chloramphenicol, polymyxin B, colistin, and tigeglycine. High-resistance potential antibiotics
used for GNBs include imipenem, ciprofloxacin, ceftazidime, TMP-SMX, and gentamicin.
There is no good explanation for why within each antibiotic class there are one or more
antibiotics that have high resistance potential while the others in the group with a similar
structure and pattern/volume of use have not been associated with significant resistance
problems. Low-resistance potential antibiotics have been used for decades without causing
widespread resistance, i.e., doxycycline, minocycline, amikacin, ceftriaxone, nitrofurantoin,
fosfomycin, and amphetamine salts (1–5).
Antibiotic-induced resistance, therefore, is not related to antibiotic class, volume, or
duration of antibiotic use, but rather is an attribute of one or more antibiotics in each antibiotic
class that may be considered as high-resistance potential antibiotics whereas the other
antibiotics in the class may be termed low-resistance potential antibiotics. This distinction is
clinically useful and has practical applications. However, it should be remembered that if an
institution has a resistance problem with a particular organism, i.e.,P. aeruginosa, MDR
P. aeruginosastrains may not be eliminated by single substitutions in an antibiotic formulary.
For example, if an institution has a problem with MDRP. aeruginosa, that appears to be related
to gentamicin usage, the mere substitution of amikacin for gentamicin may not eliminate the
resistance problem. All antibiotics with anti-pseudomonal activity in the institution must also
be changed substituting anti-pseudomonal, low-resistance potential antibiotics for those on
formulary that have a high antibiotic resistance potential. Therefore, in this case, not only
should amikacin be substituted for gentamicin but meropenem must be substituted for
imipenem, cefepime should be substituted ceftazidime, and levofloxacin substituted for
ciprofloxacin. By implementing formulary changes that address the problem in the total
microbiological milieu of the institution, recognizing that the resistance problem cannot be
eliminated without making appropriate formulary substitutions for all antibiotics that have
activity against the problematic MDR pathogen, for example, MDRP. aeruginosa. If multiple
formulary substitutions are not implemented, the antibiogram of the institution will show
increasing resistance among the low-resistance potential anti-pseudomonal antibiotics that
have not replaced their high-resistance potential counterparts. In this setting, if amikacin is
substituted for gentamicin but imipenem, ciprofloxacin, and ceftazidime usage continues,
resistance problems will be manifested by the worsening susceptibility patterns of
meropenem, levofloxacin, and cefepime. This may be manifested in individual isolates by
slowly increasing minimal inhibitory concentrations (MICs), i.e., “MIC creep.” In an institution
to eliminate a widespread MDR resistance effectively due to GNBs requires preferential use of
all low-resistance potential antibiotics that have activity against the resistant strain and by
eliminating or limiting the use of the high-resistance potential antibiotics that have activity
against the MDR species (1,4,5).
There are other considerations in dealing with MDR GNBs. Antibiotic resistance may be
classified as intrinsic or natural. Intrinsic resistance refers to the lack of activity of an antibiotic
against an isolate, e.g.,P. aeruginosais intrinsically resistant to chloramphenicol. In contrast,
acquired antibiotic resistance refers to isolates that were once formally sensitive to an antibiotic
that have subsequently become resistant and the resistance is related to antibiotic use not
mutation, i.e., ampicillin was formerly highly effective againstE. colibut is now much less
effective. Acquired antibiotic resistance may be further subdivided into relative resistance and
absolute or high-level resistance. High-level resistance refers to an MIC of isolate that is far in
excess of achievable serum/tissue levels when using an antibiotic at the usual or even at higher
than usual doses, i.e., an isolate ofP. aeruginosawith an MIC of> 200 mg/mL to gentamicin
(susceptible MIC< 4 mg/mL/resistant> 16 mg/mL). “Relative resistance” refers to isolate
MICs somewhat above the susceptibility break point for an antibiotic. Although reported as
“resistant,” such an isolate may in fact be susceptible in body sites that concentrate the
antibiotic to greater than serum levels, i.e., bile or urine or by using the usual or higher doses of
antibiotics that achieve site concentrations above isolate-resistant MICs reported. For example,
if aP. aeruginosaisolate is reported as “resistant” to meropenem (susceptible breakpoint MIC
< 4 mg/mL/resistant> 16 mg/mL). A higher than usual dose of meropenem, i.e., 2 g IV will be
effective in most body sites. After a 2 g dose of IV, serum concentrations of meropenem are
- 100 mg/mL, well in excess of the concentration (MIC) necessary to eradicate most “relatively
Antibiotic Therapy of MDRP. aeruginosa, K. pneumoniae, andA. baumanniiin CCU 513