The potential risks of probiotics among HIV-infected persons: Bacteraemia due to Lactobacillus acidophilus and review of the literature

Abstract

Lactobacillus sp. are commensal organisms that are increasingly reported to cause invasive infections among immunosuppressed persons. However, few data exist regarding the occurrence and risk factors of these infections among HIV-infected persons. Further, the safety of products that contain lactobacilli (e.g. probiotics) in certain populations, including those with HIV/AIDS, is unclear. We report a case of Lactobacillus acidophilus bacteraemia in a patient with AIDS temporally related to excessive consumption of probiotic-enriched yogurt, and provide a comprehensive review of the literature of Lactobacillus sp. infections among HIV-infected persons.

Keywords

lactobacillemia HIV invasive infections probiotics risk factors review

Introduction

Lactobacilli are anaerobic or facultative anaerobic Gram-positive bacilli that are natural commensals of mucosal surfaces in the mouth, gastrointestinal and genitourinary tracts. The pathogenicity of these organisms has been debated; however, there have been multiple confirmed cases of invasive Lactobacillus infections, especially among immunocompromised hosts.^1–3

A novel risk factor for the development of invasive Lactobacillus infections may be the use of probiotics containing Lactobacillus acidophilus and/or Lactobacillus rhamnosus. The use of these ‘natural’ products in the form of commercial yogurt products or dietary supplements has dramatically increased over the past decade. Although probiotics have been utilized for a variety of health conditions, the most studied is for restoring the intestinal microbiome and preventing antibiotic-associated diarrhoea including Clostridium difficile.⁴ While probiotics have been shown to be safe in many populations,⁵ their safety in certain populations, including those with the human immunodeficiency virus (HIV), remains unclear.

Invasive Lactobacillus infections have been rarely described in HIV-infected persons and their relation to probiotic use has only recently been reported,^6,7 hence more data on this potential complication are needed. We report a case of L. acidophilus bacteraemia in a patient with acquired immunodeficiency syndrome (AIDS) and alcoholic liver disease in the setting of consumption of excessive probiotic-enriched yogurt. This paper also provides a comprehensive review of the literature of invasive Lactobacillus infections among HIV-infected persons, and summarizes risk factors, including probiotic use, among this population.

Case report

A 51-year-old man presented with a two-week history of epigastric pain and odynophagia. His medical history was significant for HIV infection diagnosed in 1988 with subsequent progression to AIDS. The patient had discontinued antiretroviral therapy (ART) two months prior to admission due to poor compliance with clinical follow-up visits and lack of prescriptions for these medications, but he was receiving trimethoprim-sulfamethoxazole prophylaxis. On presentation, the patient had alcohol-related liver disease (MELD score of 42) with a history of ascites and oesophageal varices. During the week prior to admission, he admitted to relapsing heavy alcohol use.

On physical examination, vital signs were blood pressure of 118/63, pulse 102/min, respiratory rate 18/min, and oral temperature of 36.3°C. He was cachectic with oral thrush, scleral icterus and jaundice. Abdomen examination demonstrated epigastric tenderness and ascites. There were no cardiac murmurs or dental disease.

Laboratory values on admission were significant for a white blood cell count of 21,200/mm³, haemoglobin 11 g/dL, platelets 220 × 10⁹/L, creatinine 7.1 mg/dL, aspartate aminotransferase (AST) 144 U/L, alanine transaminase (ALT) 50 U/L, alkaline phosphatase 194 IU/L, albumin 2.4 g/dL, total bilirubin 24.9 mg/dL and an international normalized ratio (INR) of 2.4. A CD4 cell count was 34 cells/mm³ (CD4 percentage 3%) with an HIV RNA level of 84,200 copies/mL.

An abdominal ultrasound demonstrated cirrhosis and ascites, as well as cholelithiasis with moderate gallbladder wall thickening and a negative sonographic Murphy’s sign. An abdominal CT scan showed cirrhosis, ascites and splenomegaly without biliary disease. The patient was empirically treated with cefotetan 1 g intravenously daily for suspected spontaneous bacterial peritonitis and fluconazole for presumed oesophageal candidiasis. Because the patient presented with acute kidney insufficiency, trimethoprim-sulfamethoxazole was discontinued.

Blood cultures from admission grew L. acidophilus. After further history, the patient disclosed recently eating two to three servings of a probiotic-enriched yogurt daily starting the week before admission with the belief that this may improve his liver disease and abdominal symptoms. Cefotetan was discontinued, and he was treated with ampicillin/sulbactam 3 g intravenously every 8 h. Repeat blood cultures on day 3 of admission were negative, and an echocardiogram showed no evidence of vegetations. A culture of ascitic fluid was negative.

Identification of L. acidophilus was performed using the Remel RapID™ ANA II System and antibiotic susceptibilities were performed using broth dilution methodology. Using breakpoints recommended by the Clinical Laboratory Standards Institute,⁸ the L. acidophilus isolate was susceptible to penicillin (<0.5 µg/mL), gentamicin (1.0 µg/mL), clindamycin (0.25 µg/mL) and vancomycin (<0.5 µg/mL).

The patient received a total of 14-days of antibiotics, with oral amoxicillin/clavulanate utilized for the last four days of therapy. The patient’s clinical status (tachycardia and abdominal pain) and white blood cell count (11,600/mm³) improved. His hospital course was complicated by decompensated liver disease, and he was discharged after 19 days of hospitalization on azithromycin for Mycobacterium avium complex (MAC) prophylaxis, dapsone for Pneumocystis carinii pneumonia (PCP) prophylaxis and weekly ciprofloxacin for spontaneous bacterial peritonitis prophylaxis. Given his poor prognosis, he opted to remain off of ART and enter a hospice program. He was advised against ingesting probiotics or yogurt containing live microorganisms.

Review of the literature

We conducted a review of the literature for cases of invasive Lactobacillus sp. infections among HIV-infected persons (1981–current). We utilized PubMed and the search terms ‘HIV’, ‘human immunodeficiency virus’, or ‘AIDS’ and ‘lactobacillus’ or ‘lactobacillemia’. We reviewed all identified papers for confirmed invasive infections including bacteraemia, endocarditis, pneumonia, empyema, or deep-seeded abscesses. We also searched large reviews of invasive Lactobacillus infections for cases occurring among HIV-infected persons. References of articles were examined to identify additional published cases.

Including the current case, we identified 10 cases of invasive Lactobacillus infections among HIV-infected persons (Table 1).^6,7,9–13 We excluded one case in which Lactobacillus was isolated only in a sputum culture in the setting of other pathogenic organisms.¹⁴ The median age of patients was 44 (range 4–56) years and 80% of cases occurred in men. Among cases with reported CD4 cell counts (n = 8), the median CD4 cell count was 32 (range 4–660) cells/mm³. All cases had a low CD4 cell count (<50 cells/mm³), except one which occurred in a lung transplant recipient.

Table 1.

Published literature of invasive lactobacillus infections among HIV-infected persons.

First author/ Year/Ref	Age/ Gender	CD4 cell count, cells/mm³	ART	Additional potential risk factors	Type of infection	Species	Treatment	Outcome
Sherman et al.⁹	48/M	NR	No	History of renal transplant on immunosuppressants; history of CMV oesophagitis; gastrectomy with anastomosis; diabetes	Bacteraemia, splenic abscess	L. casei subspecies rhamnosus	Clindamycin and gentamicin, and then clindamycin alone for 3-week course; splenectomy	Survived
Horwitch et al.¹⁰	44/M	28	No	Central line; recent vancomycin for staphylococcal bacteraemia	Bacteraemia	L. rhamnosus	Clindamycin for 10-day course	Survived
Horwitch et al.¹⁰	33/M	52	No	Central line; recent vancomycin for staphylococcal bacteraemia; gastrointestinal CMV and cryptosporidiosis	Bacteraemia	L. rhamnosus	None	NR
Horwitch et al.¹⁰	33/M	4	No	Central line; candida esophagitis; gastrointestinal KS	Bacteraemia	NR	Clindamycin, then cefazolin for 14-day course	Survived
Abgrall et al.¹¹	38/W	32	No	Candida oesophagitis; recent vancomycin use for staphylococcal bacteraemia	Pneumonia (based on BAL)	L. casei subspecies rhamnosus	Clindamycin	Died due to sepsis within 24 h
Schlegel et al.¹²	4/W	38	2 drug therapy	Recent use of vancomycin	Bacteraemia	L. casei subspecies rhamnosus	Amoxicillin and gentamicin, then amoxicillin alone; 12-day total course	Survived
Rogasi et al.¹³	44/M	8	No	IVDA; periodontal disease	Bacteraemia, pneumonia (no positive sputum)	L. casei	Ceftriaxone	Survived
LeDoux et al.⁶	38/M	NR	Yes	NHL; recent central line; recent staphylococcal bacteraemia; probiotic use	Bacteraemia, catheter-associated deep vein thrombophlebitis, and septic pulmonary emboli	L. acidophilus	Clindamycin and gentamicin	Survived
Luong et al.⁷	56/M	660	Yes	Lung transplant recipient; ongoing diarrhoea; probiotic use	Empyema	L. rhamnosus GG	Ampicillin-sulbactam; decortication	Survived
Current case	51/M	34	No	Alcoholic liver disease; oesophageal candidiasis; probiotic use	Bacteraemia, SIRS	L. acidophilus	Ampicillin-sulbactam and then amoxicillin/clavulanate; 14-day course	Survived

ART, antiretroviral therapy; BAL, bronchoalveolar lavage; CMV, cytomegalovirus; W, woman; IVDA, intravenous drug use; KS, Kaposi’s sarcoma; M, man; NHL, non-Hodgkin’s lymphoma, NR, not reported; SIRS, systemic inflammatory response syndrome.

Regarding underlying conditions that may have additionally predisposed HIV patients to Lactobacillus infection, the most common was a gastrointestinal condition (n = 6) including prior surgery, Kaposi’s sarcoma, infection (cytomegalovirus, cryptosporidium, Candida), and diarrhoea of unclear aetiology; some cases had multiple factors. Our case is the first to report severe liver disease as a potential predisposing gastrointestinal condition associated with lactobacillemia in an HIV-infected person. Additional potential risk factors included recent receipt of intravenous vancomycin (n = 4; most commonly for staphylococcal bacteraemia) and a history of organ transplantation (n = 2; renal, lung). Probiotic use was noted in the three most recent cases, including the present case. Of the previously published cases, one HIV patient developed empyema five weeks after ingestion of a probiotic containing L. rhamnosus GG with a genetically identical organism isolated in the pleural culture.⁷ The second case in the literature with L. acidophilus bacteraemia developed three weeks after initiation of a probiotic; the specific details of the probiotic used or the genetically relatedness of isolates were not reported.⁶ In the current case, L. acidophilus bacteraemia developed one week after initiation of probiotic-enriched yogurt; given the lack of available yogurt samples, we were unable to determine if the isolates were genetically related.

Eight of the Lactobacillus cases in the literature involved bacteraemia, while the other two cases were pulmonary in nature (empyema and pneumonia). Among those with bacteraemia, three cases had additional sites of invasive disease, including splenic abscess, septic thrombophlebitis with septic emboli and pneumonia. The causative species were L. rhamnosus (n = 5), L. acidophilus (n = 2) and L. casei (n = 1); in two cases the species was not reported. Of note, L. rhamnosus was initially a subspecies of L. casei and later reclassified as its own species. Treatment typically was with a single antimicrobial agent, most commonly clindamycin (n = 5). Of the nine cases in which the patient outcome was reported, only one death occurred near the time of the Lactobacillus infection and was attributed to sepsis suspected to be due to this organism.¹¹

Discussion

We report a case of lactobacillemia in an AIDS patient, and provide a comprehensive review of the literature of invasive Lactobacillus infections among HIV-infected persons and their associated potential risk factors. Low CD4 cell counts (<50 cells/mm³) as well as gastrointestinal pathology and recent antibiotic use lacking activity against the organism (e.g. vancomycin) are potential risk factors among HIV patients. Our report also highlights that probiotic use may represent a novel risk factor, and suggests careful consideration using these agents among HIV/AIDS patients with concurrent risk factors for invasive Lactobacillus infections.

Lactobacillus is an uncommon cause of invasive infection; however, cases have been increasingly reported.^1–3,15 Most cases of invasive disease in the literature are bacteraemia with or without left-sided endocarditis,^2,3,16–20 with additional cases including pyelonephritis, respiratory infections (pneumonia, empyema) and deep seeded abscesses (liver, spleen).^9,15,21,22 Most patients with lactobacillemia have a significant underlying comorbidity (82% in one series).³

Few data exist regarding invasive Lactobacillus infections among HIV-infected persons. Our review identified 10 cases among HIV patients. The small number of reported cases may suggest that additional potential risk factors beyond HIV itself are important for the development of invasive infection, or may reflect under-diagnosis or underreporting. In our analysis of the 10 cases in the literature, potential risk factors among HIV patients include low CD4 cell counts (<50 cells/mm³) and underlying gastrointestinal disorders (active infections, recent surgery, and malignancies) that compromise the integrity of the mucosal barrier, leading to translocation of lactobacilli into the bloodstream.²³ Alcoholic liver disease, seen in the current case, may also be a risk factor given its associated increased gut permeability.^24,25 HIV infection, especially during late stage, is associated with increased gut permeability^26,27 and loss of local host immunity in the gut-associated lymphoid tissue (GALT) that may predispose to invasive infection.²⁸ Although ART improves these alterations,²⁷ most cases of invasive lactobacillemia have occurred in late stage patients not receiving ART. In summary, among HIV-infected persons, the translocation of lactobacilli causing invasive disease may require a combination of factors including breaches in the mucosal barrier (by a gastrointestinal disorder and HIV effects), impaired host immune defences (low CD4 cell count and loss of GALT), and disruption of the normal gastrointestinal flora.

Regarding the latter factor, recent use of vancomycin was a predisposing factor in 40% of the cases among HIV-infected persons.^10–12 Antibiotics that alter the gastrointestinal microbiome, but lack activity against Lactobacillus, may lead to its overgrowth and pathogenic potential. Similarly, the direct inoculation of large quantities of lactobacilli into the gastrointestinal tract may be a risk factor.^6,7 In our patient, the heavy consumption of probiotic-enriched yogurt was the putative source of L. acidophilus (given the temporal relationship of recent consumption and the subsequent bacteraemia) which, in the setting of increased gut permeability due to end-stage AIDS and alcoholic liver disease, likely translocated into circulation. Since we did not have the Lactobacillus isolates from the yogurt to genetically compare with our patient’s isolate, a commensal source could not be definitively excluded.

Probiotics are ‘live microorganisms which, when administered in adequate amounts, confer a health benefit on the host’.²⁹ Although probiotics have been used for a variety of health conditions, the strongest evidence for their use has been for preventing antibiotic-associated diarrhoea, including C. difficile,⁴ and shortening the duration of symptoms during acute diarrhoeal illnesses.³⁰ At the current time, the Infectious Diseases Society of America (IDSA) does not recommend probiotics for C. difficile infections, citing the lack of standardization of such products and the possibility of inducing bacteraemia or fungemia.³¹ Further, most guidelines do not recommend probiotics among immunocompromised or severely debilitated persons.⁴

Are probiotics safe among immunosuppressed persons? There have been case reports linking probiotic use with invasive Lactobacillus infections among immunosuppressed persons.^{19,21,32–38} Using population data, large epidemiologic studies have not found an increase in Lactobacillus bacteraemia after the widespread availability of probiotics^39–41; however, some Lactobacillus isolates genetically matched those of the probiotic strains.⁴¹ A US study found that 2 of 1176 (0.2%) cases of lactobacillemia were potentially related to probiotic use,⁴² and another study found that the introduction of probiotics (L. rhamnosus GG) among transplant recipients, resulted in a small, but notable, increase in invasive cases.⁷ Overall, probiotic use appears safe, although immunosuppressed persons appear to have a small, albeit increased risk of infectious complications.

Among HIV-infected persons, only three cases have been published in which the use of probiotics were implicated.^6,7 There are also clinical studies evaluating Lactobacillus and/or probiotic-enriched yogurt among HIV-infected persons. A study of HIV patients with ongoing diarrhoea (n = 17) who were given L. rhamnosus GG found no effect on decreasing diarrhoeal symptoms and no adverse events.⁴³ Another study of HIV patients (n = 37) who were given small quantities of L. reuteri reported no safety issues.⁴⁴ Finally, a probiotic yogurt resulted in modest reduction in gastrointestinal symptoms among 85 patients, and had no adverse safety signals.⁴⁵ Overall, the risk of probiotic use among HIV patients appears to be small; however, caution should be considered when using probiotics among HIV patients with the aforementioned risk factors (e.g. low CD4 cell counts, presence of gastrointestinal disease). Populations at the highest risk for probiotic-related infections are summarized in Table 2.^38,46

Table 2.

Potential risk factors for invasive Lactobacillus infections due to probiotic use.^a

-HIV/AIDS -Other immunocompromising conditions: malignancy, history of organ or bone-marrow transplantation, or a debilitated state

Additional potential risk factors:

-Gastrointestinal disorder leading to impairment of mucosal barrier (infections, recent surgery, malignancy, severe liver disease) -Broad-spectrum antibiotics without activity against Lactobacillus -Administration of probiotics (especially if given via jejunostomy tube, hence bypassing gastric acid⁴⁶) -Central venous line -Cardiac valvular disease (increased risk for endocarditis)

Adapted from Boyle et al.³⁸

The risk of probiotics varies based on their contents. Virulence appears to differ by species, with L. rhamnosus being potentially the most pathogenic Lactobacillus species.⁷ Additionally, probiotics may also contain other microorganisms such as Bifidobacterium and Saccharomyces (S. boulardii), with documented cases of fungaemia due to the later species among HIV patients.^47,48

The diagnosis of Lactobacillus is based on isolation from a sterile site and should not be discarded as a contaminant, especially among persons at risk. Antibiotic susceptibility testing should be performed given variable resistance patterns that are species dependent; dilution methods and Etests are the preferred methods.⁴⁹ Penicillin and ampicillin are the drugs of choice when isolates are susceptible. Lactobacilli are typically susceptible to piperacillin-tazobactam, imipenem, clindamycin, gentamicin and erythromycin,⁵⁰ while most isolates are resistant to vancomycin (although some L. acidophilus isolates are sensitive).¹⁵

Regarding mortality, there was only one death in our review; although duration of follow-up was limited. The mortality rate of lactobacillemia in one study was 26% at one month and 48% at one year.³ Most deaths are from the underlying conditions, rather than the bacteraemia itself²; however there is a trend for higher mortality without the use of adequate antibiotic therapy, highlighting the importance of diagnosing and appropriately treating invasive Lactobacillus infections.^3,15

In conclusion, invasive Lactobacillus infections are rare, but important, and serve as a marker of severe underlying disease, including AIDS. Invasive infections are likely related to a combination of factors, including impaired host immune defences, breaches in the intestinal mucosal barrier and disruption of the gastrointestinal normal flora. Probiotics containing lactobacilli may be a potential risk factor for invasive infections among immunocompromised hosts; hence, caution is advised when using these agents among HIV/AIDS patients with factors such as low CD4 cell counts and underlying gastrointestinal disease. Additional studies clarifying the potential risks of lactobacillemia from probiotic use among HIV-infected persons are advocated.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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