**[Dealing with the problem of antibiotic resistance: the role of
immunoprophylactics and immunotherapeutics.]{.smallcaps}**

The inevitability of progression of bacterial resistance to antibiotics
used in the clinic and other settings dictates the need for approaches
that go beyond antimicrobial stewardship and the development of new
antibiotics. These include the prevention of infection by means such as
vaccination and use of passive immunoprophylaxis, as well as the
development of immunotherapeutics that are not subject to the mechanisms
of resistance that affect small molecule antimicrobials.

Prevention of infection is indisputably the optimal means of dealing
with the problem of antimicrobial resistance. Vaccines currently in use
have been very effective in the prevention of several bacterial
infections, but these have not been aimed at multidrug resistant
pathogens. Potential vaccine target bacterial pathogens exhibiting
antibiotic resistance include organisms such as *Mycobacterium
tuberculosis, Helicobacter pylori, Clostridium difficile, Pseudomonas
aeruginosa,* and *Staphylococcus aureus*. I will focus here on the last
mentioned.

*S. aureus*, as a consequence of both its increasing prevalence and
worsening antibiotic resistance, is a prime potential vaccine target.
Initial experience targeting this organism has, however, been
disappointing. Thus, e.g., despite initial evidence suggesting efficacy
in the prevention of bacteremia in chronic hemodialysis patients, a
capsular polysaccharide vaccine failed in a subsequent larger Phase 3
trial. In recognition of the need, however, at least one other vaccine,
V710, which targets *S. aureus* iron surface determinant B (IsdB), is
being evaluated in early phase trials in cardiac surgery and orthopedic
implant patients. Some of the target populations that could potentially
benefit from a vaccine against *S. aureus* are listed in the Table.

One reason for the failure of the capsular vaccine may have been the
relatively immunocompromised status of chronic dialysis patients. This
and vaccine others may prove to have greater efficacy in individuals
without evident immune deficiency. The emergence of community-acquired
methicillin-resistant *S. aureus* (MRSA) infection as a frequent cause
of recurrent infection in previously healthy individuals provides a
potential target population likely to have a more robust response to
vaccination.

It is also likely that, given the complexity of the panoply of means by
which *S. aureus* is able to avoid the innate immune response, that an
effective vaccine will have to target multiple virulence factors rather
than just one.

The development of this and other bacterial vaccines requires adequate
funding of basic and translational work and, in circumstances in which
the target population is limited (.e., *P. aeruginosa* infections),
significant incentives to industry. Successful vaccine development will,
however, be a critical element of any successful attack on the problem
of antibiotic resistance.

A complementary method of prevention of infection with multidrug
resistant pathogens is that of passive immunoprophylaxis in defined
populations, particularly those who are unlikely to have an adequate
immunological response to vaccination and/or for whom there is
inadequate time for a vaccine response prior to a potential danger
period. Such individuals may include those undergoing urgently required
cardiac or orthopedic surgery, as well as burn patients and other
patients already severely immunocompromised or about to become so.
Finally, agents developed for passive immunoprophylaxis may also prove
to be effective as therapeutic agents. With reference once again to *S.
aureus*, several agents are undergoing current investigation.

In summary, the development of vaccines and immunoprophylactics capable
of preventing infection with multidrug resistant pathogens will be a
necessary element in the struggle against antibiotic resistance. In
addition, immunotherapeutics have the capability to save lives of
patients infected with such pathogens.

**Table. Potential target population for a vaccine against *S.
aureus*.**

Chronic dialysis patients

Diabetes mellitus patients

Patients with planned device implantation

Cardiac

Orthopedic

Contact sport participants, prisoners, military, MSM, IDUs, etc.

Long term care patients

Health care workers

Correctional facility workets

Persistently colonized patients

Patients recovered from *S. aureus* infection

Family members of colonized/infected patients & pets

**Table 2. S. aureus: immunotherapeutica and**

**passive immunoproph**ylactics.

  ----------------------- ---------------------- -------------------------------
  [Product]{.underline}   [Pharma]{.underline}   [Target]{.underline}

  Altastaph™              Nabi                   Caps. Polysacch. 5,8

  Veronate™               Inhibitex              ClfA

  Aurexis™                Inhibitex              ClfA

  Aurograb™               Neutec                 GrfA

  Pagibaximab             Biosynexus             LTA

  ETI-211                 Elusys                 Spa
  ----------------------- ---------------------- -------------------------------