Acid-Suppressive Therapy and Risk of Infections: Pros and Cons

Abstract

This narrative review summarises the benefits, risks and appropriate use of acid-suppressing drugs (ASDs), proton pump inhibitors and histamine-2 receptor antagonists, advocating a rationale balanced and individualised approach aimed to minimise any serious adverse consequences. It focuses on current controversies on the potential of ASDs to contribute to infections—bacterial, parasitic, fungal, protozoan and viral, particularly in the elderly, comprehensively and critically discusses the growing body of observational literature linking ASD use to a variety of enteric, respiratory, skin and systemic infectious diseases and complications (Clostridium difficile diarrhoea, pneumonia, spontaneous bacterial peritonitis, septicaemia and other). The proposed pathogenic mechanisms of ASD-associated infections (related and unrelated to the inhibition of gastric acid secretion, alterations of the gut microbiome and immunity), and drug-drug interactions are also described. Both probiotics use and correcting vitamin D status may have a significant protective effect decreasing the incidence of ASD-associated infections, especially in the elderly. Despite the limitations of the existing data, the importance of individualised therapy and caution in long-term ASD use considering the balance of benefits and potential harms, factors that may predispose to and actions that may prevent/attenuate adverse effects is evident. A six-step practical algorithm for ASD therapy based on the best available evidence is presented.

Introduction

Over the last decades, gastric acid-suppressing drugs (ASDs), histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), revolutionised the treatment and prevention of acid-related diseases and currently are among the most commonly prescribed medications worldwide. These agents are highly effective for treating acid-mediated disorders of the upper digestive tract (peptic ulcers, eradication of Helicobacter pylori infection, acute nonvariceal bleeding, gastro-esophageal reflux disease (GERD), erosive esophagitis), prevention of nonsteroidal anti-inflammatory drug (NSAID)-related injury and stress ulcers [1–13]. ASDs are generally well tolerated and considered to have a safe profile [14–17]. However, emerging data indicate that use of ASDs, especially in the elderly in presence of comorbidities and/or co-medications, may be associated with serious adverse health effects including bacterial infections such as Clostridium difficile infection (CDI), Salmonella, Campylobacter, pneumonia, and others, all of which increase morbidity and mortality.

As the development of infections depends on a plethora of factors affecting the complex balance between immune defences and flora, any medication likely to modify this balance might be involved in occurrence of infections. Therefore, clinical decision-making, assessing and balancing the efficacy, safety and tolerability [18] as well as considering ethical dilemmas [19] of prescribing medications for an elderly patient with respect to co-existing comorbidities and polypharmacy has become challenging and complex. Moreover, while some recent publications emphasised the underuse of gastroprotective agents, especially in older patients receiving NSAIDs [7, 20, 21], others highlighted the over-utilisation of PPIs [22–27]. It has been estimated that inappropriate use of PPIs, particularly in the elderly, may exceed 75% [26, 28, 29].

The absence of unambiguous guidelines, controversial reports and recommendations in the existing scientific literature leaves the prescribing physician trying to choose “the right medication for the right patient” sometimes between Scylla and Charybdis.

This narrative review attempts to provide a comprehensive insight into the main issues and uncertainties associated with the potential infectious risks of use of ASDs, especially in an elderly often multimorbid and frail patient within the context of overall clinical benefits and harms, advocating a rationale balanced and individualised approach aimed to minimise any serious adverse consequences.

Methods of Literature Search

We performed an updated MEDLINE/PubMed search focusing mainly on publications from 1 January 2000 to 31 December 2016, and selected appropriate articles for discussion. In order to give the reader, as much as possible, a complete review of the topic, we have widened the spectrum of clinical conditions included.

General Considerations

Proton pump inhibitors covalently bind with sulfhydryl groups of the cysteine residues of the H+/K+ adenosine triphosphatase (H⁺/ K⁺ ATPase) on the plasma membrane of the gastric parietal cell irreversibly blocking the final step in acid secretion in response to all modes of stimulation—muscarinergic, gastrinergic and histaminergic [30–32], while H2RAs block only one—the histaminergic—of the three pathways in acid secretion. Therefore, PPIs are significantly more effective, faster and longer-acting suppressors of gastric acid secretion than the H2RAs. PPIs, despite the individual differences, are similar with respect to half-lives, time to maximum plasma concentration and safety [33]. All PPIs, except tenatoprazole, undergo hepatic metabolism via the CYP isoforms CYP2C19 and CYP3A4, and genetic polymorphism in CYP2C19 affects the metabolism and effectiveness of omeprazole and lansoprazole but not esomeprazole or rabeprazole [34–37]. Because omeprazole (but not pantoprazole) is a metabolism-dependent inhibitor of CYP2C19, it causes clinically significant interaction with clopidogrel [38].

The frequency of adverse reactions from H2RAs was reported to be similar to that for placebo [39, 40]. However, cytopenias and leukocytosis [41], nephrotoxicity and hepatotoxicity [42], as well as drug interactions [43–45] have been described.

Acid-Suppressing Therapy and Risk of Enteric Infections

Gastroenteritis is a common infectious disease requiring hospitalisation of approximately 1% of people ≥65 years of age annually [46]. The incidence of diarrhoea, the most common adverse effect from long-term PPI use and the most frequent indication for discontinuing PPI therapy, ranges from 3.7 to 4.1% [47–50]. In comparison, antibiotic-associated diarrhoea occurs in 5–39% [51]. The most likely causes of infectious diarrhoea include C. difficile, Campylobacter jejeuni, Salmonella spp., C. perfringens, Staphylococcus aureus, Klebsiella oxytoca, enterotoxic Escherichia coli, and viruses, although in many cases no infectious agent is ever determined [52–54]. C. difficile infection (CDI) is the leading cause of antibiotic-associated diarrhoea and accounts for 15–39% of cases [55–57]. The potential of ASDs to increase enteric infections, particularly in the elderly, has been recognised [58, 59].

Clostridium difficile Infection (CDI)

In the last decade, CDI, the most common of healthcare-associated infections [60], has become increasingly prevalent and severe [61–71]. Currently, it often (up to 75% of cases) occurs in the community or nursing homes (approximately in one-quarter of all CDI) [65, 72, 73], is not associated with healthcare/hospital exposure in up to one-third [73], and is unrelated to antibiotic use [74]. Most importantly, the incidence of CDI is disproportionately high among older patients [72, 75–78], especially among the most vulnerable and frail population of long-term residential care facilities (RCF) [73, 79–81]. The elderly with CDI often develop severe complications [82, 83] and persons aged ≥65 years account for up to 90% of CDI-related mortality within 30 days [65]. Current antimicrobial therapies for CDI still have relapse rates of 15–30% [84–86].

C. difficile, a Gram-positive, anaerobic, spore-forming, toxin-producing bacillus, is acquired by the ingestion of spores via the fecal-oral route. Pathogenesis of CDI involves a complex interplay of three key mechanisms: (1) C. difficile toxin production, (2) disruption of the gut microbiota and (3) host factors. Although antibiotics are currently recognised as a major risk factor for acquiring CDI due to their effect on the normal structure of the indigenous gut microbiota [55, 87–92], emerging data indicate that the prevalence of CDI cannot be fully explained by antimicrobial exposure, suggesting that other variables—comorbidities and medications affecting both the microbiota and the immunological status—may substantially contribute to the burden of CDI, particularly in the elderly population. Age is recognised as a major risk factor for the development of CDI with disease incidence and severity escalating as age increases [93].

Numerous epidemiological observational studies and meta-analyses [55, 74, 89, 92, 94–120] showed a statistically significant increase in both nosocomial and community-acquired CDI among patients taking PPIs or H2RAs (Table 1). In PPI users, odds ratio (OR) [or relative risk (RR)] ranges between 1.74 [46, 103]–1.90 [118]–1.96 [121]–2.15 [122]–2.90 [117]–3.3 [115] and 3.60 [97], in H2RA users between 1.40 [121]–1.44 [107] and 1.50 [123]. The pooled estimates showed a 1.3- to 3.3-fold increase in risk for CDI with ASD therapy [103, 104, 106, 115]; a lesser increase in risk with the use of H2RAs compared to PPIs as it was reported in the majority of studies may indicate a correlation with the degree of acid suppression [101, 119]. The association between ASDs and CDI appeared to be the level of acid suppression [119, 122], and is duration dependent [111]. Interestingly, in the paediatric population, CDI risk was associated with H2RAs (OR 4.6) but not PPIs use [124]. In one study, the proportion of cases of CDI among PPI users was as high as 65% [104]; others found that 31% of CDI patients without antibiotic exposure received PPIs [74]. In critically ill medical patients, risk of CDI associated with PPI therapy (OR 3.11) was comparable to the risk associated with the use of fluoroquinolones or third-generation cephalosporins [125]. Continuous PPI use (on average observed in 40–60% of CDI patients), similar to antibiotic re-exposure, was also associated with an increased risk for recurrent CDI [96, 100, 114] with an OR of 2.51 [103]–4.17 [96]. Among patients with extra-intestinal CDI, 50% used PPIs [126].

Table 1 Selected data on pooled estimates for CDI, SBP and respiratory infections in users of PPI and H2RA

Importantly, PPIs co-administered with an antibiotic increase the risk of CDI approximately two-fold above that observed with PPI alone [103, 127]. The absolute risk of CDI associated with H2RAs was highest in hospitalised patients receiving antibiotics with an estimated number-needed-to-harm (NNH) of 58 at 2 weeks compared to 425 not receiving antibiotics [107]. On the other hand, ASDs (taken by two-thirds of CDI in-patients) did not worsen clinical response or recurrence rate when used concurrently with vancomycin or fidaxomicin, and it is recommended to continue PPI or H2RA treatment in CDI patients with risk of gastrointestinal bleed or GERD [128].

The US Food and Drug Administration (FDA) required that the package insert for PPIs contain a warning that PPIs may increase the risk of CDI. Noteworthy, even in healthy subjects, daily acid suppression affects gut microbiota composition [129], and these microbiota shifts are associated with functional changes that could cause bacterial overgrowth [130] and pathogen colonisation including C. difficile [131].

However, the subject remains controversial. An increased risk of CDI in PPI users has not been confirmed by some researchers [132–135], especially after adjusting for coexisting conditions [108, 133, 136–141]. No increase in the number of patients with CDI following total gastrectomy was reported [138]. Because in the elderly the prevalence of gastric hypochlorhydria is high, ASDs may not demonstrate an additional to antibiotic use risk of CDI [135]. A case–effect relationship between PPI use and CDI has not been supported by a meta-analysis which included 37 case–control and 14 cohort studies [108]; the authors estimated that in the general population taking PPIs the risk of CDI is very low; NNH of 3925 at 1 year. A meta-analysis on CDI in H2RA users (33 studies) by the same group reported NNH of 58 (95% CI 37–115) among patients receiving antibiotics and of 425 (95% CI 267–848) among patients not receiving antibiotics [107].

A recent review concluded that the influence of acid suppression in CDI remains uncertain [93], while an expert panel of infectious disease specialists agreed that PPIs are an important risk factor [66]. The newest position statement by the Sociedad Española de Patologia Digestiva indicates that the association between PPIs and CDI is mild to moderate [142]. Obviously, for a more definitive answer a prospective randomised controlled trial is needed but it would be difficult to conduct (need of a large sample size, diagnostic suspicion bias, lack of a pharmaceutical sponsor). Meanwhile, despite the limitations of observational studies, the potential association of ASDs with CDI should not be ignored [114] and clinicians should put more attention in adhering to indications for ASDs use.

Other Enteric Bacterial Infections

Use of ASDs has also been associated with an increased risk of enteric infections [121], especially Salmonella spp. and Campylobacter spp. [101, 143–148]. Five case-controlled studies have observed an association between ASDs and Salmonella infection with ORs ranging from 1.84 to 11.2 [146, 147, 149–152]. In PPIs users, the OR of infection caused by Salmonella ranged 2.09–8.3, by Campylobacter 1.7–11.7 [101, 145–147, 149, 150]. During an outbreak of salmonellosis, residents of a long-term care facility treated with ASDs were eight times more likely to develop the infection [153]. An 11.7-fold increase in the risk of gastroenteritis due to Campylobacter spp. was reported among 211 patients (aged >45 years) receiving omeprazole in the month before infection but not in former users, and no association with H2RAs was observed [145]. The risk of Salmonella- and Campylobacter-induced gastroenteritis (n = 6414 patients) was significantly associated with use of PPIs (RR 2.9) but not H2RAs [146]. In a meta-analysis (6 studies, 11280 patients) the pooled OR of enteric infections in ASD users was 2.55, with a greater association for PPIs (OR 3.33) compared to H2RAs (OR 2.03) [121]. Similarly, a recent nested case–control study of a national database on hospitalised population (14,736 case patients and 58,944 controls) reported a significant association between occurrence of nontyphoid salmonellosis and PPIs (total OR 2.09, in current users OR 5.39) or H2RAs (OR 1.84) therapy [147]. These data are in line with many previous observations of increased occurrence of non-typhoid salmonellosis in patients with reduced gastric acid secretion [154–156] and following gastric resection for peptic ulcer disease or gastric malignancy [155, 157–160]. The protective role of gastric juice against salmonella infections was also demonstrated in mice [161]. In adult volunteers, two strains of C. jejuni produced a higher rate of infection and illness when ingested with sodium bicarbonate indicating the protective role of gastric acid [162].

However, a retrospective analysis of almost 2 million individuals (about 360,000 were prescribed a PPI) after adjusting for confounding factors and eliminating the effect of time intervals did not find that PPIs increased the rate of Campylobacter and Salmonella infections [163]. The authors concluded that patients prescribed PPIs had greater underlying predisposing risks for gastrointestinal infections with a 3.1–6.9 times higher rate of these infections compared to non-PPI users even before PPI treatment started [163]. Similarly, observations from the SOPRAN and LOTUS studies did not indicate any difference in the incidence of enteric infections between the treatment groups [15]. The conflicting results may be, at least partially, related to selection bias [164]. Of note, it was shown that ASDs increased the susceptibility to Salmonella and Campylobacter infections mainly in current users and within 1–3 months after therapy ended [145–147, 149], while no association was seen when the incidence of enteric infection was compared in PPIs users 12 months before and after the event [149, 163].

In the last decade, an increased incidence of human listeriosis, a rare but dangerous food-borne disease that accounts for 20–30% of food-borne deaths [165–168], has been reported among the elderly, especially with reduced immunocompetency (cancer, diabetes, immunosuppressive therapy) and/or ASD users, in UK [169], Austria [170], Denmark [171], Spain [168] and Germany [172], as well as in North America, Japan [166] and Taiwan [173]. Moreover, in England, prescribing patterns for PPIs closely correlated with the incidence of Listeria monocytogenes bacteraemia [169]. Previous case-controlled studies found that H2RAs and antacid use was associated with outbreaks of hospital-acquired listeriosis [174, 175]. Other researchers demonstrated that patients on long-term H2RA therapy have an increased prevalence of L. monocytogenes in the feces (20 vs. 2.1% in controls), but none of them developed listeriosis [176]. Cimetidine significantly lowered the infective dose of virulent L. monocytogenes in rats [177], although this Gram-positive bacillus and facultative intracellular organism can survive the body’s natural defences within the digestive tract, including acid conditions of the stomach and bile acids [167, 178–181].

Use of H2RAs [182] or antacids [183] has also been linked to development of acute brucellosis. Because gastric juice is lethal to Brucella spp. in vitro [183, 184] drug-induced hypochlorhydria may facilitate the transit of microorganisms and disease. Lowering suppressor/cytotoxic T lymphocyte counts [185] by cimetidine may contribute to this adverse effect [186].

A case of septicaemia due to Yersinia enterocolitica (primarily a gastrointestinal Gram-negative bacilli transmitted through consumption of contaminated food or water) in a haemodialised patient receiving omeprazole has been reported [187]; raised intra-intestinal pH and increased intraluminal iron load were suggested as the main contributing factors for the infection.

Shigella spp. are acid-resistant organisms [188] and gastric hypochlorhydria does not influence the susceptibility to this infection [189]. However, in volunteers, pretreatment with sodium bicarbonate increased the isolation of the vaccine strain of Shigella flexneri in stools three-fold [190] indicating the potential role of alteration of gastric pH and/or facilitating gastric emptying on bacterial survival.

Gastric and Small Intestinal Bacterial Overgrowth (SIBO)

Acid-suppressing drug therapy is known to be associated with gastric and duodenal bacterial overgrowth. Following both H2RAs [191–195] and PPIs [195–200] high intragastric non-H. pylori bacterial counts (in both the gastric juice and mucosa) and rises in potentially carcinogenic nitrite and N-nitrosamine concentrations [193, 194, 196] were observed in several studies. The bacterial overgrowth correlated with the intragastric pH [199, 201], daily duration and degree of hypochlorhydria [198, 199] and increases in the concentration of unconjugated bile acids [198, 202]. It was suggested that the reflux of toxic unconjugated bile acids [203] into the esophagus may cause mucosal injury even in ASD users [156]. In ASD users, the overgrowth was predominantly of Gram-positive organisms, resembling that found in the mouth and oropharynx [199]. Use of PPIs or H2RAs in H. pylori-positive subjects resulted in higher intragastric pH, greater non-H. pylori bacterial colonisation, increased cytokine and N-nitrosamine levels and higher risk of atrophic gastritis [204, 205].

However, in other studies, no significant changes in intragastric bacterial counts or in bacterial species and N-nitroso-compound levels were found after cimetidine [206] and no increases in the concentration of nitrates or nitritis were noted in healthy volunteers receiving omeprazole for 2 weeks [197, 207].

Numerous reports have found an association between ASDs and SIBO. It has been documented in H2RA users [191, 208, 209] and following PPI therapy [138, 208–222]. SIBO incidence was considerably higher in patients treated with PPIs compared with H2RAs [210, 223]. These observations are in line with an increase in number of subjects with SIBO among patients with atrophic gastritis [211] and after total gastrectomy [224, 225]. The pooled (11 studies, n = 3134) OR for SIBO in PPI users versus nonusers was 2.28 [222]; the association was highly significant with OR of 7.59 only when the diagnosis was made by an accurate test such as duodenal or jejunal aspirate culture but not glucose hydrogen breath test (GHBT). Breath tests based on bacterial metabolism of various substances may produce false results [226], especially in the elderly [208, 211, 227]. Indeed, in two large studies PPI usage was not associated with the presence of SIBO as determined by GHBT (n = 1191) [228] or a positive D-xylose breath test (n = 932) [229], and one recent small study (n = 94) failed to detect an association between PPIs or H2RAs use and SIBO assessed by the lactulose hydrogen breath test [230]. The newest and largest study on this topic [231] once again confirmed that impairment of acid barrier by current PPI therapy is an important pathomechanistic pathway for the development of SIBO (OR 1.43); a potential risk of SIBO in chronic PPI users has also been observed in children [232].

ASD-related SIBO is of clinical significance, as both SIBO and reduced gastrointestinal motility (which is also an independent risk factor for development of SIBO [217, 233]), are relatively frequent, especially in older adults, may cause malabsorption and are linked to many diseases [138], including diabetes mellitus [234], non-alcoholic fatty liver disease [235, 236], liver cirrhosis [209], chronic kidney disease (CKD) [237], hypothyroidism [238], autoimmune diseases [239], obesity, irritable bowel syndrome [240, 241], gastric bypass surgery [242], cholecystectomy [243] and chronic pancreatitis [244, 245]. Because ASDs may be one of several factors contributing to SIBO and its consequences prescribing of ASDs in individuals with these conditions needs to be carefully considered.

Spontaneous Bacterial Peritonitis (SBP)

Patients with liver cirrhosis are immunocompromised and particularly prone to developing spontaneous bacterial infections often with serious complications (acute-on-chronic liver failure, renal failure, and shock) resulting in high mortality rates (30–50%) [246–249]. Because of the high prevalence of bleeding gastroduodenal ulcers [250, 251] with high mortality [252] these patients are often prescribed ASDs, although the evidence of their protective efficacy is poor [253]. Patients with cirrhosis and ascites receiving ASDs were found to be at a higher risk of SBP, overall bacterial infection [216, 254–263] and mortality [264]. In cirrhotic patients with ascites treated with PPIs the OR for developing SBP ranged between 1.40 [258] and 4.31 [254]. Meta-analyses found pooled OR for SBP for PPIs users of 1.72 [265]−2.11 [266]−2.17 [267]−2.77 [259, 268]−3.15 [269], and for HR2A users of 1.71 [269]−2.62 [259]; an OR of 1.98 for the overall risk of bacterial infection in PPIs users was reported [267]. The risk of SBP increased significantly with longer ASD use [259, 270]. A large case–control study revealed that use of PPIs in patients with cirrhosis (n = 1166) increases the risk of development of hepatic encephalopathy in a dose-dependent fashion [271].

However, some researchers did not confirm an increased risk of SBP in users of PPIs [216, 272, 273] or H2RAs [263] and did not observe a link between PPIs and bacterial infections, prognosis and mortality in cirrhotic patients [216, 274, 275]. A recent meta-analysis (10 case–control and 6 cohort studies, 8145 patients) showed that the association of PPIs with SBP was significant only in case–control studies (OR 2.97, 95% CI 2.06–4.26) but not in cohort studies (OR 1.18, 95% CI 0.99–1.14) and was not associated with increases in 30-day mortality [266]. Of practical importance, clinical trials [276–278] and current guidelines [279] do not support PPI use for prophylaxis of portal hypertension-related bleeding and recommend only a short-course of PPI post-endoscopic variceal ligation if ulcer healing is a concern [276, 279]. Of note, in patients with liver cirrhosis the prevalence of peptic ulcers ranges between 5 and 28% [253, 277], while inappropriate prescription of PPIs was found in 34–60% of cirrhotic patients [256, 257, 274, 278, 280–282]. Interestingly, in patients with CKD undergoing chronic peritoneal dialysis, the association of ASDs with enteric peritonitis (RR 1.65) and infectious mortality was more pronounced in H2RA users but less consistent among those treated with PPIs [283].

Liver Abscess and Acute Cholangitis

Use of PPIs was shown to be associated with an increased risk of cryptogenic liver abscess: OR was 4.7 for current users and 2.9 for the past users 31–90 days [284]. PPI therapy was also related to a higher incidence of cholangitis associated with increased number and broader spectrum (oropharyngeal flora) of pathogens in the biliary tract [285].

Enteric Parasitic Infections

Amongst protozoan parasites, Giardia lamblia is one the commonest etiological agents of acute usually self-limited diarrhoea worldwide (especially in developing countries), although in some patients it may become chronic with serious long-term effects [286–289]. G. lamblia is acid-sensitive. Hypochlorhydria was found in 54% of patients with intestinal giardiasis [290, 291] and associated with more severe symptoms. As survival of the parasite in the stomach requires reduced acidity, the infection, not surprisingly, is associated with chronic atrophic gastritis [292, 293] but gastric infection is rare (less than 100 cases reported in the literature [294]). In case reports, giardiasis was associated with chronic use of PPIs [175, 295–297] and ranitidine [298] as well as following gastric surgery [299]. On the other hand, a recent experimental study demonstrated that in vitro omeprazole, by inhibiting giardial triosephosphate isomerase, is effective against G. lamblia, including drug-resistant strains [300].

Strongyloidiasis, a parasitic infection endemic in tropical and subtropical regions [301–304] and observed in immunosuppressed individuals [305, 306], is also associated with hypochlorhydria [291, 307]. Gastric strongyloidiasis has been diagnosed in patients with hypochlorhydria [156, 308] and in a woman receiving H2RAs and PPIs for 2 years [309]. Opportunistic Strongyloides stercoralis hyperinfection has been reported following cimetidine therapy in immunosuppressed patients [308, 310, 311] but there were no publications of this in PPI users [294]. In one study, gastric acid levels were not associated with giardiasis or strongyloidiasis [189].

Experimental studies showed that rats pretreated with cimetidine can be infected orally with Entamoeba histolytica [312] indicating the protective effect of gastric acid against this protozoa. Artificial gastric fluid, containing 0.6% hydrochloric acid (pH 1.8) and 0.5% pepsin, but not artificial intestinal fluid, contributes to enhancing excystation for Entamoeba infection [313].

Interestingly, recent studies revealed that many widespread bacteria (Salmonella enteric, E. coli, Y. enterocolitica, L. monocytogenes) survive inside cysts of the ubiquitous amoeba Acanthamoeba castellanii, even when exposed to highly acidic conditions (pH 0.2) or antibiotics [314, 315]. An increase in acid tolerance of C. jejuni when co-incubated with amoeba was also reported [316]. These findings suggest the important role of protozoa and their cysts in the epidemiology of food-borne bacteria and the possible ways of ASDs involvement.

Respiratory Infections, Bacterial Pneumonia

Pneumonia, one of the most common infectious diseases, is a leading cause of morbidity and mortality in the elderly [317–325]. Evidence is accumulating on an increased risk of both community-acquired respiratory infections and nosocomial pneumonia in patients receiving ASDs, although the results are mixed. Subjects using ASDs compared to non-users, 2.3 times more often experienced respiratory infections, 3.7 times more often visited a physician for an infection and 4.2 times more often received antibiotics [326]. The OR for pneumonia ranged in patients taking PPIs between 1.27 [327]–1.3 [328]−1.5 [329]–1.89 [330], and in patients taking HR2As between 1.22 [331]–1.30 [332]–1.63 [330]; a dose-dependent association with PPIs was reported by some [330] but not all [329] researchers. In a meta-analysis of 33 studies, which included 6,351,656 participants, the pooled OR was 1.49 and the risk was reported to be higher during the first month of PPI therapy (OR 2.10) [333]. The association was particularly strong within a week (OR 5.0 [329]–3.79 [334]) or even the first 2 days (OR 6.53) [334] after PPI initiation, but declined over time [326, 329, 334] and was not significant for longer-term therapy [334]. The risk for pneumonia in users of ASDs was higher among patients with chronic obstructive airway disease (COPD) (OR 1.76 with PPIs, OR 1.25 with H2RAs [335], CKD (OR 2.21 with PPIs [336]), stroke [337] (OR 1.44 [338]–2.07 [339]–2.7 [340]), and non-traumatic intracranial haemorrhage (OR 1.61 [338]); the association was not significant for HR2As in stroke patients [338, 340].

Other investigators, however, reported no association between H2RAs therapy and pneumonia [329], as well as between PPIs and respiratory infections [341] (Table 1) and between PPIs and occurrence of pneumonia in COPD patients [335]. One meta-analysis (31 clinical trials) found that esomeprazole use did not increase the risk of community-acquired respiratory tract infection including pneumonia [342]; this conclusion has been recently confirmed in a report based on 24 randomised controlled trials (RCTs) by the same authors [343]. In some studies [344], ASDs have been found to significantly increase the risk of recurrent pneumonia in the elderly (OR 2.1), whereas in other reports the risk was higher among younger PPI users [329] and not obvious in individuals >70 years old [335]. Moreover, in a study based on medical record review (vs. only administrative records in most of other studies) of community-dwelling adults aged 65–94 years and controlling for confounding factors, neither PPI nor H2RA use increased pneumonia risk [345]. In patients with acute stroke, no difference in the incidence of pneumonia between PPI and H2RA users was reported in one study [346], whereas another found that in users of PPIs compared to H2RAs the relative risk of pneumonia was 1.69 [339]. Some observational studies concluded that PPIs do not increase the risk of nosocomial pneumonia, and, in contrast, reduce the risk of aspiration pneumonia in patients with a gastric tube in place [14, 347]. Of note, usefulness of ASDs in the management of GERD-related chronic cough and asthma has been described [348–351], and no difference in the incidence of lower respiratory tract infections was seen when patients treated with PPIs or anti-reflux surgery were compared [15]. The position statement by the Canadian Association of Gastroenterology [352] emphasised that the risk-to-benefit ratio appears to be largely in favour of using ASDs for conditions in which efficacy has been demonstrated.

In the setting of stress ulcer prophylaxis, the data on ASD-related pneumonia remain conflicting and require special consideration. In an intensive care unit (ICU), stress ulcer bleeding is a rare (1–6%) but severe complication (mortality 40–50%), therefore, the majority of these patients receive H2RAs or PPIs [353–355]. In a large European study, stress ulcer prophylaxis has been recognised as an independent risk factor of ICU-acquired infections among which pneumonia accounted for more than 50% [356]. Older studies indicated that prophylaxis with H2RAs is associated with an increase in the incidence of pneumonia as compared with placebo or sucralfate treatment [354, 357–359]. The risk of developing pneumonia in H2RA-treated patients was 1.3 [332] to 2 [353, 357] times higher than in the patients receiving sucralfate, which does not raise gastric pH. No difference in the rates of ventilator-associated pneumonia was observed with these two drugs in a randomised blinded placebo-controlled trial [360]. One retrospective study showed a significant association of PPIs with pneumonia only by univariate but not by multivariate analysis [125]. A PCT found a strong increase in ventilator-associated pneumonia among the PPI users compared to those receiving placebo (36.4 vs. 14.1%) [361]. The superiority of PPIs over H2RA for stress ulcer prophylaxis in patients with severe sepsis or septic shock who require mechanical ventilation has not been supported in one study [362]. However, recent meta-analyses demonstrated that in critically ill patients, PPIs were more clinically and cost effective than H2RAs in preventing upper gastrointestinal bleeding without affecting the rates of nosocomial pneumonia, length of ICU stay or mortality [4, 355, 363, 364]. It is evident from the existing data that the role of ASDs as a risk factor for community-acquired and nosocomial pneumonia is still unclear but remains likely.

Septicaemia

In the elderly, bloodstream infections are common and often fatal [365–367]. Reports implying an increased susceptibility to septicaemia associated with ASDs are scant and conflicting. In a randomised trial of critically ill trauma patients, ranitidine use compared with sucralfate was associated with a significant increase in overall infectious complications (OR 1.5), including bacteraemia (46.9%), pneumonia (25.0%) and catheter-related infections (19.8%) [332]; the number of infectious complications per patient averaged 2.6 and 1.1 in those receiving ranitidine and sucralfate, respectively. The multiple sites of infectious complications may suggest a potential immunosuppressive effect of ranitidine. Severe postoperative systemic infection after technically uncomplicated gastric resection was observed in two patients (one died) receiving prolonged omeprazole treatment preoperatively and without perioperative antibiotic prophylaxis [368]. A recent international survey (11 countries) found that most ICU units are using stress ulcer prophylaxis with PPIs (66%) or H2RAs (31%), despite the risk of infectious complications [369].

On the other hand, in animal studies, administration of PPI decreased systemic production of proinflammatory cytokines (TNF-α and IL-1β) and protected mice with endotoxic shock from death (60% survival vs. 5% of untreated mice) [370]; PPIs were proposed as promising drugs against sepsis and severe inflammatory conditions.

Mycobacterium tuberculosis Infection

A case–control study has shown that use of ASDs increases the risk of tuberculosis infection/activation (6541 cases): OR 1.63 with PPIs and OR 1.51 with HR2As [371]. However, in a sample of near 62,000 patients, long-term PPI therapy was not associated with increased risk of acquiring gastrointestinal tuberculosis [372].

Furunculosis

A case of recurrent furunculosis associated with repeated courses of omeprazole therapy was reported [373]. Six cycles of furunculosis occurred mainly on the patient’s neck; each episode developed within 1–2 weeks of starting omeprazole, continued to be present through the duration of therapy, and resolving within 1–2 weeks of discontinuation of the drug.

Fungal Infections

Although Candida spp. commonly colonise the gastrointestinal tract in healthy humans [374, 375], high levels of their presence are associated with several severe diseases [374, 376–381]. Significant Candida overgrowth has been detected in duodenal aspirates [382] and gastric juice of peptic ulcer patients treated with H2RAs [383, 384] or omeprazole [384]. The fungal isolation rate was higher in older patients and in subjects with post-treatment gastric pH of ≥4 [384]. Candidiasis of the small intestine in association with ASDs has also been reported [385]. In healthy volunteers and gastric ulcer patients, 5 weeks of omeprazole therapy resulted in a significant bacterial and Candida albicans overgrowth in the gastric juice and jejunum fluid [386]. Surgical interventions producing hypoacidity such as vagotomy [387] or partial gastrectomy [388] are associated with massive C. albicans overgrowth. Other researchers, however, reported similar positive candidal culture rates in the stomach in patients receiving PPI (17.3%) or H2RA (11.5%) and not treated with ASDs (12.5%), although PPI use was associated with higher intra-gastric bacterial infection rates (66.7, 46.2 and 28.8%, respectively) [379]. In gastric ulcer patients treated with H2Ras, C. albicans infection did not affect the healing rate and healing time [389], while in rats, persistent colonisation with C. albicans induced with ranitidine delayed ulcer healing [390].

Systemic candidiasis, a common opportunistic infection, has been observed in immunocompromised patients treated with cimetidine [391]. Candida esophagitis has been linked to ASDs. There are case-reports of esophageal candidiasis associated with H2RSs [392, 393] and omeprazole therapy [393–397] even if patients lacked other risk factors. A recent retrospective analysis of 55,314 Koreans who underwent a screening esophagogastroduodenoscopy revealed that ASD use is an independent risk factor (OR 5.11) for Candida esophagitis in addition to malignancy (OR 18.68), use of steroids (OR 6.74) and diabetes mellitus (OR 2.67). It is thought that the physiological reflux of gastric acid into the esophagus may inhibit esophageal colonization by Candida spp. [394]. In contrast, a large (80,219 patients) Japanese endoscopic-based study did not find a significant association of PPI use with Candida esophagitis [398]. A case-controlled study of adult surgical ICU patients showed that the proportion of intra-abdominal Candida infection among patients receiving ASDs and non-ASD users was similar (30.3 vs. 32.1%), although higher in chronic PPI users and those with prior abdominal surgery [399]. Empiric antifungal therapy in patients with complicated intra-abdominal infection with a history of prior use of ASDs was not recommended. Of practical importance is the antagonism of PPIs and antifungal agent fluconazole [400]. Avoidance of coadministration of PPIs and antifungal posaconazole has been shown to be effective in neutropenic haematological patients [401]. On the other hand, as both voriconazole, a broad-spectrum antifungal drug used in severe fungal infections, and PPIs undergo hepatic cytochrome P450-dependent metabolism mainly through isoenzymes CYP2C19, CYP3A4, CYP2C9, their concurrent administration significantly increases total voriconazole exposure and may be used to achieve higher plasma concentrations [402, 403].

Parasitic Protozoan Infections

No published reports on ASD-related parasitic protozoan diseases were found. In contrast, there are data that ASDs may be beneficial, exerting antimalarial and anti-leishmanial activities (two most significant of the protozoan parasites that infect man). Astemizole, an antihistamine, has been shown to inhibit chloroquine-sensitive and multidrug-resistant Plasmodium falciparum parasites, and the drug was effective in two mouse models of malaria [404]. Studies in vitro demonstrated antimalarial activity of omeprazole against trophozoites, schizonts and ring forms [405]. Combination of omeprazole with quinine had a synergistic antimalarial effect, combination of omeprazole with artemisinin drugs had an additive effect, but when omeprazole was used with chloroquine an antagonistic effect was observed [406].

In regard to cutaneous leishmaniasis, it has been reported that omeprazole and rifampicin are a highly effective combination [392, 407]. Oral cimetidine or omeprazole [408] with low dose of systemic meglumine antimoniate are recommended in high-risk patients with heart, kidney, and/or liver disease.

In the context of enormous health, social, and economic impact of human parasitic protozoa diseases (about a million deaths annually), particularly in tropical and subtropical regions of the world, lack of vaccines and limited therapeutic strategies, ASDs appear as attractive adjuvants to antiprotozoal therapy.

Interestingly, cimetidine has been found to enhance the protective effect of a schistosome vaccine [409] and omeprazole synergistically increased the efficiency of praziquantel against schistosomiasis [410], indicating advances that may arise from use of ASDs.

Viral and Prion Infections

The data on pathophysiology and clinical significance of ASDs in human viral infections are scarce. Because many viruses are sensitive to the low pH in the gastric juice [291, 411, 412], patients with hypochlorhydria may be predisposed to viral and prion infections [156]. It has been shown that influenza viruses infect and persist in gastric mucosa in patients receiving ASDs [413]. Community-acquired respiratory infections, which are mainly viral in origin, are more common in ASD users (OR 2.34) [326]. A recent review and meta-analysis found that pooled prevalence of influenza viruses in stool was 20.6%, but the occurrence of gastrointestinal symptoms among patients with influenza was inconsistent [414]. In mice, given brain homogenates contaminated with scrapie via gastric intubation, lower doses of infectious material induced disease more often when gastric acidity was reduced by adding ranitidine to the drinking water [415]. In a similar model, omeprazole-induced gastric hypoacidity more than doubled the rate of brain infection [416]. These experiments indicate the important protective role of gastric juice against orally acquired prion diseases (transmissible spongiform encephalopathies), subacute neurodegenerative disorders with an inexorably lethal outcome.

Colonisation by Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococcus (VRE)

Advanced age, healthcare contact, invasive medical interventions, chronic illnesses and antibiotic use are well-known risk factors for nosocomial antimicrobial-resistant infections, including MRSA and VRE [417–423], which have become pandemic in recent decades causing a major public health problem, serious morbidity and mortality globally [424, 425]. A high prevalence of colonisation with MRSA, VRE, penicillin-resistant pneumococci, extended spectrum beta-lactamase-producing and fluoroquinolone-resistant Gram-negative organisms (K. pneumonia, E. coli) has been well documented in the elderly, especially among residents of long-term care facilities [426–437]. Although production of gastric acid has been recognised among factors contributing to colonisation resistance [438], the possible effect of the widely used ASDs on the dissemination of nosocomial pathogens has only been addressed in a few studies. Suppression of gastric acid with an H2RA and administration of antibiotics resulted in colonisation of MRSA in the small intestine in immunosuppressed mice [439]. Similarly, in clindamycin-treated mice, use of a PPI tripled the rate of colonisation of the large intestine by ingested vancomycin-resistant Enterococcus spp. and K. pneumoniae [440]. An increased risk of MRSA colonisation associated with ASDs use (adjusted OR 7.12) was reported in ambulatory inflammatory bowel disease patients [441]. Use of antacids was identified as an independent risk factor for acquisition of VRE in a burn ICU (OR 24.2) [442], as well as in a cohort of hospitalised patients (OR 2.9) [443]. VRE colonisation was independently associated with PPI use in liver transplant candidates (OR 2.7) [444]. Use of H2RAs was found to be a predictor of bacteraemia and colonisation with extended-spectrum beta-lactamase-producing Enterobacteriaceae (area under receiver operator characteristic curve 0.8) [445]. Taking together, these observations suggest that gastric acid suppression by ASDs may act as a factor contributing to colonisation/infection with MRSA, VRE and other antibiotic-resistant bacilli. It should be noted that subjects who are colonised with these organisms, even when at low risk of developing clinical disease (asymptomatic carriers), may act as reservoirs for spreading the infectious agents to other persons, especially in RCFs.

Proposed Pathogenic Mechanisms of ASD-Associated Infections

The available data, although incomplete and conflicting, suggest that use of ASDs, especially PPIs, may predispose susceptible individuals to infections, in particular the elderly and frail persons with multiple comorbidities, who are more likely to be prescribed these medications as well as antibiotics. The underlying biological mechanisms involved in ASD-associated infections are complex and still not fully understood. The promising and plausible biological mechanisms related to pleiotropic effects of ASDs include: (1) inhibition of gastric secretion and gastric emptying [446] and suppression of gastrointestinal motility [213, 274, 447, 448], (2) immune dysfunction (reduction of the immune-mediated resilience to infections), direct effects on the activity of neutrophils, monocytes, endothelial, and epithelial cells [449, 450], (3) metabolic disorders such as vitamin (B₁₂, C) and mineral deficiencies (iron, magnesium and calcium) [5, 451–453], (4) increased mucosal permeability [216, 454–456]—all factors resulting in (5) disruption of the natural gut microbial flora and predisposing to infectious diseases. These ASD-associated conditions may exert their effects separately but usually in concert; and in each infection type, despite differences in biology, predisposing and initiating events, the above-mentioned pathophysiological factors are linked and overlap.

The elderly, understandably, are potentially at higher risk of ASD-associated infections due to age-related decreased gastric acidity, often esophageal and gastro-intestinal motility disorders, impaired phagocytosis, decreased antibody production and compromised immune system—immunosenescence [457–461]. In addition, impaired drug metabolism (e.g. in advanced cirrhosis), especially of PPIs (except rabeprazole), may result in higher exposure to PPIs [33, 257].

Inhibition of Gastric Secretion

High gastric acidity, in combination with pepsin, lipase and mucus is a fundamental, though non-specific, natural physiological barrier against a variety of ingested bacterial and parasitic pathogens [307, 462–469]. Not surprisingly, alteration in this defence system—both acquired and iatrogenic gastric hypochlorhydria/achlorhydria—increases susceptibility to and severity of enteric infections [147, 156, 191, 195, 294, 307, 470–472] caused by bacteria such as Salmonella, Cholera, E. coli, Campylobacter and Yersinia species [156, 473], parasites and viruses; the strongest evidence is on non-typhoid salmonellosis and cholera [156, 307, 463, 474]. In mice with hypochlorhydria caused by mutation in a gastric H⁺/K⁺-ATPase (proton pump) gene significantly greater numbers of Salmonella, Yersinia, and Citrobacter cells and Clostridium spores survived, resulting in reduced median infectious doses [475]. In general, the risk of clinical infection is higher in PPIs users compared to persons receiving H2RAs because of greater gastric acid suppression with PPIs. On the other hand, some bacteria and fungi, known to inhabit the human body, contain proton pumps which belong to the family of P-type ATPases which includes the human gastric H⁺/K⁺-ATPase [476–478]. Therefore, potentially PPIs may directly target the proton pumps of these bacteria and fungi, for example, in H. pylori [479, 480], some Streptococcus spp. [481] and fungi [477, 482].

It should also be recognised that bacteria, viruses and parasites have multifaceted repertoires of strategies to evade host’s defence systems including the ability to reduce gastric secretion of acid [156, 463] and mucus production [468] as well as affect immune responses.

Loss of this major non-specific defensive mechanism—the increase in gastric pH by ASDs—allows pharyngeal commensals and ingested environmental organisms (most of which, except H. pylori, are not adapted to low pH) to survive, proliferate and colonise in the stomach, to pass into the duodenum and further along the gastrointestinal tract causing gastrointestinal dysbiosis. The normal gastrointestinal flora maintains the histological structure of the gut mucosa and is an extremely important host defence mechanism, highly effective in protecting against colonisation by potentially pathogenic invaders. The qualitative and quantitative alterations in the gut microbiota may result in a number of intestinal and extra-intestinal infections.

Effects of ASDs Unrelated to the Inhibition of Gastric Acid Secretion

The ability of a microorganism to cause infectious disease is a function of both its intrinsic virulence and the host’s defence barriers, which include immunological competence. The ASDs in addition to the inhibition of gastric acid secretion directly and indirectly influence multiple functions related to the immunological defence status [450]. PPIs reduce different neutrophil functions [483–486], including phagocytosis and acidification of phagolysosomes [487], adhesion of neutrophils to endothelial cells [488, 489], exhibit anti-oxidant properties [449, 490–497], suppress the expression of tumour necrosis factor-alpha, interleukins (IL-6, IL-8, IL-1β), intracellular and vascular adhesion molecules [488, 498–501], inhibit the nitric oxide synthase [501, 502] and lysosomal enzymes [503], dose-dependently decrease production of pro-inflammatory/profibrotic cytokines by epithelial and endothelial cells [450, 499, 504, 505], decrease natural killer cell cytotoxic activity in a dose-dependent manner [506], impair neutrophil migration from vessels to inflammatory sites by preventing the activation of heparanase [486], mitigate neutrophil adherence to endothelial cell [500], affect neutrophil chemotaxis and phagocytosis of micro-organisms [216, 483, 487, 507]. These mechanisms, although some of them remain hypothetic, might compromise immunity, contribute to bacterial colonisation and a variety of inflammatory and infectious disorders. Noteworthy, the rise of intralysosomal pH by PPIs is considered the major mode of the direct antileishmanial in vivo [392, 508] and antimalarial in vitro activities [405] and in the inhibition of the rhinovirus infection in cultured human epithelial cells [504]. PPIs might also be potentially beneficial in inflammatory diseases, in which the role of acid and pepsin is minimal (e.g. eosinophilic esophagitis, idiopathic pulmonary fibrosis) [450], as well as for antineoplastic therapeutic regimens [500, 509–512].

Immunomodulation effects of H2RAs have also been documented [332, 513]. Histamine plays an important role in the regulation of neutrophil-dominant inflammatory reactions mediating an oxidative burst, one of the most important defence mechanisms for the elimination of invading microorganisms [514–517]. H2 receptors (as well as H1 and H4 receptors) are expressed in neutrophils and other immune cells [518–521]. The results from experimental studies on the effects of H2RAs on neutrophils, monocytes and other cells are controversial [515–518, 522–526]. Clinical observations indicate that H2RAs may improve postoperative immunosuppression [523, 527], modulate IL-6 signal transduction and reduce CRP levels [528]. A potential beneficial impact of H2RAs in the treatment of multiple myeloma [522], gastrointestinal and breast cancers has also been reported [529, 530].

Altogether, simultaneous suppression of gastric secretion and modulation of multiple factors involved in the pathogenesis of infection and cell homeostasis by ASDs might affect the complex host-infective agent relationship and explain the increased incidence of infectious diseases among some ASD users, but beneficial effects in other patients (e.g. postoperative, with cancer, some parasitic infections, idiopathic pulmonary fibrosis, etc.). This suggests that the resulting effect should be considered in each patient individually taking into account the appropriateness of ASD use, underlying comorbid conditions, their severity and other medications prescribed. There is a need for a paradigm shift in the ASD use from disease-oriented to an individual patient-oriented. The risk of ASD-associated infections is usually the result of a complex interaction between multiple mechanisms, including ASD exposure-induced dysbiosis and altered immunity, as well as the patient’s underlying immunological status, which may be affected by the different conditions and diseases (age, CVDs, DM, COPD, oropharyngeal dysphagia, CLD, CKD, cancer, polypharmacy, immunosuppressive drugs, indwelling devices, etc.) (Fig. 1).

Fig. 1

Possible mechanisms linking ASD use to infections. ASD acid-suppressing drug, PPI proton pump inhibitor, H2RA histamine-2 receptor antagonist, CDI Clostridium difficile infection, CKD chronic kidney disease, CLD chronic liver disease, COPD chronic obstructive airway disease, CVDs cardio-vascular diseases, DM diabetes mellitus, Fe iron, Mg magnesium, Ca calcium. ASD exposure can induce dysbiosis and compromise the immunological status predisposing to and precipitating infectious diseases. Of note, the interaction between microbiota and immunity is bidirectional, and the underlying conditions, diseases and used pharmacotherapeutic agents can alter defence mechanisms. Thus, the risk of infection is usually the result of a complex interaction between multiple mechanisms. The elderly are at a higher risk of infections because of the number of comorbidities and more pronounced impairment of defences against infections

ASDs and CDI

With regard to the association of ASDs with CDI, it should be noted that C. difficile vegetative forms (not spores which are acid-resistant [531]) are normally killed by gastric acid but survive when the pH >5, and the stool samples of infected individuals contain 10-fold more vegetative cells than spores [532]. Bile salts, as has been shown in the Syrian hamster, stimulate the transition of C. difficile spores to vegetative cells in the duodenum and small intestine [533]. Therefore, reduced gastric acidity together with presence of bile salts in gastric contents [e.g. in gastrointestinal reflux disease (GERD)] may affect C. difficile spore germination, facilitate the survival of the vegetative forms [534] and allow them to move down causing gut dysbiosis [199, 535] and predisposing to CDI [536, 537]. ASD-associated bacterial overgrowth increases levels of unconjugated bile acids [294] and might further facilitate CDI. However, the relationship between bile acids and CDI is complex [538, 539], no change in any of ten dominant human primary and secondary bile acids has been observed in healthy volunteers receiving high doses of PPIs (40 mg omeprazole, twice daily) [129].

Recent studies indicate that ASDs, especially PPIs, may increase risk of CDI by (1) altering composition of the gut microbiota [537] (towards a less healthy one), in particular the taxa involved in colonisation resistance to C. difficile (increased Enterococcaceae and Streptococceae, decreased Clostridiales) and taxa associated with gastrointestinal bacterial overgrowth (increased Micrococcaceae and Staphylococcaceae) [129, 130, 535, 537, 538, 540, 541], (2) affecting C. difficile toxin gene expression [542], (3) increasing the pathways corresponding to genes for bacterial invasion of epithelial cells and for renin-angiotensin system [129], and decreasing the expression of genes responsible for colonocyte integrity [543], and (4) directly acting on specific bacterial taxa (e.g. some Streptococceae species), which contain proton pumps belonging to the same enzyme family as the human H⁺/K⁺-ATPase [478, 481]. Taking together, the available clinical and animal [70] data indicate that ASDs may directly and indirectly affect the gut microbiome and, therefore, increase the risk of CDI. Importantly, on the population level, PPIs more than antibiotics or other used drugs are associated with profound gut microbial alterations [535].

ASDs and Pneumonia

With regard to bacterial pneumonia in patients treated with ASDs, the possible explanations and the consequence of events include (1) rise in gastric pH, promoting the proliferation of bacteria, the upper gastrointestinal tract and tracheobronchial colonisation [544–546], (2) pulmonary micro-aspiration and bacterial exchanges between the gastric and lung fluids [547], bacterial passage into the lungs and overgrowth/colonisation [198, 200, 223, 330] together (3) with impaired immune and neutrophil functions [449, 488]. In a large healthy twin cohort, PPI users demonstrated a significant increase in Streptococcaceae family [537], whereas an increased risk of community-acquired pneumonia has been reported specifically for Streptococcus-derived pneumonia [548]. These observations support the view that in PPI users the gut is likely to become a reservoir for potential pathogens [537]. Furthermore, it has been shown that depletion of the gut microbiota reduces immune-mediated resilience to pneumococcal pneumonia in mice [549]. The postulated biological mechanisms for higher pneumonia risk in ASD users, however, do not fully explain why in some studies the correlation was weaker with the longer medication use [326, 329, 330]. Although protopathic bias (when a pharmaceutical agent is prescribed for an early manifestation of the disease that has not yet been diagnosed) could not be excluded, it is possible that susceptibility to pneumonia individuals (comorbid conditions, advanced age, poor health and immunocompromised status) might develop the disease sooner after starting ASDs [294, 334, 550, 551]. In H2RAs users, this phenomenon may also be related, at least partially, to tolerance to H2RAs (usually within the first 2 weeks) which causes decline in acid suppression.

ASDs and SBP

In immunodeficient liver cirrhosis patients, the development of ASD-associated infections, including SBP, might be related to the effects of these medications on the balance between immune defences and intestinal flora. The decreased granulocyte and monocyte oxidative burst by PPIs [552], ASD-induced dysbiosis [209] with increased intestinal permeability [456] and impaired liver drug metabolism have been suggested as important pathophysiological factors for explanation of the risk of SBP in ASD users.

Practical Implications

The reviewed scientific literature demonstrates that ASDs, which, undoubtedly, are of great value for treatment and prophylaxis of acid-related diseases, may be associated with an increased risk of infections, especially in the elderly. Although extensive associations between ASDs and a number of infections have been reported, it should be emphasised that most of the information was derived from observational retrospective cohort or case–control studies, and systematic reviews evaluating these studies revealed bias in selection, misclassification, interpretation and residual confounding; the observed associations may be confounded by multiple coexisting conditions and do not prove causality. It should also be recognised that prospective randomised controlled studies which are often considered the “gold standard” would not only be difficult to perform (e.g. recruitment of frail elderly patients, costs, etc.) and ethically questionable, but may not provide absolute certainty [553]. Despite the limitations of the available data, current lack of conclusive evidence of causality, the existing reports on possible adverse effects of ASD therapy should not be ignored, but adequately interpreted and properly applied into everyday clinical practice.

Accumulating evidence suggests that adverse effects of ASDs (mainly of PPIs) in addition to infections may include poorer cardiovascular outcomes [554], an increased risk of CKD [555], fractures, especially of the hip [123, 556–573], vitamin and mineral deficiencies [574–576], altered mental status and delirium [577, 578], development of enterochromaffin-like cell hyperplasia [579], risk of gastric neuroendocrine tumours [580], and fundic gland polyps [581]. The complexity of therapeutic ASD use is further increased by drug-drug interactions (pharmacokinetic and pharmacodynamic), which, not surprisingly, are particularly common in the elderly due to polytherapy [582]. Clinically relevant interactions were reported for PPIs with clopidogrel [583–586], dabigatran [587], bisphosphonates [559, 568], metformin [588, 589], methotrexate [590–593], antidepressants and antipsychotics [38], fluconazole [400, 594], immunosuppressants (e.g. mycophenolate) [595–597], magnesium oxide [598], different anti-cancer and antiviral medications [599, 600]. In addition, all ASDs by increasing gastric pH can affect the bioavailability of several other drugs (e.g. iron salts, ampicillin, ketoconazole). H2RAs decrease absorption of magnesium oxide [598] and dasatinib [601, 602].

Although the reports on adverse drug-drug interactions with PPIs are conflicting and when evaluated in systemic reviews such events were found to be rare and the increased risk, for the most part, mild-modest [600], a careful individualised judgement in patients taking above-mentioned medications before prescribing ASDs is needed. For example, use of ASDs was shown to be associated with an increased risk of hip fracture only among persons with at least one risk factor for osteoporosis [603]; H. pylori positivity was found to be a significant independent risk factor for osteoporosis but its eradication was not [604].

When choosing an ASD, in general a relatively safe medication [605, 606], to manage gastric acid-related disorders the potential for possible spectrum of adverse events, drug-drug, drug-nutrient interactions and agent-specific side effects should be considered. For each individual patient, the balance of risk and benefits, agent of choice, the possible dose, and duration of use, requires careful attention.

Unnecessary or inappropriate use of ASDs, especially of PPIs, has been consistently documented in the adult population (ranged from 34.2 to 63%) [22, 29, 294, 607–614], including hospitalised patients (26.8–73.9%) [23, 25, 26, 440, 609, 615–622] and after discharge (>50–80.2%) [616, 618–620, 623–625] as well as among nursing home residents (24–93%) [626–630]. Long-term use of ASDs, which are now available over-the-counter in many countries, may represent a prescribing cascade [630] with minimal therapeutic benefits and excess costs [606, 618, 621, 623]; unfortunately, the inappropriate use of ASDs is increasing [631], especially among patients of a lower socio-demographic status [611, 631].

On the other hand, there are reports that ASDs are underused. For example, only 31.7% of patients with Barrett’s esophagus or GERD were prescribed either PPI or H2RA [632], adequate gastroprotection was not provided to more than 50% of short-term users of NSAIDs who were at an increased risk for upper gastrointestinal complications [633], and only 3.5% of low-dose aspirin users received PPIs, H2RAs or mucoprotective drugs [634]. Because the world population is ageing and age is an important risk factor for CVDs, arthritis and chronic pain, as well as for antiplatelet- and NSAID-associated ulcers and bleeding [635–638], in the coming years the prophylactic ASD use is likely to increase significantly. A recent meta-analysis demonstrated that the combination of selective COX-2 inhibitors with PPIs provides the best gastrointestinal protection, followed by selective COX-2 inhibitors, whereas co-administration of H2RAs with nonselective NSAIDs did not significantly reduce the risk of clinical gastrointestinal events [639]. PPI therapy is needed in 10 high-risk and 268 moderate-risk patients to prevent one NSAID-related ulcer [640].

The data presented above raise serious challenges and the following steps may be helpful in clinical practice when considering ASD treatment: (1) evaluate for evidence-based indications for ASD therapy, (2) weigh the risks for adverse effects of ASDs in the individual patient (primum non nocere, do not harm), (3) assess potential drug-drug interactions, (4) choose an adequate drug, dose (minimal effective) and duration (consider discontinuation if indications are not certain) tailored to the specific constellation of a patient’s conditions and preferences, (5) consider interventions that may prevent/reduce infectious and other adverse effects associated with ASD use, and (6) monitor the patient carefully after therapy starts and decide when it could be ceased (Fig. 2). While basic sanitation, hand-washing and monitoring of antibiotics use remain central to preventing and limiting nosocomial infections, appropriate use of ASDs, especially in elderly, chronically ill and immunosuppressed patients, is also important.

Fig. 2

Suggested algorithm for an optimised acid-suppressing drug (ASD) therapy. GI gastro-intestinal, GERD gastro-esophageal reflux disease, NSAID non-steroidal anti-inflammatory drug, PPI proton pump inhibitor

ASD-associated infections (and other adverse effects) are not a class effect. Differences of clinical relevance exist between PPIs and H2RAs as well as in the pharmacokinetic profiles of individual PPIs and H2RAs. These include (1) absorption of H2RAs is not affected by food, while meal-related dosing is necessary with PPIs especially when treating GERD; (2) tolerance to H2RAs, though of minor clinical significance, may develop after 2–7 days of therapy [641, 642], but tolerance does not occur with PPIs [643]; (3) in patients with renal impairment, the doses of H2RAs, but not of PPIs, should be reduced [644–648]; (4) although PPIs in general are more effective than H2RAs in preventing upper GI bleeding, the increased risk of CDI, pneumonia and other infections as well as fracture is lower in patients taking H2RAs compared with patients taking PPIs; (5) the risk of drug interactions mediated by cytochrome P450 enzymes should be considered for both omeprazole and cimetidine (because of their high affinity for CYP2C19 concomitant use of these medications with clopidogrel affects the biotransformation of clopidogrel by competitive inhibition of CYP2C19 [649–652]); in contrast, other PPIs (pantoprazole, lansoprazole, rabeprazole, esomeprazole and dexlansoprazole [600]) and H2RAs (famotidine, nizatidine or ranitidine, rabeprazole [653, 654]) have lower potential for drug-drug interactions; however this suggestion has not been fully confirmed in a recent meta-analysis [655]. Omeprazole when used concomitantly with protease inhibitors can cause different adverse effects [503] because of its potent pH alteration and inhibition of p-glycoprotein pathway [590]. These potential benefits and harms of PPIs and H2RAs should be considered before initiating ASDs to manage gastric acid-related disorders, especially if treatment includes polypharmacy, which for vulnerable geriatric patients can be unavoidable [656, 657].

As PPIs which are associated with a variety of adverse events do not reduce the number of reflux events and do not provide long-term cure for GERD, use of H2RAs and prokinetics and non-medical interventions should also be considered [658].

Although ASD prophylaxis against stress ulceration in critically ill patients has been part of routine clinical practice for several decades, the data on its benefits are controversial [353, 354, 359, 363, 364, 659–663]. It was concluded that the quantity and quality of evidence supporting the use of ASDs in ICU is low [664, 665]; PPIs might reduce the rate of gastrointestinal bleeding, but increase rates of nosocomial infections (especially pneumonia and CDI), myocardial ischemia [666] and mortality (e.g. patients with liver cirrhosis) [667]. The recommended alternatives to PPI prophylaxis are H2RAs [667] and sucralfate [332, 353, 358, 667], an agent which does not alter gastric pH and exerts its topical effect by binding to proteins of the ulcer site [332, 353, 358, 667]. In contrast, in three other meta-analyses, PPIs were superior to H2RAs in preventing gastrointestinal bleeding without significantly increasing the risk of pneumonia or mortality [363, 364].

Finally, strategies for reducing potential ASD-associated infections in addition to avoiding inappropriate prescribing, implementation of standardised guidelines, antibiotic stewardship programmes and sound infection control practices, should, as adjuvant therapy, consider: (1) use of probiotics (live microorganisms with beneficial physiologic or therapeutic properties) or prebiotics (non-digestible dietary components that beneficially affects the host by stimulating the growth and/or activity of beneficial bacteria in the colon) and (2) correction of the vitamin D status. Implications of such potentially effective interventions have been, unfortunately, largely overlooked.

Currently, probiotics are recommended and used (with varying success) to protect against infections [668, 669], particularly for reduction of antibiotic-induced primary CDI [66, 670–681], travel-related diarrhoea associated with antibiotic use [682], especially in the elderly [683], and as adjuvant therapy for H. pylori eradication therapy [8, 684, 685], as well as for acute upper respiratory tract infections [686, 687], ventilator-associated pneumonia in critically ill patients [688, 689], pneumonia caused by K. pneumonia (in mice) [690], urogenital infections [691], postoperative infections [692] and oral candidiasis [693] protection. Because ASD-related alterations in composition and function of the microbiota are associated with the development of infections, use of pro- and prebiotics may provide a simple preventive measure in ASD users. It is well documented that the gut microbiome plays a significant role in the regulation of host metabolism and immunity [694–710], and a wide variety of systemic diseases and conditions are associated with gut dysbiosis. Increased intake of yogurt with a sufficient number of viable probiotic bacteria (mainly Lactobacillus and Bifidobacterium spp.) positively modulates gut microbiota, prevents dysbiosis, improves immune status [705, 711–713], the barrier function of the gut [697, 714] and possess antagonistic activity against C. difficile, S. aureus, Salmonella spp., E. coli, P. aeruginosa, Enterobacter, L. monocytogenes, C. perfringens and other bacterial agents [705, 715–721]. Also reduces gastrointestinal carriage of VRE [722, 723], displays antiviral, detoxifying, cholesterol-lowering, anti-diabetic and antioxidant properties [705]. Therefore, it is likely that probiotic use, a diet rich in yogurt and fibre may have significant potential health and nutritional benefits, including a protective effect on decreasing the incidence of ASD-associated infections, especially in the elderly [724, 725]. Such an approach can be considered a promising add-on therapy to counteract the effects of ASDs on gut dysbiosis. However, because of existing gaps in the understanding the human microbiota and the multiple mechanisms by which probiotics modulate various physiological functions, challenges and concerns persist regarding appropriate treatment regimens (specific probiotic strain(-s), most effective combinations, optimum dosing, use of nutrients), and even safety (mainly the potential of opportunistic infection in immunocompromised patients) [705, 714, 726–728] and genetic stability.

Recent research demonstrated the critical role of vitamin D in human innate and adaptive immunity [729–731]. Vitamin D insufficiency, which is highly prevalent (40–60% in the healthy general adult population), may lead to dysregulation of immune responses and increases susceptibility for infections and mortality in different settings [732–737]. Vitamin D deficiency is also reported to be associated with increased risk [738] and greater severity of CDI in some [739–741] but not all [742] studies. Animal studies found that dietary-induced vitamin D deficiency increases susceptibility to Citrobacter rodentium-induced colitis and exacerbates intestinal inflammatory response impairing mucosal defence [743]. Although results of several trials assessing the effects of vitamin D supplementation on infections were mixed [732, 736, 744–746], the currently available balance of evidence supports such intervention as a promising one for prevention the risk of infectious diseases, including ASD-related diseases. Potential benefits of correction of vitamin D insufficiency and maintaining vitamin D levels in the normal range also include reduced risk of many common bone, immune, cardiovascular, renal, liver, metabolic, malignant, and mental disorders, as well as mortality; these have been shown in numerous observational studies and meta-analyses, but adequate randomised trials are still lacking.

In view of current evidence and the underlying biological plausibility adding probiotics (e.g. yoghurt) and correcting vitamin D status may have beneficial consequences. However, given the limited and conflicting reports, further well-designed studies are needed to determine the effects of both probiotics and vitamin D supplementation as adjunctive therapies in infection prevention.

We hope that this review will help clinicians cope with information overload, enable them to individualise decisions regarding the use of ASDs, selection of a specific drug, and clearly discuss the balance between benefits and potential harms with the patient before starting long-term treatment.

Conclusions

Development and use of ASDs (H2RAs and PPIs), one of the most commonly prescribed classes of medications, has been revolutionary. Their therapeutic and prophylactic benefits are well recognised and the absolute risk of the complications including ASD-associated infectious diseases is relatively low. Accumulating data, however, indicate the complexity of ASD effects involving important defence systems, non-immunological and immunological, resulting in dysbiosis and increased risk for enteric, including CDI, and other infections, particularly in the elderly. Despite the limitations of the existing data, the importance of individualised therapy and caution in long-term ASD use considering the balance of benefits and potential harms, factors that may predispose to and actions that may prevent/attenuate adverse effects is evident. A six-step practical algorithm for ASD therapy based on the best available evidence is presented.