In an open study, 24 intensive care patients were treated with imipenem/cilastatin as monotherapy for serious bacterial infections. Twenty-one patients were treated for bronchopulmonary infection, two patients for septicaemia, and one patient for an empyema. Initially all strains were susceptible to imipenem. Gram-negative bacilli accounted for 80% of these isolates. The most frequently isolated species were Proteus mirabilis, Escherichia coli and Pseudomonas aeruginosa. All 24 patients were considered clinically cured. Sixteen of these patients (67%) were both clinically and microbiologically cured. In eight of the 24 patients (33%), the strains isolated initially persisted. In eight of the 24 patients (33%), colonization of the respiratory tract developed. Two of the five Ps. aeruginosa isolates developed resistance during therapy but in none of these patients was therapy considered to have failed. In 12 patients (50%), transient elevations in hepatic function tests were observed and these were probably drugrelated. The present study supports the view that imipenem/cilastatin may be useful as monotherapy in the treatment of severe infections in intensive care patients

J B J Boerema

J S F Gimbrere

M S C Dirksen

R G F Wintermans

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Journal of Antimicrobial Chemotherapy (1986) 18, Suppl. E, 145-151 
Imipenem as mono therapy in the treatment of 
intensive care patients with severe infections 
M. S. C. Dirksena, R. G. F. Wintermansb, J. B. J. Boeremac 
and J. S. F. Gimbrerea 
aDepartment of Intensive Care, bDepartment of Microbiology, 
St Radboud Hospital, Catholic University of Nijmegen; 
cMedical Research Bureau, Nijmegen, The Netherlands 
In an open study, 24 intensive care patients were treated with imipenem/cilastatin as 
monotherapy for serious bacterial infections. Twenty-one patients were treated for 
bronchopulmonary infection, two patients for septicaemia, and one patient for an 
empyema. Initially all strains were susceptible to imipenem. Gram-negative bacilli 
accounted for 80% of these isolates. The most frequently isolated species were 
Proteus mirabilis, Escherichia coli and Pseudomonas aeruginosa. All 24 patients were 
considered clinically cured. Sixteen of these patients (67%) were both clinically and 
microbiologically cured. 
In eight of the 24 patients (33%), the strains isolated initially persisted. In eight of 
the 24 patients (33%), colonization of the respiratory tract developed. Two of the 
five Ps. aeruginosa isolates developed resistance during therapy but in none of these 
patients was therapy considered to have failed. In 12 patients (50%), transient 
elevations in hepatic function tests were observed and these were probably drug-
related. The present study supports the view that imipenem/cilastatin may be useful 
as monotherapy in the treatment of severe infections in intensive care patients. 
Introduction 
Imipenem is a stabilized amidine derivative of thienamycin, a carbapenem p-lactam 
antibiotic produced by Streptomyces cattleya. Because thienamycin tends to break 
down spontaneously at high concentrations, a more stable amidine derivative, N-
formimidoyl thienamycin (MK0787, Merck, Sharp & Dohme, Rahway, New Jersey), 
was developed. It is administered in combination with an equal amount of cilastatin, a 
substance that was developed to inhibit metabolism of imipenem in the kidney. In 
vitro, imipenem has a broad antibiotic spectrum and is highly active against most 
clinically important species of bacteria, including isolates resistant to other antibiotics 
(Kropp et al., 1980; Jones, 1985). This new drug may be useful particularly in the 
treatment of mixed bacterial infections for which a combination of antibiotics, often 
including an aminoglycoside, would otherwise be necessary. 
In the present study imipenem/cilastatin was administered as mono therapy to 24 
patients with serious bacterial infections admitted to an intensive care unit (ICU). 
145 
0305-7453/86/ 18E 145 + 07 $02.00/0 © 1986 The British Society for Antimicrobial Chemotherapy 
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146 M. S. C. Dirksen et al. 
Patients and methods 
Patient population 
All patients were treated in the ICU. Diagnosis of bronchopulmonary infection was 
made by the primary physicians using the usual criteria of fever, purulent sputum, 
leucocytosis and the appearance of a new infiltrate seen on chest radiographs in the 
appropriate clinical setting. Diagnosis of septicaemia was made by the criteria of two 
positive blood cultures before therapy in combination with clinical signs of infection. 
Reasons for exclusion from the study included: patients less than 12 years of age, 
pregnant or nursing women, previous hypersensitivity reactions to any of the fJ-Iactam 
antibiotics, high probability of death within 48 h, patients whose initial pathogen was 
known to be resistant to imipenem prior to entry into the study, and patients who had 
received antimicrobial therapy known, or presumed to be, effective against the 
infecting pathogen(s) within 72 hr preceding the initiation of treatment. Informed 
consent was obtained from each patient or nearest family relative according to the 
declaration of Helsinki and the amendments of Tokyo (1978) and Venice (1983). 
Drug administration 
Imipenem was given with cilastatin parenterally in a total daily dose of 1,0-3,0 g, in 
two to four divided doses. The drugs were administered over a 20-30 min infusion 
time. Patients with creatinine clearances greater than 30 ml/min/l·73 m2 received the 
standard dose. Patients with creatinine clearances of 30 ml/min/l·73 m2 or less 
received half the recommended daily dose. Patients with a glomerular filtration rate of 
less than 10 ml/min/l·73 m2 received not more than 500 mg of imipenem/cilastatin 
every 12 h. A supplementary dose was given after haemodialysis. 
Laboratory studies 
In septicaemic patients, blood specimens were collected prior to therapy, and cultured 
routinely in trypticase soy broth with sodium polyanethol-sulphonate and brain heart 
infusion broth with saponin (BHI). In bronchopulmonary infections, specimens of 
expectorated sputum were collected before therapy and cultured on 7% sheep blood 
agar, Levine EMB agar and Haemophilus selective blood agar (bacitracin and 5% 
rabbit blood). Potential pathogens were identified and their susceptibility to standard 
antibiotics, as well as to imipenem, was determined by disc testing. Sensitivity to 
imipenem was defined as an inhibition zone with a diameter> 16 mm (imipenem 10 J.1g 
disc, BBL Microbiology Systems, Cockeysville). MICs were also measured for most of 
the isolates by an agar dilution method (Washington, 1974). Sputum samples were also 
collected within three days of the termination of therapy. 
Laboratory tests performed prior to therapy, at five days into therapy, and after the 
termination of therapy included a complete blood cell count, differential count, a 
platelet count, and estimations of blood urea nitrogen, creatinine, serum glutamic 
oxaloacetic transaminase, serum glutamic-pyruvic transaminase, alkaline phosphatase, 
total bilirubin, potassium, sodium, chloride and urinalysis. Chest radiography was 
performed before and after therapy and at other times when indicated. Examination of 
the injection site was performed daily. 
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Treatment of intensive care patients 147 
Evaluation of patients 
Patients were excluded from evaluation if no pathogens were isolated from sputum 
samples, if the total course of imipenem was less than five days, or the patient received 
concomitant antibiotic therapy that was potentially active against the aetiological 
organism. 
Clinical cure was defined as resolution of signs and symptoms of infection and 
sustained improvement as shown by chest radiography in respiratory tract infection. 
Microbiological response was classified as cure, cure with superinfection, cure with 
colonization, and failure. Microbiological cure was defined as eradication of the initial 
causative organism without relapse. Superinfection was defined as the appearance of a 
new pathogenic organism that was either susceptible, or resistant to the study drug, 
and subsequently required further antibiotic treatment. Colonization was defined as 
the appearance of a new organism that was susceptible, or resistant to the study drug, 
without clinical symptoms of infection. Microbiological and clinical cure was defined 
as eradication of the presumed pathogen and elimination of the clinical parameters 
of infection. 
Results 
Of the 30 patients initially included in the study, 24 were considered evaluable: six 
women with a mean age of 47 years (range 17-74) and eighteen men with a mean age 
of 45 years (range 18-72). Of those excluded, five had no pathogens isolated from their 
sputum samples, and one received a therapeutic course that was too short. 
Twenty-one patients were treated for a bronchopulmonary infection, two patients 
for septicaemia (of urinary origin), and one patient for an empyema. The patients were 
all mechanically ventilated. Significant underlying diseases were present in all patients 
(Table I). Twenty-three patients had central venous lines. Twenty patients had 
indwelling urinary catheters. Thirteen patients had received previous antibiotic 
treatment one week prior to imipenem. The average length of imipenem therapy for 
the entire group was 9·1 days (6-13 days). 
Table I. Underlying conditions in intensive care patients 
treated with imipenem 
Underlying condition 
Post-traumatic 
Post-surgical 
abdominal 
cardiac 
thoracotomy 
neurosurgical 
amputation 
Rejected renal graft 
Intra-abdominal abscesses 
(pancreatitis) 
Aspiration 
Guillain Barre syndrome 
Total 
Number of patients 
6 
12 
2 
2 
1 
24 
3 
6 
1 
1 
1 
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148 M. S. C. Dirksen et al. 
Microbiology 
Forty bacterial isolates were cultured before therapy in the 24 evaluable patients. 
Sputum isolates were considered pathogenic if they were the only or predominant 
organism, and had been recognized as a cause of pneumonia. Twelve of the 20 patients 
had more than one pathogen isolated from sputum samples. One patient had a positive 
blood culture (Streptococcus faecalis). 
Two patients were treated for septicaemia. The source of the septicaemia was the 
urinary tract in both cases (Escherichia coli, Pseudomonas aeruginosa + Enterobacter 
cloacae). One patient was treated for an empyema (Str. agalactiae). 
All strains were susceptible to imipenem initially. Gram-negative bacilli accounted 
for 80% of these isolates (Table II), of these Proteus mirabilis (5), Esch. coli (5), H. 
injiuenzae (5) and Ps. aeruginosa (4) were the most frequent. 
Outcome 
All 24 patients were considered clinically cured. Sixteen of these patients (67%) were 
both clinically and microbiologically cured. In eight of the 24 patients (33%), the 
strains isolated initially persisted bur the patients were considered clinically cured. In 
two patients, persistence was associated with the emergence of Ps. aeruginosa resistant 
to imipenem (Table III). In six patients, the persistent isolates were still sensitive to 
imipenem. In eight of the 24 patients (33%) colonization of the respiratory tract 
developed with five different isolates (Table IV). 
Bacteria recovered included: Ps. maltophilia (one), Pro mirabilis (one), Ent. cloacae 
(two), Morganella morganii (one) and Staphylococcus epidermidis (four). Four of the 
nine isolates were resistant to imipenem: Ps. maltophilia (one), M. morganii (one) and 
Staph. epidermidis (two). None of these resistant isolates was associated with clinical 
deterioration (Table V). 
Table II. MICs of imipenem against 40 initial isolates from intensive care patients 
Isolate 
Str. pneumoniae 
Str. faecalis 
Str. agalactiae 
Acinetobacter anitratus 
Pro mirabilis 
H. injiuenzae 
Staph. aureus 
Klebsiella pneumoniae 
K. oxytoca 
Pasteurella multocida 
Aeromonas hydrophila 
Esch. coli 
Ent. cloacae 
Citrobacter freundii 
Serratia marcescens 
Ps. aeruginosa 
Number of isolates with MICs (mgjl) of: 
:( 0·03 0·06 0·125 0·25 0·50 1·0 2·0 4·0 g·O 16 
2(S)* 
5 
2 
1 
1 
2 
1 
2 
2 
2 
1 
1 
1 
2 
3 
2 
*Sensitive strains in agar diffusion (Kirby-Bauer), which were lost before MIC determination. 
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Treatment of intensive care patients 
Table III. Susceptibility to imipenem of organisms persisting 
after treatment 
Patient Persisting Imipenem MIC 
number organism (mg/I) 
4 Ser. marcescens 2 
8 Esch. coli 0·5 
10 Ps. aeruginosa 32 
12 Ps. aeruginosa 4 
14 Ps. aeruginosa 32 
14 Pro mirabilis 4 
21 Pro mirabilis 8 
23 Pro mirabilis 4 
Infections due to Ps. aeruginosa 
149 
Four patients with a broncho-pulmonary infection and with Ps. aeruginosa isolated 
from sputum samples, and one patient with a septicaemia (Ent. cloacae) and Ps. 
aeruginosa isolated from urine samples, were treated with imipenem. Initially the 
isolated strains were sensitive to imipenem (MIC, 2-4 mg/I). Two of the five Ps. 
aeruginosa isolates developed resistance during therapy (MIC, 32 mg/I). Resistant 
organisms were encountered after an average treatment period of 6·8 ± 2·2 days. In 
none of the patients in whom imipenem-resistant Ps. aeruginosa developed was therapy 
considered to have failed clinically. 
Tolerance and adverse effects 
In 12 patients (50%) transient elevation in hepatic function tests was observed and was 
probably drug-related. Incompatibility with other drugs was not observed. 
Discussion 
Infection remains a problem in intensive care units (Thorp, Richards & Telfer, 1979). 
Bacterial pneumonia is one of the most common infections and the one most often 
associated with significant morbidity and mortality. The patient who is intubated or 
has a tracheostomy is particularly susceptible to respiratory tract iQfections (Gaya, 
Table IV. Susceptibility of colonizing organisms after 
imipenem treatment 
Patient Colonizing organism 
number after treatment 
6 Ps. maltophilia 
8 Ent. cloacae 
14 M. morganii 
16 Staph. epidermidis 
25 Staph. epidermidis 
25 Ent. cloacae 
28 Pro mirabilis 
Imipenem MIC 
(mg/I) 
> 128 
0·5 
> 128 
32 
32 
2 
8 
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150 
Infecting isolate 
Str. agalactiae 
Str. pneumoniae 
Str. faecalis 
Acin. anitratus 
Pro mirabilis 
M. morganii 
H. injiuenzae 
Staph. aureus 
K. pneumoniae 
K. oxytoca 
Past. multocida 
Aerom. hydrophila 
Esch. coli 
Ent. cloacae 
C.freundii 
Ser. marcescens 
Ps. aeruginosa 
Ps. maltophilia 
Staph. epidermidis 
M. S. C. Dirksen et al. 
Table V. Bacteriological response to therapy 
eradicated 
I 
I 
I 
4 
2 
5 
5 
2 
I 
I 
I 
4 
2 
I 
Number of isolates 
persisting 
3 
I 
3 
colonizing 
2 
1 
4 
1976). Optimal choice of antibiotics for bacterial pneumonia is problematical because 
of the multitude of potential bacterial pathogens and the difficulty in making a specific 
aetiological diagnosis. In this prospective open trial we have demonstrated the high 
efficacy and relative safety of imipenem/cilastatin as treatment for bronchopulmonary 
infections in intensive care patients. 
The majority of patients had significant underlying diseases. These included 
cardiopulmonary, neurological and renal diseases as well as diabetes, endotracheal 
intubation, recent surgery and prior antibiotic administration. The majority of isolates 
were aerobic Gram-negative rods reflecting the high proportion of hospital-acquired 
infections and the serious underlying conditions of patients. Excluding H. injluenzae, 
Gram-negative bacilli accounted for 70% of pre-therapy isolates. 
The results presented in this study are similar to those reported by other 
investigators (Scandinavian Study Group, 1984; Salata et al., 1985; Zajac et al., 1985), 
and further support the clinical efficacy of imipenem/cilastatin as monotherapy in the 
treatment of serious polymicrobial infections. The spectrum indicated by other in-vitro 
studies (Kropp et al., 1980; Jones 1985) was confirmed by the susceptibility data in 
this study. Strains with MICs for imipenem above 8 mg/l were found only in 
Pseudomonas spp., Staph. epidermidis and M. morganii. In agreement with these 
microbiological findings a high proportion of the less sensitive bacterial strains isolated 
persisted at the end of treatment or colonization of the respiratory tract occurred 
during treatment. 
The emergence of two isolates of Ps. aeruginosa resistant to imipenem occurred in 
this study; neither was associated with a clinical deterioration. The potential for a 
stepwise increase in the resistance to imipenem in nosocomial strains of Ps. aeruginosa 
suggests that these infections should not receive monotherapy with this drug. The 
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Treatment of intensive care patients 151 
emergence of resistance during monotherapy for Ps. aeruginosa is also seen with other 
fJ-Iactam antibiotics (Wardle et al., 1981; Berger & Arango, 1985). 
Transient elevations in hepatic function tests were the most common changes noted 
in laboratory tests. No cases of infusion site phlebitis developed. No incompatibility 
with other drugs was observed. 
In conclusion it may be said that monotherapy with imipenem/cilastatin was well-
tolerated and effective, but caution should be exercised when this agent is used alone 
for the treatment of serious pseudomonas infections. In view of its extremely broad 
spectrum of activity, physicians may be tempted to use imipenem/cilastatin for a 
variety of purposes. One should be aware, however, that intensive use of the drug 
might lead to the selection of resistant strains in the hospital environment. 
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of Medicine 78, Suppl. 6A, 22-32. 
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Imipenem as mono therapy in the treatment of intensive care patients with severe infections

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Imipenem as mono therapy in the treatment of intensive care patients with severe infections

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