Download Review New treatments for viral respiratory tract infections

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Journal of Antimicrobial Chemotherapy (2001) 47, 251–259
Review
New treatments for viral respiratory tract infections—opportunities
and problems
N. J. C. Snell*
Bayer Pharma, Stoke Court, Stoke Poges, Slough SL2 4LY, UK
Introduction
Viruses are the most common cause of respiratory tract
infections (RTIs), yet in contrast to the plethora of antibiotics available for the treatment of bacterial RTI, until
very recently only three agents were widely approved for
the treatment of viral RTIs: amantadine and rimantadine
for influenza A, and ribavirin for respiratory syncytial virus
(RSV) infection—and amantadine was first marketed in
1966.
In 1999 the novel anti-influenza agents, zanamivir and
oseltamivir, were launched. Controversy has attended the
failure to reimburse zanamivir therapy in some countries,
and the initial advice from the new National Institute for
Clinical Excellence (NICE) in the UK that it should not be
generally prescribed.1 With several new therapies for viral
RTIs in late stages of clinical development, now is perhaps
an appropriate time to take stock of the situation.
Disorders due to viral RTI
The most frequent symptom complex due to viral infection
of the respiratory tract is the common cold (coryza). This is
most often caused by rhinoviruses (of which there are more
than 100 serotypes). Some 20% of colds are caused by
coronavirus infection; identical symptoms can be caused
by influenza and parainfluenza viruses, adenoviruses, RSV
and various enteroviruses.2 The same viruses cause descending infections of the respiratory tract, but the aetiology
differs in frequency; adenoviruses are common causes of
viral pharyngitis and tonsillitis, while croup (subglottic
oedema due to laryngotracheitis) is particularly associated
with parainfluenza virus infection.3 All these viruses can
cause acute bronchitis in healthy people, and infective
exacerbations in patients with chronic obstructive pulmonary disease (COPD).4 Viral RTIs are also implicated in
exacerbations of asthma5 and cystic fibrosis.6 Acute bronchiolitis in infants is most commonly the result of RSV
infection, but this virus is also an under-recognized cause of
lower RTI in the elderly.7 Viral infection (particularly with
influenza, parainfluenza and RSV) is a common cause of
acute respiratory disorders leading to hospitalization in
patients with chronic underlying conditions,8 particularly
COPD, asthma, cardiac disease and diabetes.
Viral pneumonias are uncommon in the previously
healthy and are most commonly associated with influenza,
but also occur rarely owing to measles and varicella-zoster
infection.9 Life-threatening viral pneumonias may occur
in immunocompromised patients; this increasing group
includes subjects with advanced HIV infection, patients
receiving anti-cancer treatment, transplant patients on
immunosuppressive therapy and the very young (premature neonates) and very old. Pneumonia may be caused by
any of the ‘conventional’ respiratory viruses described
above, but is commonly due to herpesviruses, particularly
cytomegalovirus (CMV) and herpes simplex virus (HSV).10
In addition to predisposing to opportunistic lung infections, HIV infection may be associated with lymphocytic
and non-specific interstitial pneumonitis, and also appears
to increase susceptibility to smoking-induced emphysema.11
Rare specific viral RTIs include recurrent respiratory
papillomatosis (caused by the human papillomavirus) and
the serious pneumonia caused by a hantavirus that has
recently been described in parts of North and South
America.12 Chronic or latent viral infection has been implicated in the aetiology of idiopathic pulmonary fibrosis
(Epstein–Barr and hepatitis C viruses)13 and COPD (adenovirus),14 but these links remain unproven. Empirical therapy
of idiopathic pulmonary fibrosis with nebulized ribavirin (a
broad-spectrum antiviral) produced no clinical benefit15
(and N. J. C. Snell, unpublished observations). It has also
been suggested that viral RTIs could be co-factors in the
development of hypersensitivity pneumonitis.16
*Tel: 44-1635-566743; Fax: 44-1491-638842; E-mail: [email protected]
251
© 2001 The British Society for Antimicrobial Chemotherapy
N. J. C. Snell
Therapy for rhinovirus and coronavirus
infection
The British Medical Research Council’s Common Cold
Research Unit laboured for 43 years (1946–1989) without
discovering a cure. Several compounds with promising
anti-rhinovirus activity in vitro failed to demonstrate useful
clinical activity. Both - and β-interferon, given intranasally before viral challenge, were shown to be effective in
protecting against rhinovirus, coronavirus, influenza and
RSV infection; however, local side-effects and the fact that
they were most effective given prophylactically inhibited
their utility in these indications.17 Recently, better understanding of the morphology and mode of action of the
rhinovirus has permitted the development of more
specific antiviral agents.
The discovery that a deep surface depression or ‘canyon’
on the surface of the rhinovirus was the site of receptor
attachment18 led to the development of drugs that bind to
this site. A series of compounds synthesized by SterlingWinthrop bind to a hydrophobic pocket in the canyon floor
and are thought to act by preventing viral uncoating,
through stabilization of the viral capsid.19 The most promising of this series is pleconaril (WIN 63843), which has been
licensed out to Viropharma for clinical development in
rhinovirus and other picornavirus infections. It has good
oral bioavailability and is widely distributed in the tissues,
attaining high concentrations in nasal epithelium, and is
well tolerated in animal models and in man.20 Prophylactic
administration of pleconaril to healthy volunteers before
intranasal inoculation of coxsackievirus A21 (a model of
picornavirus RTI) led to significant reductions in viral
shedding, nasal secretions and symptom scores compared
with placebo.21 Phase II clinical trials in approximately
1500 patients presenting with a viral respiratory illness
showed that pleconaril reduced the duration of symptomatic illness by about 3 days compared with placebo, and
had a similar adverse event profile.22 However, a more
detailed abstract of a single large (875 subject) placebocontrolled study found a 1–2.25 day reduction in symptoms
that was statistically significant only in patients positive for
picornavirus infection by culture or polymerase chain
reaction (PCR), who were not taking concomitant cold
medications.23
Agouron Pharmaceuticals has elucidated the structure
of the rhinoviral enzyme 3C protease, which splits viral precursor proteins into structural and enzymic proteins essential for replication, and has synthesized a specific 3C
protease inhibitor, AG-7088. This has similar in vitro
antirhinoviral activity to pleconaril, and was well tolerated
when given intranasally up to six times daily in volunteer
studies. Phase II clinical trials in experimentally infected
healthy volunteers showed significant reductions in symptoms, nasal secretions and viral concentrations compared
with placebo.24 Other companies developing rhinovirus 3C
protease inhibitors include Lilly, Cytoclonal Therapeutics
and Apotex. Lilly is also studying a 2A protease inhibitor.
All these projects are currently at the preclinical stage.25
Rhinoviruses attach to specific cellular receptors in
order to initiate infection. It has been shown that 90% of
rhinovirus serotypes attach to a cell surface glycoprotein
known as intercellular adhesion molecule-1 (ICAM-1).
The remaining 10% probably all utilize members of the
low-density lipoprotein receptor (LDLR) family.26 Two
pharmaceutical companies (Boehringer Ingelheim and
Bayer) have managed to produce truncated, soluble forms
of ICAM-1 by genetic engineering; since free ICAM-1 will
attach to the rhinovirus binding sites, the virus should
effectively be ‘neutralized’ and prevented from attaching
to the cell-surface receptors and initiating replication.
Boehringer’s product, tremacamra, has demonstrated a
potent inhibitory effect on human rhinovirus in vitro.27 In
phase II clinical trials, when given intranasally, tremacamra
significantly reduced the symptoms of experimental rhinovirus colds, regardless of whether it was administered
before or after viral challenge. There were no adverse
effects, and drug administration was not associated with the
development of neutralizing antibodies.28 Bayer’s product,
given intranasally to chimpanzees, has been shown to protect against infection on subsequent challenge with virus.29
Despite these promising findings clinical development of
both projects is apparently on hold. One problem is the
short residence time of intranasal medication, owing to
mucociliary clearance and evacuation by sneezing and
nose-blowing;30 another is the fact that protection is specific for only 90% of rhinovirus strains and not for other
causes of the common cold.
The difficulty in attaining and maintaining effective
concentrations of drug in the nasopharynx is probably the
reason for the failure of a number of compounds that
showed promise in preclinical studies—for example, the compound 7-thia-8-oxoguanosine (NARI 10146) was highly
effective as prophylaxis against an otherwise lethal coronavirus infection in a rat model, but had no influence on the
course of an experimental coronavirus infection in human
volunteers.31 On the other hand, the anti-influenza agent
zanamavir has been proved to be efficacious when administered intranasally; positron emission tomography has
shown that 50% of the deposited drug remains in situ for at
least 1.5 h.32 The reason for this long residence time is
unclear, although in subjects with active influenzal infection mucociliary clearance may be impaired. It may prove
possible to prolong the intranasal residence time of inhaled
drugs by utilizing thixotropic formulations.33
Anti-influenza agents
The anti-influenza activity of amantadine was first described in 1964. It and its analogue rimantadine have
been shown to be effective both in the prophylaxis and
treatment of influenza A infection.34 Their activity appears
252
Viral respiratory tract infections
Table. Selected viral pathogens of the respiratory tract, approved therapy and key antiviral agents undergoing
clinical trials or with evidence of clinical activity
Currently approved therapya
Causative virus
Rhinovirus
–
Influenza A virus
Influenza A + B virus
Respiratory syncytial virus
amantadine, rimantadine
zanamivir, oseltamivir, ribavirin
ribavirin
palivizumabb
–
–
–
Parainfluenza virus
Adenovirus
Papillomavirus (recurrent
respiratory papillomatosis)
Hantavirus
Cytomegalovirus
Herpes simplex virus
–
ganciclovir
immune globulin
acyclovir
Varicella-zoster virus
acyclovir
a
Agents under clinical investigation or
used empirically
t-ICAMs (tremacamra, BAY z 9700)
pleconaril
AG-7088
RWJ-270201
ribavirin
ribavirin
-interferon
cidofovir
ribavirin
cidofovir
foscarnet
famciclovir
valaciclovir
famciclovir
valaciclovir
Licensed in North America and/or EU countries.
Prophylaxis only.
b
to be because of interaction with the M2 membrane protein
of the influenza A virus, which acts as an ion channel with
a pH regulatory function.35 However, their usefulness is
limited by their specificity for influenza A (they have no
activity against influenza B, which does not possess the M2
membrane protein), and by the occurrence of central
nervous system side-effects (less frequent with rimantadine).36 Both compounds are fetotoxic in rodent studies.34
Administration by nebulization has been tried in an
attempt to improve the risk:benefit ratio, but has not
become an accepted route of treatment.37 Resistance to
both agents develops readily during treatment (see below).
Until recently the only other agent available for the treatment of influenza was the broad-spectrum antiviral nucleoside, ribavirin. This is active against both influenza A and B
in vitro; it showed low clinical efficacy in a series of trials
when given orally, but by the nebulized route was shown to
accelerate recovery from influenza A and B infections in
infants and young children,38 although it has not been
widely approved for this indication.
Advances in our knowledge of the biology of the
influenza virus have led to the recent development of a new
generation of anti-influenza agents. The major influenza
virus surface proteins are haemagglutinin and neuraminidase (sialidase). Haemagglutinin mediates binding
and fusion of the viral and host cell membranes; it is the
major target for neutralizing antibodies (and hence
influenza vaccines) but is highly variable. Neuraminidase is
essential for facilitating release of new virions from the host
cell surface and preventing their aggregation. Although
there is also variability in this protein, the amino acid
sequence and three-dimensional structure of the enzyme’s
active site are highly conserved, making it a suitable therapeutic target.39 Several neuraminidase inhibitors are now
in preclinical or clinical development,40 and two (GlaxoWellcome’s zanamivir and Roche/Gilead’s oseltamivir)
have received marketing authorization. Both have been the
subject of recent comprehensive reviews.41–3
Zanamivir has poor oral bioavailability and is administered by po inhalation from a dry-powder inhaler (the
Diskhaler), although in early volunteer studies it was given
intranasally. Clinical trials have shown that it shortens
the symptomatic duration of the disease and the time taken
to resume normal activities by at least a day, and its use
is associated with a reduced consumption of over-thecounter medications and prescribed antibiotics. It has also
given promising results when used for the prophylaxis of
influenza,44 but this is not yet an approved indication. The
fact that the nasopharynx is bypassed when administering
medication is a potential drawback, and may relate to the
fact that treatment has no effect on the incidence of complicating sinusitis and otitis media,45 although concentrations in excess of the viral neuraminidase MIC50 have been
demonstrated to persist in nasal washings for at least 12 h
253
N. J. C. Snell
after oral inhalation.46 On the other hand, po inhalation
does limit systemic exposure and hence potential systemic
side-effects.
In contrast, oseltamivir is well absorbed orally and
widely distributed throughout the tissues, attaining high
concentrations throughout the respiratory tract. A plasma
half-life of approximately 8 h allows bd dosing (zanamivir
is also recommended for bd administration, although the
serum half-life is shorter at 4–5 h). The zanamivir and
oseltamivir clinical trials are not strictly comparable, but
overall the oseltamivir studies show a shortening of symptom duration of about 1.5 days, and a greater reduction
than for zanamivir in associated antibiotic prescribing, for
secondary infections of both the upper and lower respiratory tract.43,47 Both drugs are well tolerated, although a few
cases of bronchospasm following inhalation of zanamivir
have been reported;48 a small study in mild to moderate
asthmatics found no significant effects of zanamivir inhalation on lung function or airway responsiveness.49
Several more neuraminidase inhibitors are under development, including analogues of zanamivir and oseltamavir, in addition to novel compounds.40 The most advanced
of these is a cyclopentane derivative, RWJ-270201 (BCX1812),50 which is under joint development by Johnson and
Johnson and BioCryst Pharmaceuticals. Given orally in
mouse models of influenza A and B infection it appears to
be at least as effective as oseltamivir, with no observed
toxicity. Phase II clinical data were promising, and it is
currently in phase III clinical trials.51 Abbott Laboratories
is studying a series of novel substituted pyrrolidine neuraminidase inhibitors.52
Other recently described agents with potentially useful
activity include a series of compounds derived from podocarpic acid53 and antisense phosphorothioate oligonucleotides,54 both of which exhibit in vivo activity against
influenza A. Provir (SP303), a naturally occurring phenolic
polymer derived from a plant of the Euphorbiaceae family,
showed promising activity against influenza viruses in vitro
and in vivo (and also against RSV and parainfluenza type
1),55 but proved to have very poor oral bioavailability, and
clinical development in these indications has been discontinued.
Therapy for RSV infection
There is currently no effective vaccine against RSV infection; clinical trials with a formalin-inactivated vaccine in
the 1960s not only demonstrated a lack of protective effect,
but infected infants actually experienced more severe disease, probably because of an immune-mediated response.
Efforts to develop an effective vaccine continue.56 Meanwhile it has been shown that both hyperimmune globulin56,57 and a humanized RSV-specific monoclonal antibody
(palivizumab)58 can reduce the incidence of RSV bronchiolitis requiring hospitalization when given prophylactically.
Palivizumab significantly decreased the replication of RSV
in tracheal secretions of ventilated infants,59 but is not
currently licensed for treatment of established disease. It
is expensive, and it has been suggested that its use is not
cost-effective in the majority of premature infants, with or
without chronic lung disease.60
The only approved therapy for established RSV infection is the nucleoside antiviral, ribavirin. A series of clinical
trials and ancillary studies established the safety and tolerability of this agent when administered by nebulization,
and suggested efficacy in improving clinical signs,
oxygen saturation, and duration and severity of the illness.61 However, most of these studies were small, and their
design and the relevance of the clinical effects seen have
been questioned.62 Subsequent studies looking at longterm effects of therapy on lung function and bronchial
hyperactivity have given varying results, some showing
marked benefit, some none.63 Ribavirin therapy is expensive and inconvenient (current recommendations are to
nebulize for 12–18 h daily, although studies have shown
equivalent effects from a higher-dose, shorter-duration
administration).64 Its use should probably be restricted to
high-risk infants with pre-existing cardiopulmonary disorders or immune deficiencies. Several ribavirin analogues
have been shown to inhibit RSV replication in vitro, but
in vivo studies have not been reported.65
-Interferon has been shown to have modest beneficial
effects on the course of RSV infection when given intramuscularly66 or as an aerosol,67 but this mode of therapy
does not seem to have been pursued. Several other novel
agents are at an early stage of development,65,68 including a
nebulized antisense oligonucleotide (NIH 315) and a number of compounds that interact with the viral F protein and
inhibit fusion with the host cell, including the biphenyl
derivative CL-387626 (Wyeth-Ayerst), VP14637 (Viropharma) and a RhoA-derived peptide.69
Rare or novel viral RTI
Juvenile laryngeal papillomatosis (recurrent respiratory
papillomatosis) is a rare condition (prevalence approximately 2 per 100 000 population in the USA)70 caused by
the human papillomavirus, and characterized by recurrent
papillomas of the aerodigestive tract, most frequently
affecting the glottis where they can cause hoarseness,
stridor and respiratory distress; rarely, spread to the airways and lung parenchyma can occur, and the condition
can progress to malignancy. The condition also affects
adults, when it is generally less aggressive.71
Conventional management involves frequent endoscopic surgery. Treatment with several antiviral agents has
been studied; intramuscular -interferon has been associated with sustained or repeated responses in a substantial
proportion of patients.72 There have been anecdotal
reports of benefit from ribavirin73 and from acyclovir
254
Viral respiratory tract infections
therapy.74 A promising new approach appears to be the use
of cidofovir, either intralesionally75 or intravenously.76
Hantaviruses have been known for many years as the
cause of haemorrhagic fever with renal syndrome (HFRS),
which varies from a mild condition (nephropathia epidemica) in Scandinavia, to a more serious form in Asia (Korean
haemorrhagic fever). Respiratory symptoms are not a
feature. However, in 1993 a cluster of cases of severe respiratory disease occurred in the South Western USA,
characterized by non-cardiogenic pulmonary oedema and
a high mortality rate. These were eventually shown to be
due to a hantavirus (Sin Nombre virus), and subsequently
further cases due to the same or closely related viruses have
been reported in both North and South America.12 Intravenous ribavirin has been shown to reduce mortality in
HFRS,77 but an open-label trial in hantavirus pulmonary
syndrome was not associated with a dramatic effect on
mortality.78 Treatment with corticosteroids has given
promising results in South America.12
Viral pneumonitis in the immunosuppressed
Immunosuppressed subjects, particularly bone-marrow
and solid-organ transplant patients, are prone to develop
severe viral RTI. Normal community viruses (adenovirus,
influenza, parainfluenza and RSV) are commonly implicated, but a specific problem in these patients is severe
herpesvirus infections, most importantly due to CMV and
HSV. The relative scarcity of such patients and the fact that
they are usually already the subjects of polypharmacy have
made formal clinical trials of antiviral agents difficult.79
There are no therapeutic agents approved specifically for
the treatment of parainfluenza or adenovirus infections;
because of its broad spectrum of antiviral activity, ribavirin
has been tried empirically in RSV infection,80 influenza,81
parainfluenza82 and adenovirus infection,83 with varying
degrees of success.
The management of herpesvirus infections in transplant
patients has been the subject of a recent report from a
working party of the British Society for Antimicrobial
Chemotherapy.84 The antiviral agent ganciclovir has been
shown to be of value in the prophylaxis of CMV pneumonitis associated with bone-marrow85 and solid-organ86
transplants, while acyclovir is inferior to ganciclovir in the
prophylaxis of CMV infection and obliterative bronchiolitis in lung transplant patients.87 Current therapy for established CMV pneumonitis is a combination of ganciclovir
with immune globulin, based on open-label studies that
showed, respectively, a significantly improved survival on
this regimen compared with historical controls88 and significantly better survival with the combination therapy than
with ganciclovir or immune globulin alone.89 Foscarnet is
also active against CMV but its use is limited by renal toxicity. Cidofovir is undergoing clinical trials. Novel agents
(e.g. BAY 38-4766)90 are under investigation; an interest-
ing new approach is the use of a bioengineered proteinase
inhibitor (1-PDX), a selective and potent furin inhibitor,
which is highly active against herpesviruses (including
CMV) in cell-culture models.91 High-dose acyclovir (plus
-interferon) was ineffective in the treatment of CMV
pneumonitis following bone-marrow transplantation,92 but
acyclovir is currently the recommended agent for prophylaxis and treatment of HSV pneumonitis84,93 and also for
varicella-zoster virus infection,84 although both valaciclovir
and famciclovir exhibit better oral availability and may well
become the treatments of choice in these two infections.
The problem of resistance
The problem of increasing resistance to antiviral agents
was highlighted in an editorial in the New England Journal
of Medicine in 1989.94 However, selection of a strain of
influenza A virus in vivo with increased resistance to amantadine was demonstrated as early as 1970.95 The emergence
of resistance to rimantadine during therapy was first noted
in 1987.96 Numerous subsequent reports have documented
the development of resistance to both amantadine and
rimantadine during treatment.97 The genetic basis for the
development of resistance appears to be a single amino
acid change in the transmembrane portion of the M2 protein, which is the target area for these two antiviral agents
(leading to blockade of viral fusion or release).97
Although transmission of resistant influenza virus has
been demonstrated in the family setting and probably during nursing-home outbreaks,98 and prolonged shedding
may occur in immunosuppressed patients,99 persistence of
resistant strains in the community does not seem to be a
problem, perhaps owing to the regular emergence of new
strains.98 Interestingly, the development of resistance
during therapy appears to have little effect on the clinical
outcome in treated patients,97,98 although it does limit the
use of the adamantanes for concurrent treatment of an
index case and prophylaxis of contacts. A survey of rimantadine resistance in field isolates of influenza A virus in 43
countries and territories, in some of which rimantadine
has been widely used for more than 20 years, found only
0.8% of 2017 isolates to be drug resistant,100 which is quite
reassuring.
The nucleoside antiviral agent, ribavirin, has a broad
spectrum of activity against respiratory tract and other
viruses. In contrast to amantadine and rimantadine, viral
resistance to ribavirin has not been demonstrated. This
may be because at least three mechanisms of antiviral activity have been described:101 depletion of cellular nucleotide
pools, inhibition of cap formation of mRNA and inhibition
of influenza virus RNA polymerase.
Strains of both influenza A and B virus resistant to the
neuraminidase inhibitor zanamivir have been produced by
repeated passage in vitro, owing to mutations in the haemagglutinin or neuraminidase. However, resistance to zana-
255
N. J. C. Snell
mivir develops much less readily than it does to amantadine
and rimantadine in similar experiments, and has not been
shown in animal models under conditions that readily
select for resistance to amantadine and rimantadine.102
The zanamivir-resistant strains appear to replicate less well
in culture and are very much less infectious in mice than the
wild-type virus.103 In clinical practice only one case of
resistance developing to drug during therapy has been
reported, in an immunocompromised child receiving prolonged treatment with zanamivir.104 Oseltamivir-resistant
influenza virus has been detected in in vitro experiments
and in <1% of isolates from treated patients; this is because
of mutations at the active site of neuraminidase, which are
associated with greatly impaired replication in vivo, suggesting that the development of resistance is unlikely to
limit the clinical usefulness of this class of drugs in immunocompetent subjects,41 for therapy or prophylaxis.
The development of resistance by herpesviruses to
specific antiviral agents has been well studied. At least
three mechanisms have been described in HSV, two involving mutations in the viral enzyme thymidine kinase, the
other involving alterations in the viral DNA polymerase.105
Although acyclovir-resistant HSV is generally considered
to have reduced virulence, cases of severe HSV pneumonia
due to resistant strains of virus have been observed.106
Variants of CMV conferring multidrug resistance have also
been reported.107 In general, the development of resistance
has been associated with prolonged monotherapy, usually
in immunocompromised patients.
The use of soluble ICAM receptor therapy as prophylaxis against rhinovirus over several winter months could
put a selection pressure on those viruses that do not use
ICAM-1 as their attachment receptor and they might
become dominant in the community. Strains of rhinovirus
resistant to several novel anti-rhinoviral agents including
dichloroflavan and chalcone, neither of which is still in
development, have been described.108
What can be done to limit the development of viral resistance? By analogy with bacterial infections one can propose
a general rule that monotherapy of acute viral infections in
patients with normal host defences seldom leads to the
development of clinically significant resistance, whereas
monotherapy of chronic infections is much more likely to,
particularly in the immunosuppressed (this was discovered
half a century ago with tuberculosis, and the same lesson
had to be relearned in the treatment of HIV infection).
Additive or synergistic effects of combinations of agents
active against influenza viruses have been reported109,110
and it may be prudent to consider whether we should be
prescribing combination chemotherapy for viral RTI,
where the patient is immunosuppressed or treatment is
likely to be prolonged. Combination therapy with ganciclovir and foscarnet has been proposed for the treatment of
CMV patients with a high viral load.84 Now that we have
reached a point where effective chemotherapy for most
viral RTIs is a real possibility, it would be sensible to try to
avoid a similar situation to that with antibacterial agents,
where widespread resistance has developed largely because of inappropriate prescribing.
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