Proton Pump Inhibitor

PPIs Linked to Kidney Failure in Seniors

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Older patients taking proton pump inhibitors had doubled risk for renal failure. Older patients taking proton pump inhibitors, a common remedy for heartburn and acid reflux, are two times more likely to be hospitalized with kidney failure than peers who don’t take the pills, a study finds.

While the side effect is extremely rare, and the study doesn’t prove the drugs cause kidney failure, the association is worrisome because tens of millions of people a year take these pills, sold by prescription and over-the-counter in some countries, with brand names including Prilosec, Prevacid and Zegerid.

“Generally, the drugs are very well tolerated, and the vast majority of patients who take them will not develop (kidney failure) or other serious problems,” lead study author Tony Antoniou, a researcher at the Institute for Clinical Evaluative Sciences and St. Michael’s Hospital in Toronto, said by email. “But the drugs should be used for the shortest possible duration.”

Antoniou and colleagues identified about 290,000 people aged 66 or older taking proton pump inhibitors in Ontario between 2002 and 2011, as well as a similar number of individuals not taking the drugs.

The researchers then looked at how many people were hospitalized for acute kidney injury within 120 days of starting treatment, and compared that to the group not taking the drugs.

In an effort to capture only new users of the drugs, the researchers excluded people from the study who had a prescription for these medicines in the past year. They also excluded people diagnosed in the past five years with illnesses linked to kidney failure such as HIV and lupus. And, they barred people prescribed antibiotics within the last four months because kidney failure can be caused by infections or the drugs used to treat them.

Acute kidney injury occurred in 1,787 people, substantially less than 1% of the total study population. People taking proton pump inhibitors had a hospitalization rate of 13.49 per 1,000 persons per year, compared with 5.46 per 1,000 without the drugs, according to the results online April 16 in CMAJ Open.

“I would not restrict proton pump inhibitors based on this study alone; the overall risk of (kidney failure) in the study population was still quite low and the association with proton pump inhibitors and renal injury is still only an association,” said Dr. John O’Brian Clarke, a gastroenterologist at the Johns Hopkins Hospital in Baltimore.

Of all the possible side effects of these drugs, the most concerning isn’t kidney failure, it’s osteoporosis, Clarke, who wasn’t involved in the study, said by email. There is also a risk that people won’t absorb certain vitamins and minerals such as magnesium, iron, B12 and calcium.

“This study supports a growing body of literature to suggest that proton pump inhibitor use is not risk-free,” Clarke said. “Clinicians should make every effort to restrict these agents only to patients who truly need proton pump inhibitor therapy and to find the minimum dose and duration of therapy necessary to treat their issues.”

While certain patients may be able to take antacids to relieve symptoms of heartburn, proton pump inhibitors play an important role in treating people with more serious medical problems, Dr. George Sachs, a professor at the David Geffen School of Medicine at the University of California Los Angeles, said by email.

For patients with gastroesophageal reflux disease, or GERD, the drugs can prevent the development of life-threatening esophageal cancer, said Sachs, who wasn’t involved in the study.

 Patients should regularly review whether proton pump inhibitors are necessary, said Antoniou.

“In many cases, lifestyle modifications (e.g. avoiding precipitating foods, weight loss) may be all that are required,” he said.

Ulcer pills linked to B12 deficiency

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Medication used to treat stomach ulcers may cause potentially harmful vitamin B12 deficiency, say experts.

A US study of 200,000 people in the Journal of the American Medical Association found the link.

People who took tablets known as proton pump inhibitors (PPIs) or histamine antagonists (H2RAs) were more likely to lack enough vitamin B12 for good health.

Left untreated, B12 deficiency can lead to dementia and neurological problems.

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Only a minority of patients on long term proton pump inhibitors showed evidence of vitamin B12 deficiency”

Prof Mark Pritchard of the British Society of Gastroenterology

The study authors say doctors should still prescribe these medicines, but that they should weigh possible harms against any benefits in patients who need the drugs for prolonged periods of time.

More investigations are needed to fully evaluate the risk which appears to be in people who take these medications for two or more years, they say.

Link not proof

The Kaiser Permanente researchers found that the link with B12 deficiency increased with dose and was stronger in women and younger age groups.

But the overall risk was still low.

PPIs and H2RAs are commonly prescribed for patients with symptoms of stomach ulcers such as heartburn and indigestion.

The tablets are also widely available to buy without a prescription, ‘over-the-counter’ at pharmacies.

They work by reducing the amount of acid made by your stomach.

Stomach acid is needed for us to absorb vitamin B12 from our food, such as meat, fish and dairy.

If identified, most cases of B12 deficiency can be easily treated by giving supplements or an injection of vitamin B12.

But symptoms, such as lethargy, can be vague and overlooked.

Prof Mark Pritchard of the British Society of Gastroenterology said people should not be concerned by the findings.

“Only patients who had taken these tablets for more than two years were at risk and only a minority of patients on long-term proton pump inhibitors showed evidence of vitamin B12 deficiency.”

He said people taking ulcer medications could ask their GP for a simple blood test to measure vitamin B12 levels if they are worried.

Anti-acid treatment for idiopathic pulmonary fibrosis.

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The idea that idiopathic pulmonary fibrosis (IPF) could be mechanistically and pathogenetically attributed to repeated, often silent events of gastric fluid microaspiration (so-called lungburns) was first introduced almost 40 years ago.1 Since then, an increasing body of evidence has provided useful insights about a potential link between diffuse lung fibrosis and gastro-oesophageal reflux. A high prevalence of abnormal acid gastro-oesophageal reflux (identified by 24-h pH monitoring) in patients with IPF—almost 90%—was first reported in two different cohorts.2, 3 However, a much smaller proportion of patients complain of heartburn-related symptoms,4 rendering the diagnosis of abnormal acid gastro-oesophageal reflux clinically occult and thus insidious.

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Several reports have associated anti-reflux treatment with improved survival and substantial functional and radiological benefits in patients with IPF.5 Additionally, increased amounts of microaspiration biomarkers, such as pepsin, in bronchoalveolar lavage fluid of patients with IPF experiencing an acute exacerbation6 directly implicates clinically silent microaspiration of gastric fluid as a triggering factor of fibrogenesis.5

In The Lancet Respiratory Medicine, Joyce Lee and colleagues present results of an analysis of the potential usefulness of anti-acid treatment (proton-pump inhibitors [PPIs] and histamine-receptor-2 [H2] blockers) in patients with IPF.7 Their method was well designed: they used prospectively obtained data from the placebo groups of the three randomised clinical trials from the Idiopathic Pulmonary Fibrosis Clinical Research Network (PANTHER, ACE, and STEP). They assessed the effect of anti-acid treatment on functional deterioration in a 30-week period for 242 patients.

The most important finding of their study was that patients taking anti-acid treatment (n=124) had a significantly smaller decrease in forced vital capacity (—0·06 L, 95% CI −0·11 to −0·01) than did those who were not taking anti-acid treatment (n=118; −0·12 L, −0·17 to −0·08; difference 0·07 L, 0—0·14; p=0·05). Moreover, patients taking anti-acid treatment had significantly fewer acute exacerbations (no events) than did those who were not (nine events; p=0·0017). Although the results suggested improved survival with anti-acid treatment, the difference was not significant (p=0·12).

Nevertheless, several mechanistic issues and safety concerns should be addressed before anti-acid treatment in patients with IPF can be widely implemented. So far, no rigid pathogenetic link between gastro-oesophageal reflux and IPF has been identified, and anti-acid treatment has inconsistent effects on survival, because it does not inhibit reflux.5 Patients included in Lee and colleagues’ analysis,7 and those in previous retrospective analyses,8 were heterogeneous in terms of disease severity and presence of comorbidities, such as sleep apnoea, that can significantly affect survival and cause further deterioration of abnormal gastro-oesophageal reflux. Finally, assessment of abnormal acid gastro-oesophageal reflux and gastro-oesophageal reflux disease was superficially based solely on heartburn symptoms in most patients; endoscopy was used in a small proportion of patients.

But do physicians really need to treat symptoms of gastro-oesophageal reflux? Or should the primary outcome be to prevent further lung injuries by intervening directly in the fibrogenic cascade? A study by Ho and colleagues8 extended the beneficial contribution of PPIs beyond neutralisation of highly acidic gastric juice. The investigators concluded that PPI inhibition of dimethylarginine dimethylaminohydrolase and inducible nitric oxide synthase, which are known to be increased within lung epithelium and fibroblastic foci,9, 10 eliminated aberrant signalling in the TGF-β pathway, ultimately leading to decreased collagen production in an experimental model of lung fibrosis. These findings suggest a novel antifibrotic mechanism for PPIs in patients with IPF.

Another crucial issue is to clarify whether anti-acid treatments will be used as adjunctive or primary therapeutic regimens. Many questions about which patients, the length of treatment, and what doses to use remain unanswered. The idea that all patients with IPF could receive anti-acid treatment as prophylaxis could be risky in view of the potentially harmful side-effects, such as infections, electrolyte disturbances, and, importantly, drug interactions. H2 blockers and PPIs are potent inducers of P450 enzymes, particularly CYP1A2, and therefore might limit the plasma concentrations of several antifibrotic agents, including pirfenidone, which has been approved for IPF treatment.11

Overall, a randomised placebo-controlled trial of patients with IPF, with and without symptoms of gastro-oesophageal reflux, is needed. Assessment of agent-specific and dose-dependent therapeutic outcomes will be necessary to better define individuals who could benefit from such interventions.

Source: Lancet

Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials.

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Background

Abnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF.

Methods

In an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker.

Findings

Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (—0·06 L, 95% CI −0·11 to −0·01) than did those not taking anti-acid treatment (—0·12 L, −0·17 to −0·08; difference 0·07 L, 95% CI 0—0·14; p=0·05).

Interpretation

Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed.

Source: Lancet

Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials.

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Background

Abnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF.

Methods

In an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker.

Findings

Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (—0·06 L, 95% CI −0·11 to −0·01) than did those not taking anti-acid treatment (—0·12 L, −0·17 to −0·08; difference 0·07 L, 95% CI 0—0·14; p=0·05).

Interpretation

Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed.

Soure: Lancet

Frequent Acid Reflux Associated with Throat Cancers.

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Gastric reflux is a risk factor for cancers of the pharynx and larynx, and the use of antacids seems to lower that risk, according to an observational study in Cancer Epidemiology, Biomarkers and Prevention.

In a multicenter collaboration, researchers matched some 630 cases of laryngopharyngeal squamous cell carcinomas with twice the number of controls without cancer. Analyses were adjusted for demographics, smoking history, and HPV16 seropositivity.

Among patients who were not heavy smokers or drinkers, a history of self-reported frequent heartburn was significantly associated with throat cancers relative to those without heartburn (odds ratio, 1.78). Use of antacids for heartburn was associated with a lower risk (OR, 0.59). However, there was no such inverse association seen with the use of proton-pump inhibitors or histamine H2 receptor antagonists — possibly due to confounding from increased disease severity leading to their use.

 

The authors speculate that acid reflux may cause cancers by, for example, inducing chronic inflammation or activating signaling pathways of cellular proliferation.

Source: Cancer Epidemiology, Biomarkers and Prevention

The Effect of Dexlansoprazole MR on Nocturnal Heartburn and GERD-Related Sleep Disturbances in Patients With Symptomatic GERD.

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OBJECTIVES:

 

Nocturnal heartburn and related sleep disturbances are common among patients with gastroesophageal reflux disease (GERD). This study evaluated the efficacy of dexlansoprazole MR 30 mg in relieving nocturnal heartburn and GERD-related sleep disturbances, improving work productivity, and decreasing nocturnal symptom severity in patients with symptomatic GERD.

METHODS:

 

Patients (N=305) with frequent, moderate-to-very severe nocturnal heartburn and associated sleep disturbances were randomized 1:1 in a double-blind fashion to receive dexlansoprazole MR or placebo once daily for 4 weeks. The primary end point was the percentage of nights without heartburn. Secondary end points were the percentage of patients with relief of nocturnal heartburn and of GERD-related sleep disturbances over the last 7 days of treatment. At baseline and week 4/final visit, patients completed questionnaires that assessed sleep quality, work productivity, and the severity and impact of nocturnal GERD symptoms.

RESULTS:

 

Dexlansoprazole MR 30 mg (n=152) was superior to placebo (n=153) in median percentage of nights without heartburn (73.1 vs. 35.7%, respectively; P<0.001). Dexlansoprazole MR was significantly better than placebo in percentage of patients with relief of nocturnal heartburn and GERD-related sleep disturbances (47.5 vs. 19.6%, 69.7 vs. 47.9%, respectively; P<0.001), and led to significantly greater improvements in sleep quality and work productivity and decreased nocturnal symptom severity. Adverse events were similar across treatment groups.

CONCLUSIONS:

 

In patients with symptomatic GERD, dexlansoprazole MR 30 mg is significantly more efficacious than placebo in providing relief from nocturnal heartburn, in reducing GERD-related sleep disturbances and the consequent impairments in work productivity, and in improving sleep quality/quality of life.

DISCUSSION

Dexlansoprazole MR 30 mg daily was significantly better than placebo in improving symptoms of nocturnal heartburn in symptomatic GERD patients with frequent, moderate-to-very severe nocturnal heartburn leading to improved sleep quality, and decreased symptom severity and impact on morning activities. Dexlansoprazole MR 30 mg was also effective in increasing work productivity and reducing activity impairment. It should be noted that patients enrolled in this study had to be responsive to acid-suppression therapy. This inclusion criterion was used to limit the number of functional heartburn patients enrolled in the study.

During this study, the median percentage of nights without heartburn over 4 weeks for the intent-to-treat patients receiving dexlansoprazole MR 30 mg was 73.1%. In a previous dexlansoprazole MR phase 3 study, which assessed efficacy and safety among patients with non-erosive reflux disease, this value was 80.8%(vs. 51.7% for placebo; P<0.00001) (23), supporting the results of our study. Furthermore, the therapeutic gain, or the difference between active study drug and placebo, seen in this current nocturnal heartburn study was greater than that observed in a previous phase 3 symptomatic GERD trial (37 vs. 29%) (23).

Stratification of the primary end point by baseline mean nocturnal symptom severity reveals that patients with the most severe symptoms experience the greatest therapeutic gain. Although the median percentage of nights free of nocturnal heartburn declined with increasing baseline severity, the therapeutic gain increased. The therapeutic gain experienced by patients receiving dexlansoprazole MR with severe-to-very severe baseline nocturnal symptoms is more than twice that experienced by patients with mild-to-moderate or moderate-to-severe baseline nocturnal symptoms. Patients in the severe-to-very severe group who received placebo experienced a median of 0% heartburn-free nights, while the 34 patients in the dexlansoprazole MR group reported a median of 66%of their nights as heartburn free during the 4 weeks of the trial. This could be explained by the finding that patients with more severe non-erosive reflux disease (NERD; as determined by pH testing) are more responsive to PPI therapy than patients with less severe NERD (24). This is in contrast to the response of erosive esophagitis patients receiving anti-reflux treatment (25).

During the last 7 days of the study, 48 and 70% of patients receiving dexlansoprazole MR reported relief of nocturnal heartburn and GERD-related sleep disturbances, respectively, which were significantly greater than with placebo (P<0.001 for each comparison). A similar pattern was observed by Johnson et al.(26), where patients receiving esomeprazole, 20 or 40 mg, reported higher rates of relief from GERD-related sleep disturbances from nocturnal heartburn during the last 7 days of a 4-week study.

A significantly lower frequency of GERD-related sleep disturbances was observed in the dexlansoprazole MR group. Dexlansoprazole MR resulted in a significantly lower frequency of the different types of sleep disturbances attributed to nocturnal heartburn. Of note, the percentage of nights with sleep disturbances due to other causes did not differ significantly between treatment groups. Taken together, these results suggest that patients taking dexlansoprazole MR 30 mg can expect a reduction in or relief from nocturnal heartburn symptoms and therefore better sleep quality.

Recording daily symptoms via diaries is common in clinical trials where symptom relief is a primary outcome (27). However, the limitations of this approach, particularly with paper diaries, include non-adherence (skipping entries) and “hoarding” (the retrospective completion of entries), which can lead to recall errors (28,29). Objective analyses of paper diary use have shown high rates of both non-adherence and hoarding (29). Electronic diaries, such as those used during this study, do not allow for hoarding beyond 24 h before the scheduled entry. Compliance with diary entries was high: ≥90% in 87% of patients.

The efficacy of dexlansoprazole MR for the relief of nocturnal heartburn and relief from GERD-related sleep disturbances is further supported by the improvements seen in the patient-reported outcomes. Patients receiving dexlansoprazole MR reported significantly greater improvements from baseline in sleep quality compared with placebo, which manifested as greater decreases in PSQI scores. Decreases in overall and subscale N-GSSIQ scores also showed greater efficacy for dexlansoprazole MR 30 mg compared with placebo in decreasing symptom severity, next morning impact of nocturnal symptoms, and concern regarding nocturnal GERD among the patients, thus demonstrating improvements in HRQoL. Significant improvements in HRQoL due to treatment of heartburn, both daytime and nocturnal, have been documented previously (23,26,30,31).

Accompanying these improvements in sleep quality, decreased symptom severity, and reduced impact the following morning were decreases in impairments in work productivity, as demonstrated by decreases in the WPAI scores. Treatment with dexlansoprazole MR was more effective than placebo in decreasing impairment while working and improving overall work productivity and functionality during regular activities. Furthermore, this treatment was more effective in reducing the number of work hours missed due to GERD-related sleep disturbances. These results are not unexpected when one considers the connection between repeated lack of sleep during the night and daytime sleepiness (9), as well as reduced HRQoL and work productivity (11). The negative impact of nocturnal GERD on HRQoL and work productivity is well recognized (7,8,10).

A recent survey of over 600 GERD patients on various PPI therapies found that the majority of patients continued to experience heartburn, with 83% experiencing nocturnal symptoms and almost a quarter of these patients reporting severe or very severe nocturnal symptoms (32). Daily dosing of dexlansoprazole MR 30 mg may reduce the likelihood of persistent nocturnal symptoms due to its extended duration of plasma drug levels (33); however, additional studies are needed to determine if this property equates to improved clinical outcomes.

In the above-mentioned survey (32), only approximately one-half of the patients surveyed took their PPI within the recommended 1 h to 30 min before breakfast. Poor compliance with PPI therapy is likely the most common cause for PPI failure (25). In this study, patients were to take the study drug in the morning, without regard to food. Comparable acid suppression with dexlansoprazole MR dosing has been demonstrated regardless of the timing of food intake (fasting, before or after breakfast) (34) or the time of day (before breakfast, lunch, dinner, or evening snack) (35). Although additional studies are needed to assess the impact of various dosing timings of dexlansoprazole MR on GERD symptoms, it is not unreasonable to suggest that increased flexibility in administration, and therefore increased compliance, would lead to reduced symptoms, particularly at night.

Dexlansoprazole MR 30 mg was well tolerated by patients in this current trial. Rates of treatment-emergent AEs were low and similar between the dexlansoprazole MR and placebo groups, including the premature discontinuation due to AEs. Recent analyses of pooled safety data from the phase 3 pivotal trials demonstrated that the safety profile of dexlansoprazole MR 30 mg was comparable to that of lansoprazole 30 mg (36).

The economic implications of this study are readily apparent. The favorable effect of improvement for work productivity has significant implications to payers and employers. For the patients receiving dexlansoprazole MR compared with placebo, there was an apparent work productivity advantage—$38 for the fourth week ($227 vs. $189). If these savings were extrapolated over the 4-week study, the advantage would be $152/treated patient. This type of modeling allows for the development of a business plan for payers–employers to evaluate the cost benefits of effective therapy. By this type of analysis, the “investment” cost of therapy can be analyzed against the returns of improved work productivity.

This study has several limitations, the first being the lack of an active comparator, another PPI. Although direct comparisons of efficacy results from different trials cannot be made, a recent review comparing the efficacy of various PPIs (not including dexlansoprazole MR) in relieving or resolving nocturnal heartburn in a clinical trial setting found no outstanding differences in efficacy between comparable doses (37). Placebo has been the standard comparator used in other studies assessing the efficacy of a PPI for nocturnal heartburn and in all studies of GERD-related sleep disturbances (23,26,38).

A second limitation is the lack of pH monitoring to document the level of acid suppression or to distinguish symptomatic non-erosive reflux from functional heartburn. It is difficult to attribute any symptom to reflux without direct esophageal monitoring. The primary reason for no pH monitoring during this study was the potential sleep disruption caused by an intra-esophageal pH electrode. However, to mitigate lack of pH monitoring, inclusion criteria mandated previous response to acid-suppression therapy. We also did not utilize sleep labs for an objective assessment of sleep quality, which could be considered another limitation. Because a sleep lab is an artificial environment, it is likely that many patients would not have slept the same way there as they would at home. Changes in sleep quality are subjective, whether as reported in the daily diaries or in the PSQI and N-GSSIQ.

A third limitation is the assessment of response for productivity analysis limited to the fourth week of therapy. Questions remain as to what the effect is on a weekly basis beyond the early therapy effect on these particular measurements. Furthermore, an area of further research is to evaluate whether these favorable effects persist, wane, or continue to improve with extended therapy.

In summary, dexlansoprazole MR 30 mg was significantly more efficacious in providing relief from nocturnal heartburn and in reducing GERD-related sleep disturbances compared with placebo in symptomatic GERD patients with moderate-to-very severe nocturnal heartburn. This study also demonstrated significantly greater improvements in sleep quality, HRQoL, and work productivity for patients receiving dexlansoprazole MR compared with those receiving placebo.

Furthermore, there were notable economic implications with favorable advantages evident for patients treated with dexlansoprazole MR—allowing for estimates of a calculable rate of return on investment for effective therapy.

Source: Nature/AJG

 

Acid Suppression and Effectiveness of Ampicillin for Helicobacter Pylori.

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At a low pH, H. pylori bacteria stopped dividing, making ampicillin ineffective. More sustained acid suppression might be useful for refractory infections.

Standard therapy for treating Helicobacter pylori infection typically includes ampicillin, a second antibiotic, and a proton-pump inhibitor (PPI). However, the effectiveness of this regimen has been decreasing with increasing antibiotic resistance. Because ampicillin acts on bacterial cell walls and requires actively dividing bacteria to be effective, investigators examined whether H. pylori growth — and, consequently, ampicillin effectiveness — was affected by gastric pH level.

H. pylori were incubated in dialysis chambers with 5 mM urea and varying pH levels with or without ampicillin for 4, 8, or 16 hours. Changes in the expression of genes associated with bacterial growth, viability, and survival were determined.

Ampicillin was bactericidal at pH levels of 4.5 or 7.4, but at a pH level of 3.0, the bacteria seemed to become dormant, with decreased expression of a host of genes associated with cell envelope biosynthesis. In this environment, ampicillin did not affect bacterial viability or survival.

The authors suggest that PPIs are associated with nocturnal acid breakthrough that might reduce the pH level, rendering ampicillin ineffective, and that more persistent acid reduction could potentially improve the clinical effectiveness of amoxicillin therapy.

Comment: This paper provides a compelling argument for the importance of PPI therapy in antibiotic treatment of H. pylori. It further suggests that sustained acid reduction should be the goal to improve the effectiveness of ampicillin or other drugs that require bacterial growth. The frequency of nocturnal acid breakthrough is likely overstated, and the ability of PPI therapy to maintain a pH of 4.5 is likely better than the authors suggest. The decreasing eradication rate is associated with antibiotic resistance, often to the second antibiotic (e.g., clarithromycin). Knowing the patterns of antibiotic resistance in a population will allow for more effective therapy. In refractory cases, higher PPI doses to sustain a high pH might be a reasonable approach to optimizing the effectiveness of the antibiotic that requires active cell growth.

Source: Journal Watch Gastroenterology

Proton-Pump Inhibitor Use and Risk for Community-Acquired Pneumonia.

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In patients with community-acquired pneumonia, PPI use was associated with a twofold increased risk for infection with oropharyngeal bacteria but not other pathogenic agents.

The decrease in gastric acidity that results from treatment with proton-pump inhibitors (PPIs) has been linked with bacterial colonization of the stomach and outcomes such as nosocomial pneumonia in the inpatient setting (Ann Intern Med 1994; 120:653) and community-acquired pneumonia (CAP; JAMA 2004; 292:1955).

To further investigate the possible link between PPI use and CAP, investigators prospectively assessed PPI use and microbiological etiology of pneumonia in patients treated for CAP in the emergency room of a large general hospital in the Netherlands. A diagnosis of CAP was based on symptoms and radiographic findings. Microbiological etiology of the pneumonia infection was assessed using sputum and blood cultures, urine antigen tests, and serum antibody tests. Relevant demographic and clinical covariates (e.g., medication use, comorbidities, severity of illness) and treatment outcomes (e.g., length of hospital stay, in-hospital mortality) were assessed.

Of 463 patients with CAP, 29% were using PPIs. The cause of pneumonia in PPI users was more likely to be oral flora than in nonusers (adjusted odds ratio, 2.0; 95% confidence interval, 1.22–3.72). PPI users were more likely than nonusers to be infected with Streptococcus pneumoniae (28% vs. 14%; adjusted OR, 2.23; 95% CI, 1.28–3.75) and had a lower rate of infection with Coxiella burnetii than nonusers (8% vs. 19%), which was not significant after adjustment for covariates. PPI use was not associated with any other pathogens. CAP severity, length of hospital stay, and in-hospital mortality did not differ between PPI users and nonusers.

The authors conclude that PPI use doubles the risk for CAP, possibly from infection with oropharyngeal flora, including S. pneumoniae.

Comment: This study confirms the previously observed increased risk for developing pneumonia from oropharyngeal bacteria in patients with reduced gastric acid. However, in the absence of a controlled study design, a possible mechanism for causality cannot be determined. We can only conclude that in this cohort of patients with CAP, oropharyngeal bacteria — specifically S. pneumoniae — were more common pathogens in PPI users than in nonusers. PPI users in this study had more comorbidities and poorer baseline lung function than the comparison group, suggesting that despite the attempt to control for comorbidities, other factors might have also contributed to the observed difference in risk for CAP.

Source: Journal Watch Gastroenterology

 

Proton-Pump Inhibitors Raise Risk for C. difficile Infections.

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In two meta-analyses, PPI use was associated with a 1.7-fold higher risk for Clostridium difficile infection.

In February 2012, the FDA issued a safety alert regarding an association between proton-pump inhibitors (PPIs) and Clostridium difficile infection. In new meta-analyses, two groups of researchers used slightly different criteria to select studies in which this association could be evaluated; all included studies (23 and 42, respectively) were observational (cohort or case-control). Each meta-analysis involved roughly 300,000 patients.

In both meta-analyses, risk for C. difficile infection was significantly higher in PPI users than in nonusers (risk ratio, about 1.7). Although results across individual studies were heterogeneous, nearly all trended toward higher risk. Most of the included studies were adjusted for confounding variables, including antibiotic use. Concomitant use of both PPIs and antibiotics — examined in one meta-analysis — was associated with greater risk for C. difficile infection than was use of PPIs alone or antibiotics alone. Risk for C. difficile infection was higher with histamine (H)2-receptor antagonists than with no acid-suppressive therapy, but lower with H2-receptor antagonists than with PPIs.

Comment: The opportunity for residual confounding in these studies is substantial, because sicker patients are more likely both to receive PPIs and to be vulnerable to C. difficile infection. Still, these worrisome findings should remind clinicians to initiate PPIs only for valid indications and to stop PPIs in patients who take them for unclear reasons.

Source:Journal Watch General Medicine