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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 51  |  Issue : 3  |  Page : 360-366
Utility of lytic bacteriophage in the treatment of multidrug-resistant Pseudomonas aeruginosa septicemia in mice


1 Department of Microbiology, SS Institute of Medical Sciences and Research Centre, Davanagere, India
2 Department of Physiology, SS Institute of Medical Sciences and Research Centre, Davanagere, India
3 Department of Microbiology, Gulbarga University, Gulbarga, Karnataka, India

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   Abstract 

Drug resistance is the major cause of increase in morbidity and mortality in neonates. One thousand six hundred forty-seven suspected septicemic neonates were subjected for microbiological analysis over a period of 5 years. Forty-two P. aeruginosa were isolated and the antibiogram revealed that 28 P. aeruginosa were resistant to almost all the common drugs used (multidrug-resistant). The emergence of antibiotic-resistant bacterial strains is one of the most critical problems of modern medicine. As a result, a novel and most effective approaches for treating infection caused by multidrug-resistant bacteria are urgently required. In this context, one intriguing approach is to use bacteriophages (viruses that kill bacteria) in the treatment of infection caused by drug-resistant bacteria. In the present study, the utility of lytic bacteriophages to rescue septicemic mice with multidrug-resistant (MDR) P. aeruginosa infection was evaluated. MDR P. aeruginosa was used to induce septicemia in mice by intraperitoneal (i.p.) injection of 10 7 CFU. The resulting bacteremia was fatal within 48 hrs. The phage strain used in this study had lytic activity against a wide range of clinical isolates of MDR P. aeruginosa. A single i.p. injection of 3 × 10 9 PFU of the phage strain, administered 45 min after the bacterial challenge, was sufficient to rescue 100% of the animals. Even when treatment was delayed to the point where all animals were moribund, approximately 50% of them were rescued by a single injection of this phage preparation. The ability of this phage to rescue septicemic mice was demonstrated to be due to the functional capabilities of the phage and not to a nonspecific immune effect. The rescue of septicemic mice could be affected only by phage strains able to grow in vitro on the bacterial host used to infect the animals and when such strains are heat-inactivated, they lose their ability to rescue the infected mice. Multidrug-resistant bacteria have opened a second window for phage therapy. It would seem timely to begin to look afresh at this approach. A scientific methodology can make phage therapy as a stand-alone therapy for infections that are fully resistant to antibiotics.

Keywords: Bacteriophage, multidrug-resistant, P. aeruginosa, mice, septicemia

How to cite this article:
Vinodkumar C S, Kalsurmath S, Neelagund Y F. Utility of lytic bacteriophage in the treatment of multidrug-resistant Pseudomonas aeruginosa septicemia in mice. Indian J Pathol Microbiol 2008;51:360-6

How to cite this URL:
Vinodkumar C S, Kalsurmath S, Neelagund Y F. Utility of lytic bacteriophage in the treatment of multidrug-resistant Pseudomonas aeruginosa septicemia in mice. Indian J Pathol Microbiol [serial online] 2008 [cited 2019 Oct 18];51:360-6. Available from: http://www.ijpmonline.org/text.asp?2008/51/3/360/42511



   Introduction Top


Pseudomonas aeruginosa , a Gram-negative bacterium is one of the most important causative agents in neonatal septicemia. [1] Several outbreaks of infection caused by P. aeruginosa isolates that are simultaneously resistant to broad-spectrum cephalosporins and aminoglycosides have been reported. Some of these multidrug-resistant isolates produce "Extended spectrum β-Lactamases" that are able to hydrolyze expanded spectrum cephalosporins, aztreonam and related oxyimino-β-lactam. [2] Colonization of such multidrug-resistant P. aeruginosa in the hospital settings has become very common in our region. Such colonization predisposes premature and underweight babies to multidrug-resistant P. aeruginosa. [3] According to National Neonatal Perinatal Database 2000, the incidence of neonatal septicemia caused by P. aeruginosa is 18%. [4] The potential clinical significance of P. aeruginosa in neonatal septicemia continues to increase as medical therapy involves more invasive intervention procedures. Emergences of P. aeruginosa as one of the leading nosocomial pathogens in neonatal intensive care units, especially in high-risk babies and the widespread occurrence of multidrug-resistant among them pose a therapeutic problem. [1]

With the rising prevalence of antibiotic-resistant bacteria, alternatives to treatment with antibiotics are receiving increased attention. One such alternative is the possible therapeutic use of bacteriophages - viruses that parasitize and kill bacteria. [5] The suggestion of administering phages as pharmaceutical agents has been mooted for more than 85 years. The relative simplicity and economy of phage therapy should have gained much momentum and magnitude earlier. This has not happened, probably because of a poor understanding of mechanism of bacterial pathogenesis and of the nature of phage-host interactions and the absence of animal models of diseases and also due to badly designed and executed experiments and field trials which led to failure in using phages in therapy. [5],[6],[7],[8],[9] Another reason was due to the fact that the scientists concentrated on escalated production of newer and newer antibiotics of commercial importance. However, the increasing incidence of multidrug-resistant bacteria and a deficit in the development of new chemotherapeutics to counteract bacteria, [2],[4],[10] have rekindled the interest in phage therapy. This work was carried out to investigate the possibility of use of lytic phage in the treatment of experimental septicemic mice, which are infected with MDR P. aeruginosa .


   Materials and Methods Top


Ethical clearance

The institutional ethical review board at Gulbarga University, Gulbarga approved all the study procedures.

Bacterial strain and antibiotic sensitivity pattern

P. aeruginosa strain was isolated from the blood of a neonate with septicemia and was designated as YFN-58 in our nomenclature. Antibiotic susceptibility testing by Kirby-Bauer's method [10] revealed that the YFN-58 strain was resistant to most of the commonly used drugs. Staphylococcus aureus (ATCC no. 25923) and  Escherichia More Details coli (ATCC no. 25922) were used as control strains in antibiotic susceptibility testing.

Establishing the minimum lethal dose (MLD) of P. aeruginosa in the mouse model

One-month-old BALB/c male mice (four per group) free from specific pathogen, belonging to the same race, weighing 22.0 ħ 1.5 g, caged singly and maintained on a proper diet were used for infection experiments. All the mice were housed in a pathogen-free environment within the animal-care facility at Gulbarga University. Bacterial innocula were prepared by culturing P. aeruginosa in brain-heart infusion overnight and centrifuging it at 2,000 × g for 5 min, washing, recentrifuging it twice and then resuspending it in saline to various densities. Each group of mice received intraperitoneal inoculation of 400µl aliquots of bacterial suspension in different densities (10 2 -10 7 CFU). The animals were observed for 100 hrs. Mice inoculated with bacteria were scored for their state of health on a scale of 5 to 0, based on progressive disease states reflected by several clinical signs. [11],[12],[13],[14] A normal and unremarkable condition was scored at 5; slight illness, defined as lethargy and ruffled fur, was scored as 4; moderate illness, defined as severe lethargy, ruffled fur and hunched back, was scored as 3; severe illness, with the above signs plus exudative accumulation around partially closed eyes, was scored as 2; a moribund state was scored as 1; and death was scored as 0. Scores were determined by two independent observers.

Isolation and purification of phage strains for P. aeruginosa

The P. aeruginosa phage was isolated from raw sewage at a municipal sewage treatment plant, Gulbarga by the method of Smith and Huggins. [8] Sewage water (50 ml) was collected in a sterile conical flask and treated with a few drops of chloroform. To this, an equal volume of sterile nutrient broth and 1 ml of the 24-hour-old broth culture of P. aeruginosa YFN-58 were added. The sample inoculated with bacterial pathogens was incubated at 37°C for 12-24 hrs in shaker water bath. After 12-24 hrs, the lysate was shaken with few drops of chloroform for about 10 min, centrifuged at 10,000 rpm for 10 min and the supernatant was filtered through 0.22 µ pore size acrodisk membrane filters (PALL, German Laboratory) to remove the bacteria, [11] and subjected to plaque-forming unit (PFU) assay using the double-layer agar method described by Smith and Huggins. [8] The phage was denoted as CSV-31.

In vitro confirmation of bacteriophage activity on P. aeruginosa

The bacterial lawn was prepared on nutrient agar plates employing 1.0 ml of 24 hrs P. aeruginosa YFN-58 culture by flooding and draining out the excess. Wells were dug into the agar by employing a sterile cork borer and the 20µl phage suspension (3 × 10 9 PFU/ml) was loaded into each of the well. Sterile distilled water served as the control. The plates were incubated at 37°C for 24 hrs. Thereafter, the zone of inhibition, if any, was recorded. [12],[13]

Treatment with phage

The efficacy of phage therapy was evaluated in two separate experiments using MDR P. aeruginosa bacteremic mouse model. The first experiment was to examine the effect of phage dose on the ability of phage to rescue mice from MDR P. aeruginosa bacteremia. In the second study, on the outcome of delaying treatment for various periods. In the dose-ranging study, five groups of mice (four mice in each) were challenged by i.p. injection of the MLD of YFN-58. Each of these groups was treated with a single injection of phage CSV-31 administered i.p. 45 min after the bacterial challenge at 3 × 10 9 , 3 × 10 8 , 3 × 10 4 and 0 PFU. As an additional control, a sixth group (two mice) was not challenged with bacteria, receiving only the injection of phage (at the highest dose). The state of health of these animals was monitored for 20 days. [14]

In the delayed-treatment study, treatment (a single injection of phage at the highest dose) was initiated at 5, 8, 12, 16 and 24 hrs after the bacterial challenge with the MLD P. aeruginosa YFN-58. The state of health of these animals was also monitored for 20 days. [10],[13],[15]

Effects of heat-inactivated phage

A sample of phage with a titer of 3 × 10 9 PFU/ml was heat-inactivated by incubation at 80°C. Phage that had been heated for a total of 20 min, at which time no viable phage was detectable, was used to determine whether phage rescue mice with MDR Pseudomonas bacteremia requires functional phage or whether the rescue might be associated with nonspecific immune activation. [16],[17] The mice in this study were divided into two groups of four each. All of the mice were challenged by i.p. injection of 3 × 10 9 PFU of phage CSV-31, 45 min after the bacterial challenge. The second group was treated with i.p. injection with 3 × 10 9 PFU of heat-inactivated phage particles 45 min after the bacterial challenge.


   Results Top


Antibiotic susceptibility testing

Antibiotic sensitivity testing revealed that out of 42 P. aeruginosa isolated from neonatal septicemia, 28 isolates were multidrug-resistant. All these 28 isolates were extended spectrum β lactamase producers.

Lethality of MDR P. aeruginosa bacteremia

As seen in [Figure 1], all mice inoculated i.p. with MLD 10 7 CFU of the clinical isolate MDR P. aeruginosa YFN-58 died within 48 hrs.

Phage strain antibacterial activity

Of the phage strains isolated in the present study, phage CSV-31 was found to form plaques on 66% of the MDR Pseudomonas clinical isolates and inhibited bacterial growth of an additional 8% of the strains, thus exhibiting an antibacterial effect against 74% of the strains in our collection.

Ability of the phage preparation to rescue mice from MDR Pseudomonas bacteremia

A single dose of phage CSV-31 was administered i.p. 45 min after the challenge with the MLD of bacteria. By 24 hrs, a dose effect on the state of health of the infected animals was clearly visible. At higher doses of phage, 100% of the animals survived and only minimal signs of illness (mild lethargy) were seen (in the first 24 hrs). As the phage dose decreased, the animals became critically ill, with survival rates of 40% and 60%, respectively, at day 6 and beyond [Figure 2]. All the mice that were alive and healthy at day 6 remained so for an additional 20 days, at which time the experiment was terminated.

Effect of delay in treatment on the ability of the phage preparation to rescue mice from MDR Pseudomonas bacteremia

In this experiment, the MLD of MDR Pseudomonas strain YFN-58 was injected i.p. to induce fatal bacteremia. At various intervals thereafter, ranging from 2 to 24 hrs, the mice received a single i.p. injection of the high dose (3 × 10 9 PFU) of phage CSV-31. The results of treatment at the time points are illustrated in [Figure 3]. The state of health of these mice was monitored for 20 days following bacterial infection. The experiments demonstrate that a single injection of phage can rescue 100% of the animals, even when treatment is delayed until 5 hrs after lethal bacterial challenge and if treatment is delayed beyond that point, morbidity increases and mortality begins to appear. However, even with delay of 18 and 24 hrs, at which point all the mice are moribund, approximately 50% of the animals are rescued and recovered completely.

Effects of heat-inactivated phage

An experiment was performed to determine whether phage rescue of mice with multidrug-resistant Pseudomonas bacteremia requires phage that can grow on the bacterial host or whether phage rescue might be associated with a nonspecific immune activation response. Heating at 80°C for 5 min decreased the phage titer by 1000-fold and no viable phage was detected after heating for 15 to 20 min. As illustrated in [Figure 4], only mice inoculated with plaque-forming phage had enhanced survival, with 75% survival at 4 days and with 10% of the mice injected with heat-inactivated phage surviving.

Rescue is associated with a significant decrease in bacterial titer

In a similar experiment, blood was obtained by cardiac puncture during a rescue experiment in order to compare bacterial titers from two groups of four mice each, 20 hrs after i.p. inoculation with 3 × 10 7 CFU of YFN-58. Forty-five minutes after the bacterial inoculation of the first group, 250µl of PBS was injected i.p. as a control. The bacterial titer in the blood 20 hrs after bacterial inoculation for this group of mice was 1.4 × 10 7 ħ 1.2 × 10 7 CFU/ml (Mean ħ standard error). Forty-five minutes after bacterial inoculation of the second group, the mice were injected i.p. with 9 × 10 9 PFU of phage CSV-31. The mean bacterial titer in the blood 20 hrs after bacterial inoculation for this group was 6.4 × 10 4 ħ 4.8 × 10 4 CFU/ml. Phage therapy thus resulted in a 300-fold decrease (compared to control group) in blood bacterial titers at 20 hrs. This reduction in bacterial titers was reflected in the lower morbidity and mortality observed in the treated group. Whereas at the 20-hr time point the control group had a median health score of 2 (severe illness), with scores ranging from 0 (one death) to 4, in contrast the phage-treated group had a median health score of 3 (moderate illness), with no deaths and scores ranging from 2 to 5. In both groups, there was a correlation between the state of health of the mice and the concentration of bacteria in the blood. Mice with bacterial titers of 10 6 CFU/ml or more had a score of 1 (moribund condition), while titers in the range of 10 5 to 10 4 CFU/ml resulted in a score of 2. Mice with 10 3 CFU of bacteria/ml in their blood displayed a score of 3 and mice with titers of 10 2 CFU/ml or less had scores of 4 to 5 (mild illness or no signs of illness, respectively).


   Discussion Top


Septicemia is a leading cause of morbidity and mortality among neonates in developing countries. But, the indiscriminate overuse of antibiotics for the treatment of septicemia has triggered an increase in the development of multidrug-resistant "Super bugs" and has been posing serious problems. [1],[4] Therefore, in the present investigation, an attempt is made to develop an alternative to conventional drugs. One possible option is to use bacteriophages as antimicrobial agents; the bacteriophages, which are highly specific for the target bacteria, without affecting the normal microflora and are effective against multiple drug-resistant bacteria.

Although phages were discovered nearly a century ago, Western medicine's interest in them as therapeutic agents was relatively short-lived, in part because of the eventual discovery and immediate success of antibiotics and in part because of the highly empirical and counterproductive approach that had been used by phage practitioners in the early era. In the modern era (1980s and 1990s), some rigorously controlled animal experiments have been conducted (Smith Soothill), [8],[16],[17],[18] but the clinical reports in this same era have been of an anecdotal nature rather than describing controlled studies. [19],[20],[21] The experiments in the present study represent solutions to many of the problems that hindered the prior applications of phage therapy. For example, the relatively narrow host range of most phages which caused many of the early attempts at phage therapy to fail can be overcome by isolating phages that have a broad host range within the species being targeted. For example, phage CSV-31 forms plaques on more than 66% of the MDR Pseudomonas isolates tested and inhibits growth of an additional 8%, thus providing an antibacterial effect against more than 74% of approximately 46 clinical isolates of MDR Pseudomonas isolated from neonatal septicemic cases. The inhibition of bacterial growth in strains that the phage could not form plaques (in 26% of clinical isolates) is most likely due to partial expression of the phage genome, [19],[20] sufficient for killing but not enough for phage production to a level necessary for plaque formation.

With the emergence of antibiotic-resistant bacteria, such as MDR Klebsiella , methicillin-resistant Staphylococcus aureus, E. coli, P. aeruginosa and vancomycin-resistant Enterococci , there is a need to explore the potential therapeutic applications of bacteriophages. [14],[15],[21] That exploration is facilitated by knowledge gained during the development of the science of molecular biology about the mechanisms of phage interactions with bacteria. This knowledge, coupled with rigorously controlled animal models and clinical trials, should permit the rational development of phage therapy. In this regard, the inocula of bacteria used in the animal experiments described in this study are higher than those normally encountered in clinical situations. However, the ability of phage to rescue animals infected with these high titers of bacteria is especially convincing of the potential of phage as an antibacterial therapeutic agent. Given the encouraging results of these initial experiments, it may be useful to develop more sophisticated experiments that portray normal clinical situations.

The results obtained in the present study are encouraging: a single injection of either of the two dosages of phage used in this study (10 9 and 10 8 PFU) rescued 100% of MDR Pseudomonas septicemic mice, even if treatment was delayed up to 5 hrs. Moreover, even when phage treatment (with the highest dose) was delayed until all animals were moribund, approximately half the animals were rescued and went on to recover completely. The ability of phage to rescue bacteremic animals was a phage function and not nonspecific immune response activation, since rescue was observed with heat-inactivated phage.

Each of the above experiments independently demonstrates the requirement for active phage, that is, phage that are capable of growing in and lysing the infecting bacterial strain, for the rescue of animals that are bacteremic with that bacterial strain. This conclusion was further strengthened by observations concerning the fate of the bacteria during infections. In these experiments, we observe a 300-fold decrease in blood bacterial titers in mice treated with phage therapy when compared with blood bacterial titers from the PBS-treated control mice 20 hrs after initiation of the experiment.

Phage CSV-31 persisted long enough in the tissues to be effective when administered to the mice a day or two before challenge with the P. aeruginosa . This was also reported previously with chicken [20],[21] and suggests that there are possibilities for prophylaxis. More interestingly, it was possible to delay administration of the phage until signs of disease were evident in the mice and yet retain considerable protection, suggesting that acute infections might also be amenable to phage treatment.

Pioneering study by Shankar Adhya indicated that bacteriophage therapy could be used in gastrointestinal colonization with vancomycin-resistant Enterococcus infection. [11] A single i.p. injection of the phage strain was sufficient to rescue 100% of the animals. Even in the present study, we could demonstrate that viable phage were able to rescue 75% of the septicemic mice.

We focused our efforts on MDR Pseudomonas because we anticipated that positive results would demonstrate the potential of this form of therapy in situations where few alternatives are available today. It is tempting to advocate research investigations into many bacterial infections for which animal models are available and for which phages may be isolated. The potential of phage therapy has been the subject of several recent reviews, [15],[16],[17],[18] and the present study reinforces the view that this therapy is worth exploring.


   Acknowledgments Top


The authors would like to thank the Department of Pathology, NIMHANS, the Department of Zoology and the Department of Microbiology, Gulbarga University, Gulbarga for the facilities.

 
   References Top

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5.Barrow PA. Novel approaches to control of bacterial infections in animals. Acta Vet Hung 1997: 45:317-29.  Back to cited text no. 5    
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9.Alisky JK, Rapoport, Troitsky. Bacteriophage shows promise as antimicrobial agents. J Infect 1998;36:5-15.  Back to cited text no. 9    
10.Bauer AW, Kirby WM, Sherris JC, Jurek M. Antibiotic susceptibility testing by a standardized disc method. Am J Clin Pathol 1966;45:493-6.  Back to cited text no. 10    
11.Biswas B, Adhya S, Washart P, Paul B, Trostel AN, Powell B, et al . Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium . Infect Immun 2002;70:204-10.  Back to cited text no. 11    
12.Tartero C, Araujo R, Michel T, Jofe J. Culture and methods affecting decontaminating, enumeration of phage infecting Bacteriodes fragilis in sewage. Appl Envir Microbiol 1992;58:2670-3.  Back to cited text no. 12    
13.Sambrook JE, Fritsch, Maniatis T. Molecular cloning: A laboratory manual. 2 nd ed. New York: Cold Spring Harbor Laboratory Press, Cold Spring Harbor; 1989.  Back to cited text no. 13    
14.Bojovazova GG, Voroshilova NN, Bondarenko VM. The efficacy of Klebsiella bacteriophage in the therapy of experimental Klebsiella infection. J Microbiol Epidemiol Immunobiol 1991;4:5-8.  Back to cited text no. 14    
15.Gowri SR, Madhusudhan V, Palaniappan P. Evaluation of phage therapy to treat experimental infection in mice. Indian J Microbiol 1998;38:101-3.  Back to cited text no. 15    
16.Soothill JS. Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa . Burns 1994;20:209-11.  Back to cited text no. 16    
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18.Bush K. New beta lactamases in Gram-negative bacteria: Diversity and impact on the selection of antimicrobial therapy. Clin Infect Dis 2001;32:1085-9.  Back to cited text no. 18    
19.Westwater C, Kasman LM, Schofield DA, Werner PA, Dolan JW, Schmidt MG, et al . Use of genetically engineered phage to deliver antimicrobial agents to bacteria: An alternative therapy for treatment of bacterial infections. Antimicrob Agents Chemother 2003;47:1301-7.  Back to cited text no. 19    
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21.Barrow P, lovell M, Berchieri A. Use of lytic bacteriophage for control of experimental Escherichia coli septicemia and meningitis in chickens and calves. Clin Diagn Lab Immunol 1998;5:294-8.  Back to cited text no. 21    

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Correspondence Address:
C S Vinodkumar
Department of Microbiology, SS Institute of Medical Sciences and Research Centre, Vidhyanagar Post Box-1, NH-4, Bypass, Davanagere - 577 005, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.42511

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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23 Bacteriophage and their lysins for elimination of infectious bacteria: Review article
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24 Bacteriophage and their lysins for elimination of infectious bacteria
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    Abstract
    Introduction
    Materials and Me...
    Results
    Discussion
    Acknowledgments
    References
    Article Figures

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