The role of probiotics in nosocomial infections

Z. Mahmmudi

and A.A. Gorzin*

M.Sc. in Biology, Kazeroun Branch, Islamic Azad University, Kazeroon, Iran

Assistant Professor of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences,

Shiraz, Iran

ABSTRACT

There is an increasing scienti c and commercial interest in the use of bene cial microorganisms, or “probiotics,” for

the prevention and treatment of disease. The microorganisms most frequently used as probiotic agents are lactic-acid

bacteria such as Lactobacillus rhamnosus GG (LGG), which has been extensively studied in recent literature. Multiple

mechanisms of action have been postulated, including lactose digestion, production of antimicrobial agents, competi-

tion for space or nutrients, and immunomodulation. We have reviewed recent studies of probiotics for the treatment

and control of infectious diseases. Studies of pediatric diarrhea show substantial evidence of clinical bene ts from

probiotic therapy in patients with viral gastroenteritis, and data on LGG treatment for Clostridium dif cile diarrhea

appear promising. However, data to support use of probiotics for prevention of traveler’s diarrhea are more limited.

New research suggests potential applications in vaccine development and prevention of sexually transmitted dis-

eases. Further studies are needed to take full advantage of this traditional medical approach and to apply it to the

infectious diseases of the new millennium.

KEY WORDS: INTENSIVE CARE UNITS; PEDIATRIC; CROSS INFECTION; BACTEREMIA; PNEUMONIA; URINARY TRACT INFECTION; PROBIOTICS

ARTICLE INFORMATION:

*Corresponding Author:

Received 27

Nov, 2016

Accepted after revision 29

March, 2017

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007

Thomson Reuters ISI ESC and Crossref Indexed Journal

NAAS Journal Score 2017: 4.31 Cosmos IF : 4.006

reserved.

Online Contents Available at: http//www.bbrc.in/

INTRODUCTION

Despite marked improvements in antimicrobial ther-

apy and critical care technology, nosocomial infection

remains a signi cant cause of morbidity and mortality

in critically ill patients (Salminen et al. 1998; Savaiano

et al, 1984; DeVrese et al. 2001; Kim and Gilliland, 1983).

Because the  nal common pathway of Gram-negative

bloodstream infection, ventilator-associated pneumo-

nia, and urinary tract infection (UTI) involves patho-

genic enteric organisms, recent interest has emerged in

how to suppress the growth of these organisms. Mul-

tiple studies have demonstrated that the colonization

of the bowel with nonpathogenic commensal bacteria

Biosci. Biotech. Res. Comm. Special Issue No 1:48-53 (2017)

Mahmmudi and Gorzin

(probiotics) competitively inhibits the attachment of

these pathogenic organisms (Kolars et al. 1984; Allen et

al. 2003; Guandalini et al. 2000). In addition, probiotics

have been shown to augment the local gut immunity by

enhancing immunoglobulin (Ig)-A–speci c responses to

enteric pathogens (Shornikova et al. 2003; Pant et al.

1996). Probiotics also are thought to produce a variety

of antimicrobial substances that may interfere with the

growth of pathogenic bacteria (Raza et al. 1995; Sepp

et al. 1995; Szajewska et al. 2001; Mastretta et al. 2002).

Finally, probiotics have been shown in numerous animal

models to reduce intestinal permeability and decrease

the bacterial translocation of pathogenic bacteria (Ober-

helman et al. 1999; Shornikova et al. 1997; Cetina-Sauri

and Sierra Basto, 1994).

Moreover, probiotics also have been shown to non-

speci cally stimulate the systemic immune system. Pro-

biotic bacteria have been shown in several studies to

enhance the phagocytic ability of neutrophils (Ho¨chter

et al. 1990; Arvola et al. 1999). Multiple trials also have

demonstrated an improvement in natural killer cell

activity following the administration of various probi-

otic agents (Vanderhoof et al. 1999). Probiotic intake also

has been shown to modulate production of interleukin-6

and -10, as well as tumor necrosis factor- (Armuzzi et

al. 2001a). Speci c stimulation of the systemic immune

system also has been shown using probiotic bacteria as

vehicles for vaccines with resultant increases in antigen

speci c T-cell and immunoglobulin G responses (Cre-

monini et al. 2002; Armuzzi et al. 2001b).

As a result of these studies demonstrating stimulation

of local and systemic immune defenses and a reduction in

bacterial translocation, there has been a rapidly growing

interest in the clinical applications of probiotics. A few

small clinical trials in intensive care settings have begun

looking at the incidence of nosocomial infections with

probiotic use and have demonstrated promising results

(Siitonen et al. 1990). Therefore, the purpose of this study

was to evaluate the hypothesis that the administration of

probiotics in infants and children admitted to a pediatric

intensive care unit setting would reduce the incidence of

nosocomial infection, bloodstream infection, pneumonia,

tracheobronchitis, and UTI.

MATERIAL AND METHODS

Episode occurring after 48 hours of hospitalization,

resulting in a positive blood, CSF, or urine culture.4 Hos-

pital-acquired bloodstream infection: clinical signs of

sepsis occurring after 48 hours of life and followed by a

positive blood culture drawn after 48 hours of life. If cul-

ture was positive for a coagulasenegative Staphylococ-

cus species, an additional positive culture with the same

organism was required for con rmation and treatment.

Nosocomial pneumonia: development of respiratory dis-

tress after 48 hours of hospitalization evidenced by rapid,

noisy, or dif cult breathing, respiratory rate .60 breaths

per minute, chest retractions or grunting, and con rmed

with a chest radiograph, a blood culture, or additional

blood work. If the chest radiograph was suggestive of

pneumonia and the blood culture was negative, clini-

cal signs of sepsis or laboratory tests were required for

diagnosis (Duke28 modi ed de nition). Chest radiograph

suggestive of pneumonia: presence of nodular or coarse

patchy in ltrate, diffuse haziness, or granularity, or lobar

or segmental consolidation. Clinical signs of sepsis: pres-

ence of lethargy, recurrent apnea, hypothermia (axillary

temperature ,37°C) or hyperthermia (.38°C).

Laboratory tests suggestive of sepsis: a leukocyte

count out of the reference range (neutropenia ,5000 or

neutrophilia .25 000), a ratio of immature to total neu-

trophilic forms .0.2 or an elevated C-reactive protein. Uri-

nary tract infection: clinical signs of sepsis and a positive

urine culture with .104 organisms of a single pathogen

obtained by the use of standard sterile technique and ure-

thral catheterization.4 Meningitis: clinical signs of sepsis

with a CSF white blood cell count .29/mm3 and neutro-

phil count .60%, or a positive CSF Gramstain, culture, or

polymerase chain reaction for bacterial antigens.4 Feed-

ing intolerance: any of the following: recurring emesis,

gastric residuals with 50% or more of the previous feed

volume, abdominal distension, or the presence of macro-

scopic blood in stools. Necrotizing enterocolitis: modi -

cation of Bells criteria for stage II29 based clinical and/

or radiographic data: (1) pneumatosis or portal vein gas,

(2) localized pneumatosis,  xed dilated bowel loops, or

pneumoperitoneum AND 2 GI signs/ symptoms and 1 sys-

temic sign/ symptom, or (3) thickened bowel loops AND

an abnormal gas pattern AND 2 GI and 2 systemic signs/

symptoms. GI signs: abdominal distension or tenderness,

feeding intolerance, erythema of the abdominal wall,

and decreased bowel sounds. Systemic signs: lethargy,

increased frequency or severity of apnea, temperature

instability, new-onset metabolic acidosis, hemodynamic

instability, and disseminated intravascular coagulation or

thrombocytopenia.

RESULTS AND DISCUSSION

DOCUMENTATION OF THE HEALTH EFFECTS

OF PROBIOTICS FOR HUMAN DISEASES AND

DISORDERS

Lactose malabsorption. A large number of people, as

they age, experience a decline in the level of lactase

(bgalactosidase) in the intestinal brush border mucosa.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS THE ROLE OF PROBIOTICS IN NOSOCOMIAL INFECTIONS 49

Mahmmudi and Gorzin

This decline causes lactose to be incompletely absorbed,

resulting in  atus, bloating, abdominal cramps, and

moderate-to-severe (watery) diarrhea. This results in

a severe limitation in consumption of dairy products

among the elderly population. There have been several

studies that have demonstrated that, during the fermen-

tative process involved in the production of yogurt,

lactase is produced, which can exert its in uence in

the intestinal tract (Savaiano et al, 1984; DeVrese et al.

2001; Kim and Gilliland, 1983; Kolars et al. 1984). The

organisms commonly used for the production of yogurt

are Lactobacillus bulgaricus and Streptococcus sali-

varius subsp. thermophilus. Kim and Gilliland (Kim and

Gilliland, 1983) found that feeding lactose-intolerant

individuals yogurt caused a signi cant reduction in the

level of breath hydrogen compared with that in subjects

who were fed milk. The level of hydrogen in the breath is

an indication of the extent of lactose metabolism in the

large bowel. Kolars et al. (Kolars et al. 1984) observed

that the ingestion of 18 g of lactose in yogurt caused the

production of 67% less hydrogen in the breath compared

with that produced by a similar dose of lactose deliv-

ered in milk. Analysis of aspirates obtained from the

duodenum 1 h after the consumption of yogurt showed

signi cant levels of lactase (Kolars et al. 1984). These

studies indicate that the delivery of lactase to the intes-

tine via the consumption of lactase-producing probiotics

is a practical approach for treatment of lactose malab-

sorption. Acute diarrhea. There are at least 12 studies

that have reported the use of probiotics to either treat

or prevent acute diarrhea (Allen et al. 2003; Guandalini

et al. 2000; Shornikova et al. 2003; Pant et al. 1996; Raza

et al. 1995; Sepp et al. 1995; Szajewska et al. 2001; Mas-

tretta et al. 2002; Oberhelman et al. 1999; Shornikova

et al. 1997; Cetina-Sauri and Sierra Basto, 1994; Ho¨chter

et al. 1990). The majority of these studies were done

with infants or children, the etiologic agent was either

rotavirus or unknown, and the probiotic used was Lacto-

bacillus rhamnosus strain GG (Lactobacillus GG) (ATCC

53103) (Guandalini et al. 2000; Shornikova et al. 2003;

Pant et al. 1996; Raza et al. 1995; Sepp et al. 1995; Sza-

jewska et al. 2001; Mastretta et al. 2002; Oberhelman

et al. 1999). Other probiotics that have shown positive

results for the treatment of acute gastroenteritis include

Lactobacillus reuteri and Saccharomyces boulardii

(Shornikova et al. 1997; Cetina-Sauri and Sierra Basto,

1994; Ho¨chter et al. 1990). The European Society for

Pediatric Gastroenterology, Hepatology, and Nutrition

conducted the most extensive trial using Lactobacillus

GG for the treatment of moderate-to-severe diarrhea in

children (Guandalini et al. 2000). The study included

287 children aged 1–36 months from 10 countries. The

patients were randomized to be given either placebo or

Lactobacillus GG along with the standard treatment, oral

rehydration solution. Patients who received Lactobacil-

lus GG had decreased severity and shorter duration of

illness and a shorter hospital stay and were found to

have a decreased likelihood of persistent diarrheal illness

(Guandalini et al. 2000).

A similar study was conducted with 137 children

aged 1–36 months who were admitted to the hospital

with diarrhea and were randomized to receive placebo

or Lactobacillus GG plus oral rehydration solution. Chil-

dren given Lactobacillus GG had a signi cantly shorter

duration of illness (Shornikova et al. 2003). A study of

26 children in Thailand with watery diarrhea showed

a signi cantly shorter duration of symptoms for those

who received treatment with Lactobacillus GG (Pant

et al. 1996). A similar investigation involving 40 chil-

dren that was conducted in Pakistan found that those

who received treatment with Lactobacillus GG were less

likely to have persistent diarrhea and had fewer episodes

of vomiting, compared with the placebo group (Raza

et al. 1995). In a preventive study of 81 children aged

Table 1. Medical applications in humans for different classes of probiotics

Medical condition Class(es) of probiotic Reference(s)

Lactose maldigestion

LAB and Streptococcus salivarius subsp.

Thermophiles

[2–5]

Gastroenteritis Acute diarrhea

LAB, Bi dobacterium species, or

Saccharomyces boulardii

[6–17]

Antibiotic-associated diarrhea LAB or S. boulardii

[18–24]

Traveler’s diarrhea LAB [25, 26]

Clostridium dif cile–induced colitis LAB [32–34]

Dental caries

LAB [35]

Intestinal in ammation in children with

cystic  brosis

LAB [36]

NOTE. LAB, lactic acid bacteria.

50 THE ROLE OF PROBIOTICS IN NOSOCOMIAL INFECTIONS BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Mahmmudi and Gorzin

1–36 months who were hospitalized for illnesses other

than diarrhea, symptoms of hospital-acquired rotavirus

gastroenteritis were prevented by administration of Lac-

tobacillus GG (Szajewska et al. 2001). In another preven-

tion study conducted in Peru, 204 children aged 6–24

months who were undernourished were randomized to

receive placebo or Lactobacillus GG. There was a signi -

cant decrease in the rate of incidence of diarrhea among

the children who received Lactobacillus GG who were

not being breast-fed (Oberhelman et al. 1999). In one

study, Lactobacillus reuteri was shown to shorten the

duration of diarrhea in children (Shornikova et al. 1997).

In a clinical trial involving 130 children, S. boulardii

was found to be effective for the treatment of acute diar-

rhea in children (Cetina-Sauri and Sierra Basto, 1994),

and, in another study of 92 adults, a similar  nding was

reported (Ho¨chter et al. 1990).

Probiotic Use and Safety Probiotics are widely consid-

ered to be safe for human oral and vaginal use and there

is a long history of the use of fermented milk products

with minimal recorded reported side effects. The number

of probiotic products available on the world market is

estimated to be over 2000 (Shornikova et al. 2003), but

the industry remains largely unregulated and unstand-

ardized—making comparative studies dif cult. To begin

 lling this void, scientists have formalized groups such

as the International Scienti c Association for Probiotics

and Prebiotics (ISAPP), a nonpro t founded in 2002 to

raise the scienti c credibility of the  eld by working

with experts and conducting meetings on high qual-

ity research. By providing an objective, science-based

voice, ISAPP hopes to bene t the end users of these

products by helping them make informed choices (Pant

et al. 1996). ISAPP has endorsed the guidelines set by

the World Health Organization (WHO) and the United

Nations Food and Agriculture Organization (FAO) for

evaluation of probiotics—governing, strain designation,

ef cacy/effectiveness and safety (Kim and Gilliland,

1983; Raza et al. 1995). For example, new strains and

products should be proven safe in human studies amend

those bearing some limitations, (such as use of S. bou-

lardii [S. cerevisiae]) in patients with a leaky gut or other

risks) should be clearly labeled (Sepp et al. 1995). In

the United States, probiotics are currently classi ed as —

dietary supplements, (not —drugs) and as such, the Food

and Drug Administration (FDA) only requires premar-

ket noti cation, with no demonstrations of safety and

ef cacy required (Szajewska et al. 2001). Due to their

overall safety, guidelines for use of probiotics in the

hospital are generally lacking, although some caution is

advised for use in certain disease states (e.g., severe coli-

tis, bowel leaks, neutropenia) where the potential exists

for the probiotic to enter the blood or peritoneum (Mas-

tretta et al. 2002). Likewise, special care should be taken

by healthcare personnel who handle both probiotic cap-

sules and venous catheters in order to avoid transfer to

the bloodstream (Szajewska et al. 2001). Of more recent

interest and concern are safety considerations relating to

transferable genetic elements that may confer antibiotic

resistance from the probiotic to pathogenic strains, or

even to the commensal  ora (Oberhelman et al. 1999).

In a mouse model have demonstrated a possible role

for these agents in the prevention or treatment of graft-

versus-host disease in transplant recipients (ksanen

et al. 1990).

FUTURE DIRECTIONS

The following are some of the future possibilities for

these biological products in the  eld of infectious dis-

eases.The use of LAB as live vectors for oral immuniza-

tion appears to be an exciting approach, on the basis of

their safety, ability to persist within the indigenous  ora,

adjuvant properties, and low intrinsic immunogenicity.

Medaglini et al. [38] have recently developed a genetic

system for the expression of heterologous antigens from

human papillomavirus and HIV type 1 (HIV-1) in the

surface of the human commensal Streptococcus gordoo-

nii and L. casei. Local and systemic immune responses

were detected in BALB/c mice and Cynomolgus mon-

keys after vaginal colonization with the aforementioned

Table 2. Present and future clinical applications of

probiotics, by level of evidence of ef cacy

Applications with strong evidence

Gastroenteritis

Acu

Antibiotic associated

Applications with substantial evidence of ef cacy

Allergic reactions, speci cally atopic dermatitis

Applications that have shown promise

Childhood respiratory infection

Dental caries

Nasal pathogens

Relapsing Clostridium dif cile-induced

Gastroenteritis (prevention)

In ammatory bowel disease

Potential future applications

Rheumatoid arthritis

Irritable bowel syndrome

Cancer (prevention)

Ethanol-induced liver disease

Diabetes

Graft-versus-host disease

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS THE ROLE OF PROBIOTICS IN NOSOCOMIAL INFECTIONS 51

Mahmmudi and Gorzin

recombinant strains. Both macrophage activation and

IL-12/g-IFN pathway stimulation are promising areas of

research with regard to resistance to intracellular patho-

gens by enhancement of mucosal and systemic immu-

nity (Malchow et al. 1997; Guslandi et al. 2000). More

experimental and clinical studies are needed to clarify

the role of probiotics as immunomodulators, not only in

infectious diseases of the GI tract, but also for in amma-

tory and allergic conditions.

CONCLUSIONS

The current and proposed uses of probiotics cover a wide

range of diseases and ailments. An attempt has been made

to classify the quality of evidence that supports these var-

ious applications (Nase et al. 2001). These classi cations

are based on existing studies, most of which are cited in

this article, and not on an exhaustive review of the entire

literature on probiotics. The broad classi cations include

(table 2) applications with proven bene ts, applications

with substantial evidence that require additional sup-

port, promising applications that need substantial addi-

tional evidence, and proposed future applications. Proven

bene ts of probiotics include the treatment of acute and

antibiotic associated diarrhea; applications with substan-

tial evidence include the prevention of atopic eczema and

traveler’s diarrhea; promising applications include the

prevention of respiratory infections in children, preven-

tion of dental caries, elimination of nasal pathogen car-

riage, prevention of relapsing C. dif cile– induced gastro-

enteritis, and treatment of in ammatory bowel disease;

and proposed future applications include the treatment

of rheumatoid arthritis, treatment of irritable bowel syn-

drome, cancer prevention, prevention of ethanol-induced

liver disease, treatment of diabetes, and prevention or

treatment of graft versus-host disease.

The mechanisms of action of probiotics are strain

speci c but can be summarized mainly in three areas:

changes of gut ecology, modulation of gut mucosal bar-

rier and regulation of the immune response through

interaction with gut-associated immune system (Sava-

iano et al, 1984). Several studies regarding the supple-

mentation of probiotics in nosocomial infections have

been conducted mainly in adult population. Among

pediatric studies major  ndings have been observed in

treatment of acute gastroenteritis, primarily caused by

Rotavirus (DeVrese et al. 2001; Kim and Gilliland), and

in the prevention of antibiotic associated diarrhea (AAD)

(Kolars et al. 1984). Supplementation with probiotics has

proven useful even in the treatment of Clostridium dif -

cile disease (CDD), the most common pathogen involved

in AAD (1983Allen et al. 2003). Data from meta-analysis

and cochrane review on the prevention of necrotizing

enterocolitis (NEC) show an overall bene t of probi-

otic supplementation (Guslandi et al. 2000). The limita-

tions of the above cited studies are mainly related to

heterogeneity in terms of strain, dosage and duration

of treatment and the lack of studies on extremely low

birth weight preterm infants. Data on nosocomial pneu-

monia and ventilatorassociated pneumonia in neonatal

and pediatric age is scanty. In a large randomized, dou-

ble-blind placebo controlled study, Hojsak et al demon-

strated that supplementation with Lactobacillus GG sig-

ni cantly decreased the risk of nosocomial respiratory

tract infections (Shornikova et al. 1997). On the other

hand, the data from adult studies have been con icting,

with a tendency towards the demonstration of probiotic

ef cacy in reducing the incidence of ventilatorassoci-

ated pneumonia (Pant et al. 1996). Meticillin-resistant

Staphylococcus aureus is a multidrug-resistant nosoco-

mial pathogen; a recent review of literature (Raza et al.

1995) showed that many probiotic strains inhibit MRSA

growth in vitro. Furthermore, this review describes that

there is little published clinical data on the use of pro-

biotics in prophylaxis or treatment of MRSA-mediated

infections (Nase et al. 2001).

The use of probiotics in medical practice is rapidly

increasing, as are studies that demonstrate the ef cacy

of probiotics. A note of caution should be applied: nega-

tive  ndings are being reported, as would be expected as

more studies are being performed and as more applica-

tions are being sought for the use of probiotics. Overall,

probiotics appear to be here to stay as part of the phy-

sician’s armamentarium for the prevention and treat-

ment of disease; however, more evidence-based research

is required to  rmly establish medical areas of use and

areas in which probiotics are not applicable.

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