JAC
Journal of Antimicrobial Chemotherapy (1998) 42, 793–802
Efficacy of sulbactam alone and in combination with ampicillin in nosocomial infections caused by multiresistant Acinetobacter baumannii Xavier Corbellaa*, Javier Arizaa, Carmen Ardanuyb, Maria Vueltac, Fe Tubaub, Mercedes Sorac, Miquel Pujola and Francesc Gudiola a
Departments of Infectious Diseases, bMicrobiology and cPharmacy, Hospital de Bellvitge, University of Barcelona, Spain
From March 1995 to March 1997, sulbactam was prospectively evaluated in patients with non-life-threatening multiresistant Acinetobacter baumannii infections. During this period, 47 patients were treated with sulbactam; of them, five were excluded because they had received ≤48 h of sulbactam therapy. A total of 42 patients, 27 males and 15 females with a mean age of 60 ± 15 years, were finally evaluated. Infections were as follows: surgical wound, 19; tracheobronchitis, 12; urinary tract, 7; catheter-related bacteraemia, 2; and pneumonia, 2. Eighteen patients received intravenous sulbactam alone (1 g every 8 h) and 24 patients received intravenous sulbactam/ampicillin (1 g:2 g every 8 h) with no major adverse effects. Of the 42 patients, 39 improved or were cured and showed A. baumannii eradication and one patient had persistence of wound infection after 8 days of sulbactam/ampicillin requiring surgical debridement. Two patients died after 3 days of therapy (one of the deaths was attributable to A. baumannii infection). The in-vitro activity of the sulbactam/ampicillin combination was by virtue of the antimicrobial activity exhibited by sulbactam. Killing curves showed that sulbactam was bacteriostatic; no synergy was observed between ampicillin and sulbactam. Our results indicate that sulbactam may prove effective for non-life-threatening A. baumannii infections. Its role in the treatment of severe infections is unknown. However, the current formulation of sulbactam alone may allow its use at higher doses and provide new potential synergic combinations, particularly for those infections by A. baumannii resistant to imipenem.
Introduction Multiple antibiotic resistance threatens successful treatment of Acinetobacter baumannii infections worldwide.1 Nowadays, most nosocomial isolates are resistant to the wide variety of antibiotics tested routinely, leaving carbapenems, mainly imipenem, as the only recognized therapeutic alternative.2,3 In this setting, the overuse of imipenem has been associated with the report of several outbreaks caused by carbapenem-resistant strains, often leaving polymyxins and sulbactam as the only antibiotics with in-vitro activity against these organisms.4–9 Therapy of such cases is a serious challenge and, consequently, increasing interest in the well known activity of sulbactam against the genus Acinetobacter has been aroused.10–13
Most studies have investigated only the sulbactam/ ampicillin combination since sulbactam alone is not commercially available in many countries. While several authors have reported that these two antibiotics act synergically in vitro, others have suggested that sulbactam is solely responsible for the intrinsic activity of the combination.12,14–17 The sulbactam/ampicillin combination has been used clinically with encouraging results, but there are no clinical reports regarding the use of sulbactam alone in the therapy of these infections.4,18–21 The possible role of sulbactam in multiresistant A. baumannii hospital outbreaks, to avoid the overuse of imipenem, or as a therapeutic alternative in cases involving carbapenemresistant strains, is not well established. Likewise, the suitability of sulbactam as compared with sulbactam/ ampicillin for clinical use is not known.
*Corresponding author. Tel: 34-93-335-7011 (ext. 2487); Fax:
793 © 1998 The British Society for Antimicrobial Chemotherapy
34-93-260-7637; E-mail:
[email protected]
X. Corbella et al. A large and sustained outbreak of A. baumannii infections, susceptible only to imipenem, sulbactam and polymyxins, has been occurring in our hospital recently, causing considerable overuse of imipenem.22,23 In order to reduce imipenem usage, and based on the abovementioned rationale, we undertook the present pilot study in order to evaluate the clinical efficacy of sulbactam in the therapy of non-life-threatening A. baumannii infections.
Patients and methods Setting The Hospital de Bellvitge is a 1000-bed teaching hospital for adults in Barcelona, which provides acute medical and surgical care, excluding paediatrics, obstetrics and burns. It has three 12-bed intensive care units and an active organ transplantation programme. A sustained outbreak of A. baumannii infections started in September 1992. More than 1100 patients were colonized or infected, and a specific infection control programme was introduced, as previously reported.22,23 From 1992 to 1996, most A. baumannii strains were only susceptible to imipenem, sulbactam and polymyxin, and belonged to a major clone (clone A) as judged by pulsed field gel electrophoresis (PFGE). However, a new clone (clone D), susceptible to sulbactam but with diminished susceptibility to imipenem (MICs 4–16 mg/L), emerged in January 1997.
Patients The study population included patients who had non-lifethreatening nosocomial infections with multiresistant A. baumannii from March 1995 to March 1997. Patients were not included in the study if any of the following conditions were present: serious A. baumannii infection, history of allergy to -lactam antibiotics, glycogenosis or a family history of glycogen storage disease, evidence of unstable cardiovascular, hepatic, renal, or neurological disease, immune incompetence, and patients receiving (or who had received) imipenem for the current A. baumannii infection. In addition to the initial positive sample, other cultures were repeated during and after treatment whenever the relevant sites were easily accessible and/or clinical symptoms and signs persisted. Although all patients were included according to the criteria mentioned above, special consideration was made in the case of patients 3 and 19. Patient 3 had a bone implant-associated infection due to a clone D A. baumannii strain which was only susceptible to sulbactam, moderately resistant to tobramycin, and resistant to the rest of antibiotics, including imipenem. Tobramycin was added to sulbactam since no other antibiotic alternatives would have been available if the patient had failed sulbactam therapy. Patient 19 presented with an A. baumannii bacteraemia associated with a left ventricular assist device
infection and mediastinitis during ICU admission. He was initially treated with imipenem for 17 days, but 4 days after its discontinuation the bacteraemia relapsed, at which time the patient was included in the study.
Infection definitions Since the isolation of A. baumannii from clinical specimens often reflects colonization rather than significant infection, standard Center for Disease Control nosocomial infection definitions24 were used at the time of recruiting patients for the study. Infections were considered non-lifethreatening when none of the following conditions were present: systolic blood pressure 90 mmHg or 40 mmHg below the patient’s normal pressure; oliguria/anuria; respiratory rate 30/min; room air PaO2 60 mmHg, PaO2/Fi(O2) 250; multiple lobes involved (for those patients with pneumonia); or involvement of the central nervous system.
Treatment The study was conducted in a non-comparative fashion. Patients received 3 g/day of sulbactam alone (Pfizer Karlsruhe, Germany) or a sulbactam/ampicillin combination in a 1:2 ratio (3 g/6 g), given by intermittent intravenous infusion (15–30 min) in three divided doses. The sulbactam/ampicillin combination was used in place of sulbactam during those study periods in which sulbactam alone was not commercially available in our hospital. The combination was also used in those polymicrobial infections in which, in addition to A. baumannii, we suspected or documented other susceptible microorganisms. These latter were mainly penicillin-sensitive or -lactamase-producing pathogens. In accordance with cultures and susceptibility results, sulbactam or sulbactam/ ampicillin therapy could be altered only in one of the following ways: addition of another antibiotic inactive against A. baumannii if pathogens resistant to ampicillin or sulbactam/ampicillin were cultured; switch to oral sultamicillin (at doses of 1 g every 12 h) after receiving at least 72 h of iv sulbactam.
Evaluation of efficacy Evaluation of efficacy was based on both clinical and bacteriological responses to therapy. Clinical outcomes were categorized as cure, improvement or failure. ‘Cure’ was defined as eradication of all presenting signs and symptoms of infection, and ‘improvement’ as the resolution of some, but not all, of the signs and symptoms of infection at the end of therapy. Treatment was considered to have failed if the signs and symptoms did not improve appreciably within 72 h of initiation of therapy. The possible bacteriological responses were eradication, persistence and subsequent colonization. ‘Eradication’
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Sulbactam in A. baumannii infections was defined as the elimination of A. baumannii by the time of termination of therapy; ‘persistence’ as the isolation of A. baumannii at the infection site after therapy; and ‘subsequent colonization’ as the emergence of a different pathogenic organism(s) at the site of infection. Patients could not be assessed for efficacy when the duration of sulbactam therapy was 48 h, or the patient was switched to imipenem, or a particular combination of clinical and bacteriological circumstances existed.
PFGE according to previously described procedures.22,23 Two representative A. baumannii strains belonging to the two different clones isolated in the study (strain CSUB118900, clone A, and strain CSUB12973, clone D) were selected for killing curves and chequerboard methods as previously described.26 Standard powders of ampicillin and sulbactam for laboratory use were provided by Pfizer. Escherichia coli ATCC 25922 was used as the quality control strain.
Evaluation of safety and tolerance
Results
Patients were evaluated by a physician daily for response to sulbactam treatment and development of adverse reactions. Laboratory studies included complete blood count, determination of prothrombin time and measurement of serum levels of alanine and aspartate aminotransferases, alkaline phosphatase, bilirubin, creatinine and blood urea nitrogen. These were repeated at appropriate intervals as clinically indicated.
Susceptibility testing Susceptibility studies and identification of microorganisms were performed by MicroScan NegCombo 6I and UrineCombo 6I panels (DADE, Int West, Sacramento, CA, USA) and by its ability to grow at 44°C. Susceptibility to ampicillin, sulbactam and the sulbactam/ampicillin combination (1:2 ratio) was assessed by a microdilution method according to NCCLS recommendations.25 Macrorestriction analysis of chromosomal DNA was done by
Patients From March 1995 to March 1997, clinical samples positive for multiresistant A. baumannii were documented in 569 (1%) of 52,585 patients admitted to the Hospital de Bellvitge. Forty-seven (8%) of these 569 patients were assigned to receive sulbactam therapy; five of these were excluded as they had received 48 h of sulbactam therapy, so 42 patients finally entered the study. Of these, 18 received treatment with sulbactam alone, and 24 were treated with the sulbactam/ampicillin combination. Clinical data on patients and infections are summarized in Tables I–III. Most patients with wound site infections had undergone major surgery and received antibiotic treatment several days before A. baumannii infection. All respiratory tract infections were associated with mechanical ventilation or tracheostomy; all urinary infections occurred after urinary tract catheterization; of five cases of bacteraemia, two were catheter-related.
Table I. Characteristics of the patients included in the study Characteristic
Patients included (n
Gender: male/female Age (years) Underlying disease (McCabe groups 2 and 3)a ICU-acquired A. baumannii infections Monomicrobial/polymicrobial A. baumannii clone A/clone D Median time of sulbactam therapy (range) No. of cases assessable for clinical outcome cured improved failed No. of cases assessable for bacteriological response eradicated persisted Adverse reactions Mortality attributable to A. baumannii infection
27 (64%)/15 (36%) 60 ± 15 12 (29%) 28 (67%) 27 (64%)/15 (36%) 40 (95%)/2 (5%) 13 days (3–42 days) 41 (98%) 35/41 (85%) 4/41 (10%) 2/41 (5%) 33 (79%) 32/33 (97%)b 1/33 (3%) 11 (26%)c 1 (2%)
a
See McCabe et al.58 Four patients with subsequent colonization. c Any patient with serious adverse effect.
b
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Clinical and bacteriological outcome Cure or improvement was observed in all but two of the 41 assessable cases (Tables I–III). Patient 38 was the only case not clinically evaluable since the patient died of massive aspiration pneumonia after receiving only 3 days of sulbactam treatment for a surgical wound infection of the abdomen. Sulbactam therapy was considered to have failed in patients 13 and 26 since clinical symptoms and signs of infection persisted after 3 and 8 days of sulbactam therapy, respectively. Clinical outcome was considered only improved in a number of patients: in patients 1 (as a result of persistent fistula), 17 (fever and malaise persisted despite therapy), 25 (pleural effusion and malaise persisted in spite of surgical debridement and sulbactam/ ampicillin therapy) and 33 (continued bronchoplegia). Patient 17 was the only case in which colonization was associated with the development of a subsequent clinical infection (renal abscess caused by Pseudomonas aeruginosa).
Figure 1. Bactericidal activity of ampicillin ( , 32 mg/L), sulbactam ( , 16 mg/L) and sulbactam/ampicillin ( , 16:32 mg/L) against A. baumannii CSUB118900 (clone A) compared with control ( ).
Susceptibility testing The MICs of ampicillin, sulbactam and sulbactam/ ampicillin (in mg/L) for the studied strains were as follows: strain CSUB118900 (clone A), 256, 2 and 2:4, respectively; CSUB12973 (clone D), 256, 4 and 4:8, respectively. The chequerboard method showed an indifferent effect between ampicillin and sulbactam (summed fractional inhibitory concentration, 1.01) in the two strains tested. In fact, the MICs of the sulbactam/ampicillin combination were the MIC of sulbactam alone. Results of killing curves are summarized in Figures 1 and 2. The killing curve of sulbactam showed no bactericidal effect, although it was studied at 8 MIC in clone A strains and at 4 MIC in clone D strains. The sulbactam/ampicillin combination was not bactericidal and did not show synergy.
Figure 2. Bactericidal activity of ampicillin (32 mg/L), sulbactam (16 mg/L), and sulbactam/ampicillin (16:32 mg/L) against A. baumannii CSUB12973 (clone D). Symbols as in Figure 1.
Discussion Over the past 20 years, A. baumannii has developed one of the most impressive patterns of antibiotic resistance ever observed, making it an important nosocomial pathogen. A general trend towards decreased susceptibility to antibiotics has been observed worldwide in the majority of nosocomial strains as a function of time.2 Successive increases in -lactam resistance included ampicillin,27 first- and second-generation cephalosporins,28 oxyimino- lactams,29 ureidopenicillins30 and imipenem.5,13,31,32 Sulbactam emerged in the 1980s as a -lactamase inhibitor for use along with other -lactam antibiotics, such as ampicillin. Its specific in-vitro activity against Acinetobacter spp., which is related to its affinity for penicillin-binding proteins, is well known11,12,17,33,34 but this
activity has only recently been taken into account in clinical practice. To date, most microbiological data reported have referred to the combination of ampicillin and sulbactam, and have pointed out the possible synergic antibacterial effect of this combination.35–39 However, these initial results have been interpreted from the usual point of view of the -lactamase inhibitor/ -lactam combination, highlighting the increase in ampicillin activity by the addition of sulbactam. In reality, these strains could be mainly susceptible to the combination by virtue of the antimicrobial activity exhibited by sulbactam.12,14–17,21 Our data clearly showed that there is no synergy between sulbactam and ampicillin against multiresistant A. baumannii strains. Killing curves using subinhibitory
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Sulbactam in A. baumannii infections concentrations of ampicillin at 32 mg/L showed no bactericidal activity; sulbactam alone exhibited bacteriostatic activity at 8 and 4 MIC of the two strains tested respectively; and the activity of the sulbactam/ampicillin combination was identical to that observed with sulbactam alone. Our paper includes the largest series of patients infected with multiresistant A. baumannii and treated with sulbactam, and it is the first in which sulbactam alone was used. The results confirm that sulbactam could be confidently used as alternative therapy to imipenem in nonlife-threatening infections, in order to diversify antibiotic policy or to treat those cases involving carbapenemresistant strains. Our study was not designed to compare the efficacy of sulbactam with that of the sulbactam/ ampicillin combination; moreover, our microbiological and clinical results allow us to conclude that the activity we observed was only due to sulbactam by itself. Therefore, where sulbactam is available as a single agent, its use is advisable in place of the sulbactam/ampicillin combination, in order to provide a narrower antibacterial spectrum and better profile for association with other antibiotics if necessary. Sulbactam/ampicillin could be chosen for cases with polymicrobial infections by susceptible microorganisms. In some of the patients included in this study, particularly those with polymicrobial infections or those for whom other additional therapeutical procedures were performed, it may be difficult to assess whether the favorable outcome was directly attributable to the antibiotics. However, there is no doubt that all required antibiotic therapy from the view of the current routine clinical practice. In some other patients suffering from serious infections such as mediastinitis, pneumonia, epididymo-orchitis, and Fournier’s gangrene, and in those related to orthopaedic bone implants, the contribution of sulbactam appeared to be evident. Several authors have advised against the clinical use of sulbactam as monotherapy against A. baumannii infections on the basis of its poor in-vitro bactericidal activity against some strains.40,41 In the present study, although killing curves showed that sulbactam had only bacteriostatic activity, only two cases were deemed clinical failures. It is difficult to assess the extent to which this microbiological behaviour affects clinical efficacy because, in vivo, other factors such as phagocytosis and killing by polymorphonuclear leucocytes may contribute to the favorable outcome of this kind of infections.42 The role of sulbactam in life-threatening infections by A. baumannii is not known. We believe that, before considering its clinical use in these settings, some pharmacokinetic considerations should be made. Sulbactam is a -lactam antibiotic with a pharmacokinetic profile similar to that of ampicillin, with peak serum levels after an intravenous dose of 1 g of 41–68 mg/L, a half life of 1 h, a concentration of 0.5 mg/L at 6 h and renal excretion
accounting for 75% of the total elimination.15,43–45 Data concerning penetration into tissues or human fluids are sparse. However, after 0.5 g of a parenteral dose of sulbactam, appreciable concentrations were observed in peritoneal fluid (14 mg/L), intestinal mucosa (0–28 mg/g), prostate (7 mg/g), pus (12.7 mg/L), or CSF of patients with inflamed meninges (2–32% those in serum).43 The MIC breakpoint for sulbactam alone has not been proposed yet, but the available criteria for the sulbactam/ampicillin combination (8/16 mg/L) are usually assumed.46–48 Regarding these results, in severe infections, the efficacy of sulbactam at the usual clinically recommended doses (1 g every 6–8 h or 50 mg/kg/day) could not be guaranteed since good therapeutic ranges may be difficult to assess against most of the current A. baumannii strains, even those considered to be susceptible to sulbactam (MICs ranging from 1 to 4 mg/L). With the above considerations in mind, two previous reports of sulbactam use are of note. Sulbactam alone, at higher therapeutical ranges than those currently assessable, has been shown to be very effective in experimental models of A. baumannii pneumonia.49,50 In these studies, sulbactam was used at doses of 100 mg/kg/day, and the MICs of sulbactam for the studied strains were 0.5 and 8 mg/L. To our knowledge, there are only two reports of clinical use of sulbactam at high doses. The first was in a liver transplant recipient with vancomycin-resistant Enterococcus faecium bacteraemia in whom sulbactam/ ampicillin (at doses of sulbactam of 10 g/day) was administered in continuous infusion for 4 weeks.51 In the second, sulbactam/ampicillin (at doses of sulbactam of 6 g/day) was safely used in humans with A. baumannii infections.19 On the basis of this in-vivo activity, the abovementioned results, and the knowledge that doses of sulbactam 200 mg/kg/day were found to be toxic in animals,52 we believe that sulbactam at doses of 2 g every 6–8 h, or in continuous infusion, (preferably in combination with other antibiotics such as aminoglycosides or quinolones) should be considered for the treatment of severe infections or those involving carbapenem-resistant strains.53–55 Regrettably, the possible use of sulbactam in multiresistant A. baumannii hospital outbreaks may only be short-lived since resistance has already been observed and will probably increase rapidly if this antimicrobial is used often.9,56,57
Acknowledgements This study was supported by grant no. 96/0674 from the Fondo de Investigaciones Sanitarias de la Seguridad Social, National Health Service, Spain, and was presented in part at the Thirty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 28 September–1 October 1997.
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