Opinion
Bacteriophages as potential new
therapeutics to replace or supplement
antibiotics
Mzia Kutateladze and Revaz Adamia
G. Eliava Institute of Bacteriophages, Microbiology and Virology, Tbilisi, Georgia
Over recent decades, a growing body of literature has
validated the use of bacteriophages for therapy and
prophylaxis in the war against drug-resistant bacteria.
Today, much more is known about bacteriophages than
in the 1930s when phage therapy first appeared and
began to spread to many countries. With rapid dissemi-
nation of multi-drug-resistant bacterial pathogens, the
interest in alternative remedies to antibiotics, including
bacteriophage treatments, is gaining new ground. Based
on recent experience and current results of bacterio-
phage applications against bacterial infections in coun-
tries where this alternative therapy is approved, many
scientists and companies have come to believe that the
use of phages for treating and preventing bacterial dis-
eases will be successful.
Introduction
Bacteriophages (hereafter referred to as ‘phages’) are nat-
ural bacterial viruses abundant in all environments, in-
cluding water, soil and air. Phage activity is very specific,
attacking only host bacterial cells without affecting other
(normal) microflora. The capability of phages to not only
target and destroy a specific bacterium, but also replicate
exponentially, underscores their potential role in treating
infectious diseases. Phages also have several advantages
over antibiotics (Box 1): they are ecologically safe (i.e.
harmless to humans, plants and animals), and phage
preparations are readily producible, easy to apply and
show no apparent adverse reaction to multi-component
phage preparation (sometimes called ‘cocktails’). Conse-
quently, the growing incidence of antibiotic-resistance
pathogens has led scientists and physicians to examine
the possibility of developing phage therapy as an alterna-
tive, but reliable, treatment.
The use of phages for treatment and prophylaxis of
various infectious diseases has a long history. After isolat-
ing the first bacteriophage in 1917 [1], Felix d’Herelle used
an oral phage preparation to treat bacterial dysentery.
Following that success, several commercial laboratories
and companies in the United States, France and Germany
produced phage preparations using phage-lysed, sterile
broth cultures of the targeted bacteria, or the same pre-
parations in a water-soluble jelly base [2–5]. Despite
extensive use in the 1930s, phage therapy research
and clinical applications were largely abandoned by the
Corresponding author: Kutateladze, M. (kutateladze@pha.ge).
0167-7799/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2010.08.001 Trends in Biotechnology, December 2010, Vol. 28, No. 12
Western world after World War II. This abandonment
could be attributed to the discovery and widespread intro-
duction of broad-spectrum antibiotics, coupled with the
mixed successes of the phage approach at the time (a
consequence of poor basic understanding of phage biology),
the shortage of data from clinical trials, and over-expecta-
tions resulting from commercial hyperbole.
Antibiotics can be used against various bacterial patho-
gens, but bacteriophages are only effective against specific
target microorganisms. One of the reasons for phage ther-
apy failure was difficulty in accurately identifying etiologi-
cal agents or the absence of established protocols for in
vitro testing of bacterial susceptibility to the phages. Con-
versely, broad-spectrum antibiotics acted more effectively
in the absence of a confirmed diagnosis of a specific patho-
gen, which led to the decline of interest in therapeutic
phages. Phage therapy flourished in the republics of the
former Soviet Union, despite the adoption of other anti-
bacterials. Phages remained a standard part of the health-
care systems in the USSR even during the 1960s and 1970s
when antibiotics were at their peak in the West. In the
former Soviet Union, phage preparations continued to be
used for therapy, prophylaxis and the diagnosis of many
bacterial infections. Such preparations have been success-
fully used against intestinal problems (e.g. dysentery,
diarrhea, typhoid) and purulent-septic infections, such
as infectious complications of burns, wounds, and organ
inflammation.
Emerging antibiotic resistance
The recent increase in antibiotic-resistant bacterial strains
has become a serious threat to the treatment of infectious
diseases. The time for antibiotic resistance to develop differs
for each antibiotic. For example, for penicillin, the first
observed appearance of resistance was 10 years after the
initiation of use, whereas for vancomycin, it was 30 years.
Many countries, including those considered to be ‘devel-
oped’, are reporting severe drug resistance problems. In
the United States, drug resistance of Staphylococcus aureus
has become a major health problem in hospitals and a
growing concern in health clubs, school gymnasiums and
other communal settings. More than a decade ago, the CDC
reported that approximately 95% of hospital staphylococcal
(‘staph’) infections failed to respond to first-line antibiotics
[6]. The CDC now estimates that as many as 80 000 hospital
patients are infected with methicillin-resistant S. aureus
591
Opinion
Box 1. Comparing phages and antibiotics
There are numerous differences between bacteriophages and
antibiotics. First, phages are the most abundant living entities on
the planet and are natural enemies of bacteria; however, only a
small number of these bacterial viruses have proven to be effective
as therapeutic agents. They also multiply naturally and, conse-
quently, are ‘ecologically pure’. Most antibiotics, by contrast, are
synthetic or semi-synthetic in their production. Second, the host
range of phages is much narrower than that of antibiotics: most
phages are specific to one bacterial species and many are only able
to lyse a few specific strains within a species. The advantage of a
narrow range is that the phage does not affect normal body
microflora, whereas broad-spectrum antibiotics destroy all bacterial
cells independently of whether they are pathogenic. Third, extensive
application of antibiotics might affect the human organism itself;
most currently used wide-spectrum antibiotics often have severe
side effects. By contrast, no side effects of phage application have
been described despite decades-long use for human therapy [22,35–
38]. Lastly, the ability to multiply in the presence of host bacterial
cells makes phages self-regulating tools. The concentration of an
antibiotic introduced into the human organism decreases with time
(natural drug clearance from body), whereas phages continue to
multiply, decreasing as soon as bacterial cells are eliminated.
(MRSA) every year. Community-acquired MRSA (CA-
MRSA) has also become a common and serious problem;
emerging antibiotic-resistance strains that cause the most
serious complications are Acinetobacter baumanii and Clos-
tridium difficile. In Latin America, the major dangerous
strains are referred to as ESKAPE: Enterococcus faecalis,
S. aureus, Klebsiella, Acinetobacter baumanii, Pseudomo-
nas aeruginosa and Escherichia coli. The typical cutaneous
staph infection becomes invasive and develops into a poten-
tially life-threatening infection, particularly in children,
elderly people and immunocompromised persons. At pres-
ent, approximately 70% of the bacterial strains that cause
infections in hospitals are resistant to at least one of the
drugs most commonly used for treatment. Some microor-
ganisms are resistant to all approved antibiotics and can
only be treated with experimental, and potentially toxic,
drugs.
Microbial resistance is most evident in bacterial diar-
rheal diseases, respiratory tract infections, meningitis, sex-
ually transmitted infections and hospital-acquired
infections; important examples include penicillin-resistant
Streptococcus pneumoniae, vancomycin-resistant Entero-
cocci, multi-resistant Salmonellae and multi-resistant
Mycobacterium tuberculosis. Infections caused by these
pathogens often fail to respond to conventional treatment
[7–15]. This leads to long periods of infectious complications
that increase the number of patients spreading infections in
the community, in turn exposing the general population to
the risk of contracting a resistant strain of infection.
Another set of the problems accompanying the preva-
lence of antibiotic resistance is connected to the combined
effect of inadequate infection control practices, particularly
in hospital settings, and the widespread misuse or overuse
of antibiotics in those hospital and community settings. It
has been reported that in U.S. hospitals, 190 million doses
of antibiotics are administered everyday (ACP: www.
acponline.org) [16]. Among non-hospitalized patients,
more than 133 million courses of antibiotics are prescribed
by doctors each year. It is estimated that 50% of these
latter prescriptions are unnecessary because they are
592
Trends in Biotechnology Vol.28 No.12
being prescribed for colds, coughs and other viral infec-
tions, which are not subject to antibiotic activity. In 1998
alone, the U.S. reported that 80 million prescriptions of
antibiotics for human use were filled, equating to 12 500
tons in 1 year [16].
Possible solutions to the dissemination of multi-drug-
resistant bacterial strains are better education of the
population, including the public and medical practitioners,
on the rational use of antibiotics, better control of over-the-
counter sales of antibiotics, and a total review of the health
system structure. The other solution to overcoming the
multi-resistance problem might be finding alternative
remedies against drug-resistant pathogens; this is an im-
portant challenge to modern medicine. Scientists and clin-
icians alike are looking retrospectively to find an
alternative treatment in the form of phage therapy.
Phage application modalities
Despite their marked advantages over conventional anti-
biotics (Box 1), there are several key considerations re-
garding phage application. First, it is absolutely essential
to know exactly which bacterial species is the causative
agent of the infection. Before treatment, the pathogen – or
the provocative infectious agent – has to be identified and
checked in vitro against a library of phages to select the
most effective phage for therapeutic application. Success-
ful use of therapeutic phages in modern clinical settings
depends on having a capable diagnostic laboratory. Next,
to effectively use phage preparations, it is essential to have
a set of well-characterized phages available for the broad
range of bacterial pathogens [17]. Selection of phage cock-
tail components for therapeutic preparation is a key pro-
cedure to prevent the emergence of bacterial resistance to
phages in some cases; the phages should exhibit a strictly
lytic infection cycle during propagation on the host bacteria
[18]. Possible transfer of undesired, virulent genes through
lysogeny or transduction should be excluded. In the best
case scenario, the phage DNA chosen for therapeutic pur-
poses must be sequenced to ensure that it does not include
toxin genes, islands of pathogenicity, or genes that reveal
integration of DNA into the bacterial genome [19].
The observance of bacterial resistance to phages has
significantly lower frequency (10–7 to 10–8 per cell) compared
with that of the resistance to antibiotics (frequency of mu-
tation for one specific gene is 10–5 per cell) [19]. However,
appearance of phage-resistant mutants is possible. A pre-
emptive strike against phage-resistant bacterial mutants is
the construction of phage cocktails. As the phage receptors
on the cell wall are very specific to different phages, it is
virtually impossible for the bacteria to mutate such that it
would be resistant to the cocktail containing several differ-
ent phages. Thus, constructing the ‘right’ cocktail is essen-
tial to achieving the maximum effectiveness of phage
therapy. Moreover, because the formation of antibiotic re-
sistance might proceed through disparate mechanisms, the
simultaneous application of antibiotics and phages should
decrease the appearance of resistant mutations even more.
Phage therapy in humans
Production and usage of phages for therapy and prophy-
laxis continued on a small scale, even after the advent and
Opinion
diffusion of antibiotics in Western Europe and the United
States in the 1950s and 1960s. Several companies had
small-scale production of phage preparations for various
purposes. A company based in Switzerland was producing
phages in several medicinal forms [20]. The Pasteur Insti-
tute in France was producing phage preparations against
various pathogens (Pseudomonas, Staphylococcus, E. coli,
Serratia) until 1974. These phages were used mainly
against skin infections, septicemia, osteomyelitis, wound
infections, urinary tract infections and middle ear and
sinus infections.
In the United States, phages were used mainly for the
preparation of human and animal vaccines. Staphylococcal
phage lysate (SPL) produced in the U.S. was used for
animal protection. With safety trials completed in 1959,
SPL was licensed for human therapeutic usage [21] and
administration by different routes: intranasal application
by aerosol, topically, orally, subcutaneously and even in-
travenously. Phage therapy efficacy was demonstrated in a
clinical trial (late 1950s to early 1960s), wherein 607
patients who failed to respond to conventional treatment
by antibiotics were treated by the phage. The results were
reported were good – 80% of patients recovered, 18%
improved and only 2% exhibited no changes. Furthermore,
no side effects were reported. Unfortunately, owing to
regulatory pressure, production of SPL for human therapy
was suspended in the 1990s, and the preparation is cur-
rently approved and marketed only for veterinary applica-
tions [21].
By contrast, bacteriophage therapy was extensively
exploited in the Soviet Union after World War II. Phage
preparations were widely used against bacterial pathogens
in dermatology, stomatology, otolaryngology, ophthalmol-
ogy, gynecology, pediatrics, surgery, gastroenterology,
urology and pulmonology [22]. Several production facilities
were manufacturing phages in different medicinal forms.
One of the best known centers of bacteriophage study and
production of therapeutic phage preparations was the
Tbilisi Institute of Bacteriophages, Microbiology and Vi-
rology in the Republic of Georgia, established in 1923 by
Georgian scientist Georgi Eliava and French Canadian
phage pioneer Felix d’Herelle. From its inception to
1990, the institute provided the entire Soviet Union with
phage preparations against various infectious complica-
tions. Since 1990 and the collapse of the USSR, the Insti-
tute operates under the name of its founder, Eliava.
The Eliava Institute has produced phages for the treat-
ment and prophylaxis of purulent septic and intestinal
infections. Phage preparations produced were widely avail-
able and easy to apply by different routes: orally (liquid and
tablets), locally (in tampons, rinses and creams), rectally,
as aerosols or intrapleural infusions, by nebulizer, and
intravenously (Figure 1). The preparations were subjected
to extensive preclinical and clinical trials, and many arti-
cles and papers have been published on the successful
application of bacteriophage preparations [22–31]. Howev-
er, Soviet standards of clinical trial reports did not comply
with internationally approved regulations and standards.
Moreover, Soviet scientific literature (mainly published in
Russian and Georgian) was often unavailable to the rest of
the world. Taken together, these factors appeared to cause
[(Figure_1)TD$IG] Trends in Biotechnology Vol.28 No.12
Figure 1. Dr Guram Gvasalia, chief surgeon of Tbilisi Republican Hospital, applies
bacteriophage therapy for joint inflammation caused by S. aureus.
distrust and apprehension in international approval of
bacterial viruses for treatment. Today, the emerging prob-
lem of bacterial resistance to antibiotics has revitalized the
interest in the efficacy of phage therapy.
Recently, some of the old Soviet data on phage therapy
trials in adults and infants were compiled into a mono-
graph (in English) by the Eliava Institute [22]. The book
describes a large number of case studies of phage treat-
ment, as well as combined treatment with phages and
antibiotics. One of the examples of successful phage thera-
py is staphylococcal phage usage. For many years, the
Eliava Institute produced a staphylococcal phage prepara-
tion that was effective when used locally (topically). In the
late 1970s, Institute scientists elaborated a method for
construction of the phage preparation for intravenous use.
In a series of clinical trials, the therapeutic effectiveness of
this phage preparation against different infectious dis-
eases was evaluated: acute and chronic sepsis, peritonitis,
osteomyelitis, mastitis, purulent arthritis, acute and
chronic lung abscesses, chronic pneumonia and bronchitis,
bronchoectasis, purulent cysts, and other infections. Select
data from these trials are presented in Table 1, which
shows the effectiveness of phage against staphylococcal
sepsis, septic infection of the lungs (acute and chronic
abscess of the lungs, chronic pneumonia and chronic bron-
chitis) and osteomyelitis. It appears that in the patients
with sepsis, 41% of patients (n=46) treated only by phages
recovered completely. During treatment with a combina-
tion of phages and antibiotics, 78% fully recovered, where-
as the control group (n=96), treated only by antibacterial
remedies showed 23% recovery (Table 1). The results of
treatment of other infections shown in the table suggest
that the combination of bacteriophage and antibiotics is
more efficient than bacteriophages alone.
Efficacy of combined application of phages and antibio-
tics against various infections in vivo could be illustrated
by in vitro experiments performed previously [32]. The
scientists showed that sub-lethal concentrations of anti-
biotics enhance the biosynthetic capacity of bacterial cells,
and virulent phages have evolved the capacity to take
advantage of this altered host cell state to increase their
own production. A second consequence of simultaneous
593
 Opinion
Table 1. Effectiveness of staphylococcal phage preparation against staphylococcal sepsis, septic infection of the lungs and
osteomyelitisa
Diagnosis Phage therapy only
Total Complete Improvement No
number recovery effect number recovery
(N)
Sepsis 46 19 6 21
Lung infection 60 21 25 14
Osteomyelitis 9 9 – – 51
and arthritis
a
Soviet data on phage therapy trials from the Eliava Institute [22]. In a series of clinical trials in the 1970s, the therapeutic effectiveness of the staphylococcal phage preparation
against different infectious diseases was evaluated, from which some results are listed here.
application is to accelerate the lysis of the infected cells,
thereby allowing the phages to spread more rapidly.
During the past 3 years, together with the National
Center of Cystic Fibrosis in Tbilisi, phage preparations
against secondary infections in eight patients with cystic
fibrosis were used. Phages were applied in infants and
adults via nebulizer, several times for 6–10 days. Simulta-
neously, patients were treated by conventional antibiotics,
anti-mucus medications and vitamins. Phage application
caused a substantial decrease in the concentration of
bacterial cells in all patients’ sputum specimens. The
general health of patients clearly improved and bacterio-
phage therapy provided long infection-free periods be-
tween colonization episodes in all patients. Furthermore,
the results of clinical application of phages have been
presented at several international scientific conferences:
International Phage Conference in Tbilisi, Georgia (2008);
32nd European Cystic Fibrosis Conference (2009) in Brest,
France; 18th Evergreen International Phage Biology Meet-
ing (2009) in Olympia, WA, USA; and International Con-
ference Viruses of Microbes (2010) in Paris, France.
Recently, small-scale laboratory-based quality control
experiments of the phages prepared at the Eliava Institute
have been conducted at the Burn Center of the Queen
Astrid Military Hospital in Brussels, Belgium [33]. These
studies included determination of stability, pyrogenicity,
sterility and cytotoxicity, as well as confirmation of the
absence of temperate (non-lysing) phages. The phage mix-
ture was subjected to all necessary safety procedures, was
evaluated for clinical trials, and was used topically on the
infected burn wounds of eight patients. No adverse reac-
tions were observed. The detailed description of the quality
controlled small-scale phage preparation was considered
as a first step to promote the concept of phage treatment in
Western medicine. In addition, it supported the creation of
a discussion platform for regulatory framework for approv-
al of phage therapy.
In 2009, a private company, Biocontrol Limited, per-
formed a series of clinical trials with 24 volunteer patients
with chronic otitis in London [34]. By monitoring phage
replication in treated patients, it was observed that the
phages were not present in the organism after elimination
of the target bacteria. In contrast to antibiotic treatment,
which requires gram-quantities administered over the
course of several weeks, phage therapy uses only 2.4 ng
administered one time. Even so, the phage effects have
lasted several weeks. In three previously untreatable
cases, phage treatment resulted in a complete cure [34].
These trials, alongside earlier studies, have successfully
594
Trends in Biotechnology Vol.28 No.12
Phage with antibiotics Antibiotics only
Total Complete Improvement No Total Complete Improvement No
effect number recovery effect
(N) (N)
40 31 4 5 96 22 22 52
61 31 24 6 55 10 21 24
51 – – 60 60 – –
indicated that phage therapy demonstrates considerable
promise, for treating the increasing number of infections
caused by antibiotic-resistant bacteria.
Concluding remarks
The growing problem of antibiotic resistance in combina-
tion with the environmental burden caused by the unre-
stricted use of antibiotics provides sufficient motivation for
developing alternative solutions. Phages could play an
important role in treating bacterial infections in humans,
animals, aquaculture and crops, as well as in decontami-
nating food supplies and communal environments. Com-
bined treatment of severe cases of infectious diseases with
both phage preparations and antibiotics is also a potential
approach that could be more effective than monotherapy
alone.
It is suggested that phages as therapeutic remedies
should not be regulated in accordance with the standards
applied to antibiotics. Phage cocktails against various
bacterial pathogens must continually be updated with
new components to correspond to and keep activity against
constantly emerging new strains or species. The only way
for that to occur will be to regulate phage preparations as
‘biological preparations’ rather than ‘pharmaceuticals’.
The main challenge for the expansion of phage use will
be the necessary performance of large-scale clinical trials
in accordance with U.S. FDA or European guidelines.
Usually, these procedures are very expensive and take
several years. Without profound interest from big phar-
maceutical companies, which has not been expressed to
date, it is difficult to imagine that phage therapy will gain
widespread acceptance or application in the Western world
in the near future.
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