Amarked increase in antibiotic resistance by several organisms and
a surge in recovery of one pathogen posed microbiology puzzles at our
212-bed hospital. It was important to find out why these new trends had
developed in order to help clinicians plan a better course of antibiotic
The matter of resistance surfaced two years ago. One of the
functions of the microbiology department, in conjunction with the
infection control committee, is to monitor susceptibility trends for the
hospital. From January to June 1983, I noticed frequent significant
departures from the normal susceptibility patterns for Proteus mirabilis and some Enterobacteriaceae–changes serious enough to warrant
investigation and action.
Proteus mirabilis seemed the best choice to focus on in a study
because we isolated it more often than the other organisms in question.
I looked at its susceptibilities to four antibiotics–ampicillin,
cephalothin, cefamandole, and cefoxitin–in January-June 1981, 1982, and
During the first two years, P. mirabilis susceptibilities were
stable at 90 to 99 per cent. In the first half of 1983, they plunged to
a range of 30 to 66 per cent. The precipitous decline raised two
questions: Was this trend manifesting itself in other hospitals, or was
it confined to our institution? What happened in 1982 at our hospital
to cause the increased antibiotic resistance we were finding in 1983?
To answer the first question, I enlisted the aid of detail
representatives from two pharmaceutical manufacturers. On their calls
to other hospitals in southwest Florida, they solicited susceptibility
data for P. mirabilis over the time frame of our study. Not all
laboratories kept good records on clinical isolates, but the
representatives nonetheless brought usable data from several large
A comparison of our experience with that of the other hospitals was
alarming. No other hospital recorded a substantial change in Proteus
susceptibilities in January-June 1983. Their percentages closely
mirrored 1981 and 1982 averages. That meant the problem was internal.
The second question had to be addressed. What change might have
occurred in 1982 to lead to greater antibiotic resistance the following
year? We soon had an answer.
Examination of pharmacy reports revealed that at least 50 per cent
of the antibiotic therapy administered in the hospital during 1982
involved use of the new expanded-spectrum cephalosporins. A literature
search linked this evidence to the problem we were investigating.
Although early studies of these antibiotics had been promising, one
disturbing observation was a rapid development of bacterial resistance.
I presented the findings to our hospital’s infection control
committee in November 1983. The committee granted my request to study
antibiotic therapy records of patients with multiple admissions and P.
First I listed all patients whose microbiology records showed P.
mirabilis infections between March and December 1983. Then I went
through medical records and eliminated all the patients who had only a
single admission. For the rest, I could review therapy over the entire
Twenty-four patients had more than one admission and a Proteus
infection during their last admission. Only three had Proteus
infections conforming to expected susceptibility patterns from the first
to the final admission, and none had been treated with expanded-spectrum
The other 21 patients had resistant Proteus infections at last
admission. Expanded-spectrum cephalosporins had been part of the drug
regimen for 17. I found nothing that might have induced resistance in
the remaining four patients.
All of the cases studied were enlightening–and some proved
frightening. One patient was treated with a second-generation
cephalosporin for ocular and urinary tract infections caused by a
tetracycline-resistant P. mirabilis. Susceptibility testing showed no
other resistance at the time. But when the patient was readmitted the
next month with a urinary tract infection and septicemia caused by
Proteus of the same biotype, the organism was resistant to ampicillin and the first-, second-, and third-generation cephalosporins tested.
Several other patients were admitted with Proteus urinary tract
infections that responded to a second-generation cephalosporin. They
were readmitted in less than a month with the same infections, however,
and the pathogen was now resistant to ampicillin and first-, second-,
and third-generation cephalosporins. In a number of cases, Proteus
susceptibility patterns changed midway through second-generation
What about the four cases with unexplained resistance? Three
patients had been admitted to other, distant hospitals before ours, and
I had no access to antibiotic therapy records at those institutions.
The fourt patient had been admitted to our hospital three times. In
each instance there had been a urinary tract infection. During the
third admission, for fracture therapy, the patient had a series of
infections, and resistant Proteus was the last of several pathogens
identified–but expanded-spectrum antibiotics had not been previously
used. Although I couldn’t account for the low susceptibility in
these cases, it’s possible that some were nosocomial infections from already resistant Proteus.
Once infection control committee members saw the data, they asked
me to make a presentation to the next meeting of the medical care
evaluation committee, in February 1984. That committee agreed with
infection control that clinicians should be told what was happening.
So in March, I took the data to the medical staff’s general
meeting. I stated the case succinctly: First, Proteus resistance at our
hospital was increasing, and we had reason to implicate expanded-spectrum antibiotic use, which could confer cross-resistance to
other drugs, particularly those of the same class. Second, physicians
should study the change in resistance carefuly and then weigh potential
advantages of these antibiotics against a new and serious problem. And
third, what we uncovered might be occurring with other organisms.
The medical staff asked for more Proteus data–specifically from
January to June 1984. Figure I shows the information I furnished them.
There was a clear shift in minimum inhibitory concentrations from
intermediate to resistant and from susceptible to intermediate between
1983 and the first six months of 1984.
That apparently convinced the medical staff. Prescriptions for
third-generation cephalosporins dropped considerably in mid-1984,
compared with a year earlier. This was also due to a program we
instituted that educates clinicians on antibiotic costs, described in
the October 1984 issue of MLO (“A Lab-Pharmacy Push to Cut Drug
Therapy Costs”). Many physicians still prescribe second-generation
cephalosporins, but some are returning to first-generation drugs.
In general, we must remember that pharmaceutical
manufacturers’ data reflect susceptibilities obtained largely
through in vitro tests. In our area, which has a large retirement
community, the median age of residents is 72. That means many multiple
admissions for chronic or recurrent illness, and a good opportunity to
study shifting in vivo susceptibilities in the same patients.
Uncovering a new resistance trend spells more effective therapy. It
results in more cost-effective therapy, too, because over the long term,
runaway resistance prompts development of costlier antibiotics. Since
drugs in longstanding use are generally less expensive, therapy costs
are held down when clinicians have good reason to keep using them.
We are currently looking at susceptibility patterns for other
organisms. It’s too early to be definitive, but signs point to
decreasing susceptibility among other organisms, including some of the
Enterobacteriaceae. We also want to see if reduced use of the
expanded-spectrum antibiotics will curb the increase in resistant
Let’s turn now to out second puzzle. Why did our recovery of
Group D Streptococcus isolates more than double in 1983, making this
pathogen one of the most commonly encountered at the hospital?
As in the case of our Proteus investigation, the answer lay in
discovering what had changed to being about the new trend. In February
1983, the microbiology laboratory installed a susceptibility testing
instrument with four-hour turnaround time. This promised significant
time savings, but it meant that we had to review our isolation methods.
It was quickly apparent that in the case of Streptococcus speciation,
traditional plating procedures would hold back our new acquisition from
No longer could we wait for visible strep colonies on primary
culture before carrying out a bile esculin azide test for pure culture.
That took an extra day. So to make use of the instrument’s
four-hour capability, we began using bile esculin azide as one of the
primary plates for inoculating urinary, genital, wound, and surgical
cultures, where group D strep is commonly found.
The extra plating gave us quick identification of group D, but it
also increased the number of these isolates dramatically. We were soon
reporting streptococcal infections that would have remained hidden on
other primary plates because of overgrowth by gram-negative rods and
other gram-positive organisms. After a few months we concluded that
without aggressive pursuit this pathogen easily escaped detection.
This discovery had significant implications. Group D strep is
frequently resistant to antibiotic therapy aimed at organisms that crowd
it out in culture. Incomplete response by patients to indicated drug
therapy may correlate with our failure to identify group D strep with
the other pathogens.
Month-by-month comparison of 1982 and 1983 group D strep isolation
data shows how many more infections we began picking up (Figure II). In
the year before primary bile esculin azide plating, 137 clinical
isolates represented 5.3 per cent of the pathogens reported. Afterward,
the number jumped to 294, or 11.2 per cent of all pathogens.
Group D strep recovery changed only marginally in specimens from
genital and surgical cultures. The rate moe than doubled in wound and
urinary cultures, however.
In both culture types, the organism was one of at least two
infecting agents and was usually not readily visible (except on the bile
esculin azide plates) because of faster grouwth, greater numbers,
spreading, or mucoid appearance of other pathogens.
What percentage of pathogens isolated in other labs are group D
strep? If the rate is low, a more persistent pursuit may reveal that
the organism is present more often than suspected. I don’t believe
that rising prevalence accounts for our findings.
If clinicians are able to take group D strep’s role in
infection into account whan culture reports are issued, they can choose
the best course of therapy from the start. Faster patient recovery and
discharge may result.
The added plating also saves us time and work, as first intended.
We recover group D strep in pure form and in sufficient numbers to work
directly with the isolate. Susceptibilities are charted four hours
after we examine morning plates. At 24 cents each (using about 150
plates a month that require strep speciation), the plates don’t add
much to our costs; we would need many of them for secondary isolation,
The new protocol also brings us closer to an ideal: to diligently
pursue and report every potential pathogen in a specimen. Patients then
get better care and clinicians learn to trust the laboratory team more.