# Ampicillin Resistance and Outcome Differences in  Acute Antepartum Pyelonephritis

Authors: Laura G. Greer; Scott W. Roberts; Jeanne S. Sheffield; Vanessa L. Rogers; James B. Hill; Donald D. Mcintire; George D. Wendel
Journal: Infectious Diseases in Obstetrics and Gynecology
 (2008)

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## Abstract

Objective. To measure the incidence of ampicillin-resistant uropathogens in acute antepartum pyelonephritis and to determine if patients with resistant organisms had different clinical outcomes. Study design. This was a secondary analysis of a prospective cohort study of pregnant women admitted with pyelonephritis, diagnosed by standard clinical and laboratory criteria. All patients received ampicillin and gentamicin. Results. We identified 440 cases of acute pyelonephritis. Seventy-two percent (316 cases) had urine cultures with identification of organism and antibiotic sensitivities. Fifty-one percent of uropathogens were ampicillin resistant. The patients with ampicillin-resistant organisms were more likely to be older and multiparous. There were no significant differences in hospital course (length of stay, days of antibiotics, ECU admission, or readmission). Patients with ampicillin-resistant organisms did not have higher complication rates (anemia, renal dysfunction, respiratory insufficiency, or preterm birth). Conclusion. A majority of uropathogens were ampicillin resistant, but no differences in outcomes were observed in these patients.


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## Body

## 1. Introduction

Acute pyelonephritis complicates 1-2% of  all
pregnancies, making it one of the most  common medical complications of
pregnancy [1]. Escherichia coli remains the most common pathogen
isolated in acute antepartum pyelonephritis, and ampicillin has been a mainstay
of treatment for antepartum pyelonephritis because of efficacy, cost, and
minimal risk to both the mother and fetus [2].Because of its concomitant use in the prevention of
neonatal group B streptococcal
sepsis, there is concern for increasing trends of ampicillin-resistant
organisms [2]. In 1984, Duff reported a
22% incidence of ampicillin-resistant E. coli in acute antepartum pyelonephritis. By 2001, Hart reported a 45% incidence of
ampicillin-resistant E. coli in acute antepartum pyelonephritis [2, 3].Globally, there are increasing rates of
antibiotic-resistant strains ofE. coli [4]. This trend in antibiotic resistance caused
the Centers for Disease Control and Prevention (CDC) to identify investigating
the clinical implications of antimicrobial resistance as a priority. Moreover, it has been postulated that
infections with antibiotic-resistant organisms may increase the risk of
treatment failures and morbidity [2, 5, 6]. Accordingly, we sought to measure the incidence of ampicillin
resistance in uropathogens causing acute pyelonephritis in our pregnant patient
population and to determine if resistant organisms resulted in different
clinical outcomes.


## 2. Materials and Methods

This is a secondary analysis of a prospective longitudinal cohort study of 440 pregnant women diagnosed with acute pyelonephritis [1]. The original cohort included all pregnant women with antepartum pyelonephritis admitted to Parkland Memorial Hospital, Dallas, TX, USA, from January 2000 to December 2001. The cohort study was exempted by the Institutional Review Board.The diagnosis of acute pyelonephritis was made with
clinical findings of fever (temperature≥38°C), flank pain, and
costovertebral angle tenderness along with laboratory findings of pyuria or
bacteriuria (≥20 bacteria per high power field). Clean catch mid-stream urine specimens or
catheterized urine specimens were collected for culture. The presumptive diagnosis of pyelonephritis,
however, was made and treatment initiated prior to receipt of culture
results. Antimicrobial therapy included
intravenous ampicillin two grams every six hours and intravenous gentamicin,
consisting of a loading dose of 120 mg once followed by 80 mg every eight
hours.Antimicrobial sensitivities were performed using a
broth microdilution and the study utilized breakpoints established by the Clinical and Laboratory Standards Institute (CLSI). Antimicrobial sensitivities were not
performed on uropathogens with colony counts of less than 100 000. Ampicillin resistance was defined as a
minimum inhibitory concentration (MIC) greater than 16μg/mL.Research nurses routinely entered pregnancy outcomes
and complications for all women delivered at Parkland Hospital
into a previously described, validated, and  continuously updated  computerized
obstetric database [7]. Antepartum
data on women with acute pyelonephritis were entered into a separate research
database that included length of hospital stay, days of intravenous antibiotics
received, vital signs, respiratory insufficiency, necessity of admission to an
extended care unit, amount of IV fluid received, and laboratory evaluations
including urine cultures, complete blood count, and creatinine as previously
described [1]. Anemia was defined as a
hematocrit less than 30%, and renal dysfunction was defined as creatinine ≥1.2 mg/dL. Respiratory insufficiency was
defined as dyspnea, tachypnea, and hypoxemia with radiological signs of
pulmonary infiltrates (information regarding intubation was not recorded).The database created of antepartum pyelonephritis
patient outcomes included urine culture results by organism, but it did not
originally include information on antibiotic sensitivities. We subsequently re-examined the medical
records of the 440 patients admitted with acute pyelonephritis to review the
antibiotic sensitivities of the admission urine cultures and entered these into
the database. These data were
subsequently linked electronically to pregnancy outcome data from the obstetric
research database.Statistical analyses were performed using SAS 9.1
(SAS Institute, Cary, NC, USA).
Comparisons were made with the Pearson's chi-square test for categorical data
and Student'st-test for continuous data. Statistical normality
was evaluated using the Shapiro-Wilk statistic. For statistically
nonnormal data, the Wilcoxon rank-sum test was substituted for Student's t-test. The Mantel-Haenszel chi-square was used to
analyze trends in categorical data.


## 3. Results

The original study included 440 patients with acute
antepartum pyelonephritis. Urine
cultures with identification of an organism with sufficient colony forming
units for antibiotic sensitivity testing were available for 317 (72%) of the
440 initial study patients (72%). The
organisms and resistance rates are included in Table1. Although additional patients had positive
urine cultures, our laboratory did not perform antimicrobial sensitivities for
cultures less than 100 000 colony-forming units.Table 1
Uropathogens identified by culture with antibiotic sensitivities in acute antepartum pyelonephritis. Data are reported as n (%).
OrganismAmpicillin-resistantAmpicillin-sensitiveTotaln=162(51)n=155(49)n=317Escherichia coli148 (51)144 (49)292 (92)Klebsiella pneumoniae11 (100)0 (0)11 (3)Proteus mirabilis0 (0)8 (100)8 (3)Enterbacter sp.3 (50)3 (50)6 (2)Ninety-two percent (92%) of the cultures that had
organisms identified and sensitivities performed grewE. coli. These results are summarized in Table 1. The other organisms identified with
sufficient colony-forming units to receive antibiotic sensitivity testing
included Klebsiella pneumoniae, Proteus mirabilis, and Enterbacter species. Overall, fifty-one percent (51%) of these organisms were
resistant to ampicillin.We reviewed the demographic characteristics of the
patients with ampicillin-resistant and ampicillin-sensitive organisms. As demonstrated in Table2, there was no
significant difference in the ethnicity of patients with ampicillin-resistant
organisms. The patients with
ampicillin-resistant organisms, however, were more likely to be multiparous (P=.04). The patients with ampicillin-resistant
organisms were also older (P=.04)
(see Table 3).Table 2
Comparison of demographic characteristics of women with ampicillin-resistant versus ampicillin-sensitive uropathogens in acute antepartum pyelonephritis. Data are reported as n (%) or mean±standard  deviation.
Ampicillin-resistantAmpicillin-sensitiveP-valuen=162n=155Race0.22Black12 (7)19 (12)White6 (4)11 (7)Hispanic142 (88)124 (80)Other2 (1)1 (1)Nulliparous49/133 (37)65/132 (49)0.04Table 3
Comparison of ages of women with ampicillin-resistant versus ampicillin-sensitive uropathogens in acute antepartum pyelonephritis. Data are reported as n (%).
Ampicillin-resistantAmpicillin-sensitiveTotalP-valuen=162n=155n=317Age0.0415 or younger1 (14)6 (86)7 (2)>15 to <2038 (49)39 (51)77 (24)≥20 to <35112 (51)106 (49)218 (69)35 or older11 (73)4 (27)15 (5)We analyzed the hospital courses of women with acute
antepartum pyelonephritis comparing patients infected with ampicillin-resistant
and ampicillin-sensitive organisms. As
summarized in Table4, we found no significant differences in length of
hospital stay, days of IV antibiotics required, admission to the extended care
unit, or rate of hospital readmission.Table 4
Summary of hospital stay of women with ampicillin-resistant versus ampicillin-sensitive uropathogens in acute antepartum pyelonephritis. Data are reported as n (%) or mean±standard  deviation.
Ampicillin-resistantAmpicillin-sensitiveP-valuen=162n=155Hospital days3.6±1.73.6±1.70.98Days of IV antibiotics3.5±1.63.3±1.50.42Extended care unit admission21 (13)16 (10)0.47Readmission6 (3.7)4 (2.6)0.57We also compared the rates of common complications of
acute antepartum pyelonephritis between the ampicillin-resistant and
ampicillin-sensitive groups.  Patients
with ampicillin-resistant organisms did not have higher maximum
temperatures (see Table5). Additionally, infection
with ampicillin-resistant organisms was not associated with increased rates of
anemia, renal dysfunction, or respiratory insufficiency. There was also no significant difference in
the incidence of preterm birth between the two groups.Table 5
Comparison of hospital courses of women with ampicillin-resistant versus ampicillin-sensitive uropathogens in acute antepartum pyelonephritis. Data are reported as n (%) or mean±standard  deviation.
Ampicillin-resistantAmpicillin-sensitiveP-valueMaximum temperature38.7°C±0.838.7°C±0.90.79Anemia139 (24)35 (23)0.75Renal  dysfunction22 (1)1 (1)0.59Respiratory  insufficiency315 (9)13 (8)0.79Preterm birth in weeks<37 estimated gestational age7 (5)5 (4)0.56<32 estimated gestational age4 (3)2 (2)0.41Anemia1
was defined as a
hematocrit less than 30%.
Renal2 dysfunction was defined as a creatinine ≥1.2 mg/dL.
Respiratory3 insufficiency was defined as dyspnea,
tachypnea, and hypoxemia with radiological signs of pulmonary infiltrate.


## 4. Discussion

We re-evaluated a large prospective longitudinal
study of a cohort of women hospitalized with acute antepartum pyelonephritis to
measure the incidence of ampicillin resistance in our patient population and to
determine if resistant organisms resulted in different clinical outcomes.Our review of the rate of
ampicillin-resistance revealed that the majority of organisms cultured  were resistant to ampicillin. As expected,E. coli was the most
common pathogen cultured in acute antenatal pyelonephritis, and 51% of E.
coli cultures were
ampicillin-resistant. This finding is
similar to Hart’s finding in 2001 of a 45% rate of ampicillin-resistance in E. coli causing acute antepartum pyelonephritis. Similarly, Gupta found that from 1992
to 1996, the rate of ampicillin resistance in E. coli isolates increased
from 26% to 34% in women with cystitis [8].All
theKlebsiella organisms cultured were
ampicillin-resistant, while all Proteus organisms cultured were
ampicillin-sensitive. Gupta reported
a similar trend in women with cystitis. Ninety-eight percent (98%) of Klebsiella isolates were
ampicillin-resistant, while only 8% of Proteus species were ampicillin-resistant [8].The initial report from
this study found an 11.6% rate of infection with Gram-positive organisms, and
the majority of these were identified as group B Streptococcus [1]. Our laboratory does not perform antimicrobial
sensitivities on group B Streptococcus or any other Gram-positive uropathogens with
less than 100 000 cfu.Our analysis of demographic characteristics of women
with ampicillin-resistant organisms revealed no association with ethnicity. It did, however, demonstrate that infection
with ampicillin-resistant organisms was more common in older and multiparous patients. The observed trend of increasing incidence of
ampicillin-resistance with increasing age and parity may be due to increased
exposures to antibiotics and to prior hospitalizations for deliveries. Either of these events could increase their
risk of acquiring resistant organisms compared with patients who are younger
and nulliparous.While the impact of
infection with organisms resistant to the initial antibiotic used to treat
infection has been studied in septic and ICU patients, no similar outcome
studies have been conducted in acute antepartum pyelonephritis. In septic patients, infection withβ-lactam
resistant strains of E. coli and Klebsiella resulted in
significantly higher mortality rates [6]. Other studies comparing patient
outcomes between antibiotic-sensitive and antibiotic-resistant infections have
shown increased length of hospital stay, increased rates of infectious
complications, and increased cost of treatment [9, 10]. In light of these
studies, we undertook this analysis to assess if infection with
antibiotic-resistant organisms in acute antepartum pyelonephritis would affect
patient outcomes.In acute antepartum
pyelonephritis, infection with organisms resistant to ampicillin did not affect
patient outcomes in terms of the course of their hospital stay or the frequency
of common complications of pyelonephritis.
The similarities in outcomes between patients infected with
ampicillin-resistant and ampicillin-sensitive organisms are reassuring in light
of the common use of ampicillin and gentamicin to treat acute antepartum
pyelonephritis and the increasing reports of ampicillin-resistant organisms.
There are several possible explanations for this finding.The first explanation is
that while over fifty percent of the organisms cultured were resistant to
ampicillin, all patients were  receiving gentamicin in addition to
ampicillin. Moreover, only a single
patient had an organism that was resistant to gentamicin. Ampicillin and gentamicin may create a
pharmacologic synergy that may also explain the discrepancy between in vitro susceptibilities and in
vivo findings [11]. This also raises the question of whether treatment
with gentamicin alone would be adequate to treat the majority of cases of acute
antepartum pyelonephritis.The second explanation is
that while these organisms were microbiologically resistant to ampicillin, they
may not have been clinically resistant to ampicillin. That is, resistance has been defined in a
number of different ways. It can be
defined genetically (genotypically), meaning that there is a genetic mechanism in
the bacteria that encodes for resistance against a class of antibiotics. Alternatively, resistance can be defined, as
it was here, microbiologically (phenotypically) meaning that there is an
abnormally elevated minimum inhibitory concentration (MIC) observed in
laboratory testing. Finally, resistance
can be defined clinically as the failure to demonstrate improvement in the
patient receiving the medication [6].Wing et al. alluded to this
difference in microbiological resistance versus clinical resistance in their
assessment of the utility of blood and urine culture results in acute
antepartum pyelonephritis [12]. In their study, some patients were receiving
ampicillin and gentamicin while others were receiving monotherapy with a
first-generation or third-generation cephalosporin. Although they had ampicillin resistance rates
of 46% and first-generation cephalosporin resistance rates of 7%, 94% of
patients were given appropriate antibiotics when “appropriate antibiotics” were
defined as clinical improvement. They
found only 6% of patients had changes in antibiotic regimen. Of these, the majority of changes were due to
perceived lack of clinical response, including persistent fever beyond 72 hours, rather than due to the sensitivity results of the cultures [12]. This finding led Wing et al. to conclude that
blood and urine cultures with sensitivities have limited practical utility in
the majority of patients with acute antepartum pyelonephritis. While we believe that culture results continue to have a role in determining the organisms causing infection, the success of therapy in sterilizing the urine, and the antibiotic resistance rates within our hospital, we agree that changes in antimicrobial therapy should be guided by clinical response rather than solely based on culture results.Our study has several
limitations. First, we included only patients managed as inpatients, and our findings may not apply to
populations managed as outpatients.
Second, the only patients who had cultures with antibiotic sensitivities
were those with Gram-negative organisms, so we do not know the rate of
ampicillin resistance in other pathogens or whether ampicillin resistance in
those organisms would affect outcomes.


## 6. Conclusions

In
summary, we found no association with adverse clinical outcomes in gravidas
with acute pyelonephritis treated with ampicillin and gentamicin that had
ampicillin-resistant Gram-negative uropathogens. These data should reassure clinicians that
this well-established treatment regimen is still effective in the management of
acute antepartum pyelonephritis in most settings.



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