT in third-line treatment, and three studies which mixed patients with second- and third-line treatment also reported cure rates with SGT. The majority of the studies included the patients when culture had been already obtained, and so the effectiveness of SGT and empirical therapy has never been compared. A pooled mean analysis including four observational studies (283 patients) showed intention-to-treat and per-protocol eradication rates with SGT of 72% (95% confidence interval 56-87%; I(2) : 92%) and 80% (95% confidence interval 71-90%; I(2) : 80%), respectively. CONCLUSIONS: SGT may be an acceptable option as rescue treatment. However, cure rates are, at best, moderate and this approach has never been compared with a well-devised empirical therapy. The evidence in favor of SGT as rescue therapy is currently insufficient to recommend its use.

Systematic review and meta-analysis: triple therapy combining a proton-pump inhibitor, amoxicillin and metronidazole for Helicobacter pylori first-line treatment.

BACKGROUND: Due to clarithromycin resistance, the current efficacy of Helicobacter pylori first-line triple therapies including clarithromycin is low. It seems reasonable to explore alternative clarithromycin-free therapies. OBJECTIVES: The objective of this study was to evaluate the efficacy of triple therapy including a proton-pump inhibitor (PPI), amoxicillin and metronidazole (PAM) as first-line H. pylori therapy by systematic review and meta-analysis. METHODS: Studies evaluating PAM in adult patients were included. Meta-analyses comparing PAM with other treatments were performed. The primary endpoint was the ITT eradication rate for H. pylori first-line treatment. In addition, sensitivity analyses ascertained the effects of treatment schedule, dosage and duration on cure rates. RESULTS: Ninety-four studies (8061 patients) were included. Meta-analyses comparing PAM versus clarithromycin-including triple therapies showed a significant difference in favour of PPI, amoxicillin and clarithromycin (PAC) (70% versus 77.1%; OR = 0.70, 95% CI = 0.56-0.88) and PPI, metronidazole and clarithromycin (PMC) therapy (66.4% versus 77.7%; OR = 0.55, 95% CI = 0.39-0.76). Sensitivity analyses showed a similar efficacy of PAM versus PAC when drugs were administered for 14 days (80% versus 84%; OR = 0.70, 95% CI = 0.44-1.12). There were not enough studies to perform further comparisons. Number of antibiotic doses (P = 0.012), length of treatment (P < 0.001) and use of high metronidazole doses (P = 0.021) were related to higher cure rates in the sensitivity analysis including observational studies. CONCLUSIONS: PAM was less efficacious than clarithromycin-including triple therapies. However, its efficacy was similar to that of PAC when drugs were administered for 14 days, although ITT cure rates did not reach 90%. Use of 14 day, thrice daily and high-metronidazole-dose PAM treatments markedly increased the cure rate.

Safety and effectiveness of outpatient parenteral antimicrobial therapy in older people.

OBJECTIVES: We analyse the safety and effectiveness of self-outpatient parenteral antimicrobial therapy (s-OPAT) in older patients. METHODS: We prospectively evaluated all adults admitted to our home hospitalization unit (HHU) for s-OPAT in the period 2008-12 in whom the bacteria responsible for the infection were identified. We divided patients into three age groups: <65, 65-79 and ≥80 years. s-OPAT was administered by patients or their caregivers using elastomeric infusion devices. Effectiveness was assessed by analysing readmissions to hospital for inadequate control of underlying infection. Safety was assessed by analysing adverse events, catheter-related complications and readmission to hospital for causes unrelated to inadequate control of underlying infection. RESULTS: During the study period, 420 episodes of s-OPAT were registered in 351 patients: 139 (33.1%) in patients aged <65 years, 182 (43.3%) in those aged 65-79 years and 99 (23.6%) in those aged ≥80 years. Patients aged ≥80 years had a significantly lower Barthel index. The length of stay for s-OPAT and the complete HHU stay were similar in the three groups. Older people had similar changes in antibiotic treatment and hospital readmission rates due to poor control of underlying infection but higher readmission rates due to worsening of underlying diseases than younger adults. Adverse events and catheter-related complications were similar in the three age groups. CONCLUSIONS: s-OPAT administered by patients or their caregivers using elastomeric devices was safe and effective in the treatment of infections in older people.

Systematic review and meta-analysis: susceptibility-guided versus empirical antibiotic treatment for Helicobacter pylori infection.

BACKGROUND: The cure rate of standard triple therapy for Helicobacter pylori infection is unacceptably low. Susceptibility-guided therapies (SGTs) have been proposed as an alternative to standard empirical treatments. The aim of this study was to perform a systematic review and meta-analysis evaluating the efficacy of SGTs. METHODS: A systematic search was performed in multiple databases. Randomized controlled trials comparing cure rates of SGTs versus those of empirical therapy were selected and analysed separately for first- and second-line treatments. A meta-analysis was performed using risk ratio (RR) and number needed to treat (NNT) to measure the effect. RESULTS: Twelve studies were included in the meta-analysis. In first-line treatment, SGT was more efficacious than empirical 7-10 day triple therapy (RR 1.16, 95% CI 1.10-1.23, I (2) = 33%; NNT = 8). Most studies used a 7-10 day triple therapy and randomized the patients after endoscopy and/or culture, thus precluding the comparison of SGT versus non-invasive testing and empirical treatment in clinical practice. For second-line therapy, only four studies were found. Results were highly heterogeneous and no significant differences were found (RR 1.11, 95% CI 0.82-1.51, I (2) = 87%). CONCLUSIONS: Once endoscopy and culture have been performed, SGT is superior to empirical 7 or 10 day triple therapy for first-line treatment. Further studies are needed to evaluate the effectiveness of SGT in clinical practice, especially when compared with currently recommended first-line quadruple therapies.

How and when should NSAIDs be used for preventing post-ERCP pancreatitis? A systematic review and meta-analysis.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be efficacious to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, the target patients, the type of NSAID, the route of administration and the time of drug delivery remain unclear, as well as the potential efficacy in reducing the severity of pancreatitis, length of hospital stay and mortality. The objective of the study was to evaluate these questions by performing a systematic review and meta-analysis. METHODS: Multiple searches were performed in the main databases. Randomized controlled trials (RCTs) comparing NSAIDs vs. placebo in the prevention of post-ERCP pancreatitis were included. Primary endpoint of the study was the efficacy for pancreatitis prevention. Sub-analyses were performed to determine the risk reduction in high and low risk patients, and to define optimal time, route of administration, and type of NSAID. Secondary endpoints were safety, moderate to severe pancreatitis prevention and reduction of hospital stay and mortality. RESULTS: Nine RCTs enrolling 2133 patients were included. The risk of pancreatitis was lower in the NSAID group than in the placebo group (RR 0.51; 95%CI 0.39-0.66). The number needed to treat was 14. The risk of moderate to severe pancreatitis was also lower in the NSAID group. (RR 0.46; 95%CI 0.28-0.76). No adverse events related to NSAID use were reported. NSAIDs were effective in both high-risk and unselected patients (RR 0.53; 95%CI 0.30-0.93 and RR 0.57; 95%CI 0.37-0.88). In the subanalyses, only rectal administration of either indomethacin (RR 0.54; 95%CI 0.38-0.75) or diclofenac (RR 0.42; 95%CI 0.21-0.84) was shown to be effective. There were not enough data to perform a meta-analysis in hospital stay reduction. No deaths occurred. CONCLUSION: A single rectal dose of indomethacin or diclofenac before or immediately after ERCP is safe and prevents procedure-related pancreatitis both in high risk and in unselected patients.