- Email: [email protected]
sulbactam combined with rifampicin and fosfomycin
J Infect Chemother (2012) 18:958–960 DOI 10.1007/s10156-012-0404-9
CASE REPORT
Postsurgical meningitis due to multiresistant Acinetobacter baumannii successfully treated with high doses of ampicillin/ sulbactam combined with rifampicin and fosfomycin Guillaume Mellon • Christophe Clec’h • Bertrand Picard • Yves Cohen • Franc¸oise Jaure´guy
Received: 20 February 2012 / Accepted: 27 February 2012 / Published online: 20 March 2012 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012
Abstract We report a case of postsurgical meningitis caused by multiresistant Acinetobacter baumannii successfully treated with high doses of ampicillin/sulbactam combined with rifampicin and fosfomycin. Keywords Acinetobacter baumannii Multiresistant Ampicillin/sulbactam Rifampicin Fosfomycin
multiresistant strains in recent years, the risk of inappropriate antibiotic therapy has become a major concern. We report a case of postsurgical meningitis caused by multiresistant A. baumannii that was successfully treated with high doses of ampicillin/sulbactam combined with rifampicin and fosfomycin.
Case report Introduction Acinetobacter baumannii is a gram-negative coccobacillus involved in various nosocomial infections such as bacteremia, pneumonia, and urinary tract and surgical wound infections [1]. A. baumannii meningitis is a rare but severe condition mainly observed after indwelling ventriculostomy catheter insertion, cerebrospinal fluid (CSF) leakage, or head trauma [1]. Because of the emergence of
G. Mellon (&) B. Picard F. Jaure´guy Bacteriology-Virology-Hygiene Laboratory, University Hospital, Paris-Seine-Saint-Denis, Avicenne Hospital, 125, rue de Stalingrad, 93009 Bobigny Cedex, France e-mail: [email protected] C. Clec’h Y. Cohen Intensive Care Unit, University Hospital, Paris-Seine-Saint-Denis, Avicenne Hospital, Bobigny Cedex, France B. Picard F. Jaure´guy UMR-S 722, INSERM, 75018 Paris, France B. Picard F. Jaure´guy Sorbonne Paris City, UMR-S 722, Xavier Bichat Medical School, Paris Nord University, 75018 Paris, France
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A 41-year-old man was admitted to the intensive care unit of our hospital for severe head trauma with initial loss of consciousness after a car crash. On neurological examination, he had a wound of the scalp in the left parietal region, suspicion of cerebrospinal fluid (CSF) leakage, and tetraparesia. His right elbow was seriously injured, with loss of osseous, muscular, and nervous substance. The rest of his physical examination was unremarkable. The cranial and cervical computed tomography (CT) scans revealed a left parietal hemorrhagic contusion, a left temporal intracerebral hematoma, and a complex trauma of the cervical spine. The patient underwent immediate C5–C6 laminectomy and C3–C7 osteosynthesis. No dural tear or CSF leakage was observed. On day 2, the patient had a C5–C6 discectomy. During the intervention, dural tear with CSF leakage was noticed and repaired. On day 4, the patient was receiving piperacillin–tazobactam (4 g IV every 8 h) for elbow samples containing Enterobacter cloacae, Aeromonas hydrophilia, and Pseudomonas fluorescens. His temperature was 39.3°C. The lumbar puncture was negative. Piperacillin/tazobactam was continued, and fever was no longer observed during the course of antibiotic therapy. On day 13, piperacillin–tazobactam was discontinued and fever (40°C) recurred, without any neurological symptoms. A second lumbar puncture was performed. White blood cell
J Infect Chemother (2012) 18:958–960
count was 45,000/mm3 (polymorphonuclear neutrophils 80 %, lymphocytes 20 %), CSF glucose level was 0.6 mmol/l, and CSF protein level was 3 g/l. Culture of the CSF yielded A. baumannii. An API 20E gallery (BioMe´rieux, Marcy l’Etoile, France) was used to identify A. baumannii, and antimicrobial susceptibility was determined by the diffusion method on Mueller–Hinton agar according to the standards of the Comite´ de l’Antibiogramme de la Socie´te´ Franc¸aise de Microbiologie (http://www.sfm.asso.fr). The strain was resistant to piperacillin–tazobactam, cefepim, imipenem-cilastatin, amikacin, and ciprofloxacin but susceptible to rifampicin, colistin, and fosfomycin. The minimum inhibitory concentration (MIC) of ampicillin/ sulbactam was 32 mg/l. The following antibiotic therapy was started: ampicillin/sulbactam 3/1.5 g (IV) every 4 h, fosfomycin 4 g (IV) every 6 h, and rifampicin 600 mg (IV) every 6 h. Ampicillin/sulbactam and fosfomycin were continued for 21 days and rifampicin for 11 days. After 3 days of antibiotic therapy, white blood cell CSF count was 7,400/mm3 (polymorphonuclear neutrophils 91 %, lymphocytes 9 %), CSF glucose level was 1.4 mmol/ l, CSF protein level was 3 g/l, and culture was negative. After 13 days of antibiotic therapy, white blood cell CSF count was 64/mm3 (polymorphonuclear neutrophils 74 %, lymphocytes 26 %), CSF glucose level was 2.7 mmol/l, CSF protein level was 1.8 g/l, and culture was negative. No adverse effects were observed during the course of antibiotic therapy, and the patient was discharged home on day 42 without any neurological sequelae.
Discussion Acinetobacter baumanii has been reported to account for 10 % of all gram-negative meningitis and 4 % of nosocomial meningitis [2]. The high mortality rates (20–27 %) observed in patients with A. baumanii meningitis [1] are partly ascribable to therapeutic difficulties with frequent inappropriate antibiotic therapy. Carbapenems and aminoglycosides have an excellent in vitro activity against A. baumannii and have been shown to yield significant rates of clinical success in the treatment of A. baumannii meningitis [3]. However, the increasing use of broadspectrum antibiotics including carbapenems has lead to the emergence of multiresistant strains, including meningitis [4]. In case of nosocomial infections caused by imipenemresistant A. baumannii [4], antimicrobial options are extremely limited. Polymixins and sulbactam are often the only antibiotics exhibiting in vitro activity against multiresistant strains. Colistin, an old drug, which was abandoned a few decades ago because of its nephrotoxicity, has recently gained new interest as a treatment option for multiresistant A. baumannii, despite its poor CSF
959
penetration [4]. Our patient was treated by a combination of ampicillin/sulbactam, rifampicin, and fosfomycin. Previous clinical studies have demonstrated the efficacy of ampicillin/sulbactam in the treatment of severe multiresistant A. baumannii infections, including meningitis [4–6]. Of note, although most pharmaceutical preparations of sulbactam include ampicillin, the efficacy seems to be related to sulbactam alone, as suggested by the study of Corbella et al. [7], which reported similar efficacy of sulbactam alone or combined with ampicillin in 42 patients with nosocomial multiresistant A. baumannii infections. Sulbactam is a synthetic b-lactam molecule, with structural, chemical, and pharmacokinetic properties similar to those of aminopenicillins. A feature that distinguishes sulbactam from other b-lactamase inhibitors is its direct in vitro antimicrobial activity against Acinetobacter species, which is related to its affinity for penicillin-binding proteins. Rates of susceptibility to sulbactam are high, ranging from 81 % to 100 % [8]. The minimal inhibitory concentration (MIC) breakpoint for sulbactam alone has never been decided, but the criterion for ampicillin/sulbactam combination (8/16 mg/l) is usually used [9]. The usual recommended dose (1 g every 6–8 h) may be insufficient in meningitis and might lead to therapeutic failure. Few clinical studies so far have reported the use of sulbactam at higher doses, particularly in meningitis [6]: in the study of Cawley et al., the daily dose was ampicillin 2 g/sulbactam 1 g every 3 h. In our case, the high dose of ampicillin/ sulbactam administered (3/1.5 g IV every 4 h) may have resulted in strain eradication. That the combination of ampicillin/sulbactam with rifampicin also contributed to strain eradication is another hypothesis. Although rifampicin has been shown to have in vitro and in vivo bactericidal activity against carbapenemresistant A. baumanii, it must be noticed that its combination with ampicillin/sulbactam may be efficient in meningitis only when the MIC of sulbactam against the responsible strain does not exceed 32 mg/l [10], which was not the case in our patient. For fosfomycin, a bactericidal antibiotic with a broadspectrum activity against both gram-positive and gramnegative bacteria, reported MIC against A. baumannii is very high. In a review on fosfomycin for the treatment of infections caused by multidrug-resistant nonfermenting gram-negative bacilli, among multiresistant A. baumanii, only 3.5 % were susceptible to fosfomycin [11]. Nevertheless, the addition of fosfomycin may increase the probability of therapeutic success. However, the combination of fosfomycin with other antibiotics, such as aminoglycosides, has been reported to be synergistic in A. baumannii infections [12]. In conclusion, this case report suggests that a combination of ampicillin/sulbactam (high doses), rifampicin,
123
960
J Infect Chemother (2012) 18:958–960
and fosfomycin may be an effective therapeutic option in the treatment of multiresistant A. baumannii meningitis. 8.
References 1. Bergogne-Berezin E, Towner KJ. Acinetobacter spp. as nosocomial pathogens: microbiological, clinical, and epidemiological features. Clin Microbiol Rev. 1996;9:148–65. 2. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993;328:21–8. 3. Seifert H, Richter W, Pulverer G. Clinical and bacteriological features of relapsing shunt-associated meningitis due to Acinetobacter baumannii. Eur J Clin Microbiol Infect Dis. 1995;14: 130–4. 4. Kim BN, Peleg AY, Lodise TP, Lipman J, Li J, Nation R, et al. Management of meningitis due to antibiotic-resistant Acinetobacter species. Lancet Infect Dis. 2009;9:245–55. 5. Jimenez-Mejias ME, Pachon J, Becerril B, Palomino-Nicas J, Rodriguez-Cobacho A, Revuelta M. Treatment of multidrugresistant Acinetobacter baumannii meningitis with ampicillin/ sulbactam. Clin Infect Dis. 1997;24:932–5. 6. Cawley MJ, Suh C, Lee S, Ackerman BH. Nontraditional dosing of ampicillin-sulbactam for multidrug-resistant Acinetobacter baumannii meningitis. Pharmacotherapy. 2002;22:527–32. 7. Corbella X, Ariza J, Ardanuy C, Vuelta M, Tubau F, Sora M, et al. Efficacy of sulbactam alone and in combination with
123
9.
10.
11.
12.
ampicillin in nosocomial infections caused by multiresistant Acinetobacter baumannii. J Antimicrob Chemother. 1998;42: 793–802. Murray PR, Cantrell HF, Lankford RB. Multicenter evaluation of the in vitro activity of piperacillin-tazobactam compared with eleven selected beta-lactam antibiotics and ciprofloxacin against more than 42,000 aerobic gram-positive and gram-negative bacteria. In Vitro Susceptibility Surveillance Group. Diagn Microbiol Infect Dis. 1994;19:111–20. Jones RN, Dudley MN. Microbiologic and pharmacodynamic principles applied to the antimicrobial susceptibility testing of ampicillin/sulbactam: analysis of the correlations between in vitro test results and clinical response. Diagn Microbiol Infect Dis. 1997;28:5–18. Pachon-Ibanez ME, Docobo-Perez F, Lopez-Rojas R, Dominguez-Herrera J, Jimenez-Mejias ME, Garcia-Curiel A, et al. Efficacy of rifampin and its combinations with imipenem, sulbactam, and colistin in experimental models of infection caused by imipenem-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2010;54:1165–72. Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrugresistant non-fermenting gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009;34:111–20. Martinez-Martinez L, Rodriguez G, Pascual A, Suarez AI, Perea EJ. In vitro activity of antimicrobial agent combinations against multiresistant Acinetobacter baumannii. J Antimicrob Chemother. 1996;38:1107–8.
CASE REPORT
Postsurgical meningitis due to multiresistant Acinetobacter baumannii successfully treated with high doses of ampicillin/ sulbactam combined with rifampicin and fosfomycin Guillaume Mellon • Christophe Clec’h • Bertrand Picard • Yves Cohen • Franc¸oise Jaure´guy
Received: 20 February 2012 / Accepted: 27 February 2012 / Published online: 20 March 2012 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012
Abstract We report a case of postsurgical meningitis caused by multiresistant Acinetobacter baumannii successfully treated with high doses of ampicillin/sulbactam combined with rifampicin and fosfomycin. Keywords Acinetobacter baumannii Multiresistant Ampicillin/sulbactam Rifampicin Fosfomycin
multiresistant strains in recent years, the risk of inappropriate antibiotic therapy has become a major concern. We report a case of postsurgical meningitis caused by multiresistant A. baumannii that was successfully treated with high doses of ampicillin/sulbactam combined with rifampicin and fosfomycin.
Case report Introduction Acinetobacter baumannii is a gram-negative coccobacillus involved in various nosocomial infections such as bacteremia, pneumonia, and urinary tract and surgical wound infections [1]. A. baumannii meningitis is a rare but severe condition mainly observed after indwelling ventriculostomy catheter insertion, cerebrospinal fluid (CSF) leakage, or head trauma [1]. Because of the emergence of
G. Mellon (&) B. Picard F. Jaure´guy Bacteriology-Virology-Hygiene Laboratory, University Hospital, Paris-Seine-Saint-Denis, Avicenne Hospital, 125, rue de Stalingrad, 93009 Bobigny Cedex, France e-mail: [email protected] C. Clec’h Y. Cohen Intensive Care Unit, University Hospital, Paris-Seine-Saint-Denis, Avicenne Hospital, Bobigny Cedex, France B. Picard F. Jaure´guy UMR-S 722, INSERM, 75018 Paris, France B. Picard F. Jaure´guy Sorbonne Paris City, UMR-S 722, Xavier Bichat Medical School, Paris Nord University, 75018 Paris, France
123
A 41-year-old man was admitted to the intensive care unit of our hospital for severe head trauma with initial loss of consciousness after a car crash. On neurological examination, he had a wound of the scalp in the left parietal region, suspicion of cerebrospinal fluid (CSF) leakage, and tetraparesia. His right elbow was seriously injured, with loss of osseous, muscular, and nervous substance. The rest of his physical examination was unremarkable. The cranial and cervical computed tomography (CT) scans revealed a left parietal hemorrhagic contusion, a left temporal intracerebral hematoma, and a complex trauma of the cervical spine. The patient underwent immediate C5–C6 laminectomy and C3–C7 osteosynthesis. No dural tear or CSF leakage was observed. On day 2, the patient had a C5–C6 discectomy. During the intervention, dural tear with CSF leakage was noticed and repaired. On day 4, the patient was receiving piperacillin–tazobactam (4 g IV every 8 h) for elbow samples containing Enterobacter cloacae, Aeromonas hydrophilia, and Pseudomonas fluorescens. His temperature was 39.3°C. The lumbar puncture was negative. Piperacillin/tazobactam was continued, and fever was no longer observed during the course of antibiotic therapy. On day 13, piperacillin–tazobactam was discontinued and fever (40°C) recurred, without any neurological symptoms. A second lumbar puncture was performed. White blood cell
J Infect Chemother (2012) 18:958–960
count was 45,000/mm3 (polymorphonuclear neutrophils 80 %, lymphocytes 20 %), CSF glucose level was 0.6 mmol/l, and CSF protein level was 3 g/l. Culture of the CSF yielded A. baumannii. An API 20E gallery (BioMe´rieux, Marcy l’Etoile, France) was used to identify A. baumannii, and antimicrobial susceptibility was determined by the diffusion method on Mueller–Hinton agar according to the standards of the Comite´ de l’Antibiogramme de la Socie´te´ Franc¸aise de Microbiologie (http://www.sfm.asso.fr). The strain was resistant to piperacillin–tazobactam, cefepim, imipenem-cilastatin, amikacin, and ciprofloxacin but susceptible to rifampicin, colistin, and fosfomycin. The minimum inhibitory concentration (MIC) of ampicillin/ sulbactam was 32 mg/l. The following antibiotic therapy was started: ampicillin/sulbactam 3/1.5 g (IV) every 4 h, fosfomycin 4 g (IV) every 6 h, and rifampicin 600 mg (IV) every 6 h. Ampicillin/sulbactam and fosfomycin were continued for 21 days and rifampicin for 11 days. After 3 days of antibiotic therapy, white blood cell CSF count was 7,400/mm3 (polymorphonuclear neutrophils 91 %, lymphocytes 9 %), CSF glucose level was 1.4 mmol/ l, CSF protein level was 3 g/l, and culture was negative. After 13 days of antibiotic therapy, white blood cell CSF count was 64/mm3 (polymorphonuclear neutrophils 74 %, lymphocytes 26 %), CSF glucose level was 2.7 mmol/l, CSF protein level was 1.8 g/l, and culture was negative. No adverse effects were observed during the course of antibiotic therapy, and the patient was discharged home on day 42 without any neurological sequelae.
Discussion Acinetobacter baumanii has been reported to account for 10 % of all gram-negative meningitis and 4 % of nosocomial meningitis [2]. The high mortality rates (20–27 %) observed in patients with A. baumanii meningitis [1] are partly ascribable to therapeutic difficulties with frequent inappropriate antibiotic therapy. Carbapenems and aminoglycosides have an excellent in vitro activity against A. baumannii and have been shown to yield significant rates of clinical success in the treatment of A. baumannii meningitis [3]. However, the increasing use of broadspectrum antibiotics including carbapenems has lead to the emergence of multiresistant strains, including meningitis [4]. In case of nosocomial infections caused by imipenemresistant A. baumannii [4], antimicrobial options are extremely limited. Polymixins and sulbactam are often the only antibiotics exhibiting in vitro activity against multiresistant strains. Colistin, an old drug, which was abandoned a few decades ago because of its nephrotoxicity, has recently gained new interest as a treatment option for multiresistant A. baumannii, despite its poor CSF
959
penetration [4]. Our patient was treated by a combination of ampicillin/sulbactam, rifampicin, and fosfomycin. Previous clinical studies have demonstrated the efficacy of ampicillin/sulbactam in the treatment of severe multiresistant A. baumannii infections, including meningitis [4–6]. Of note, although most pharmaceutical preparations of sulbactam include ampicillin, the efficacy seems to be related to sulbactam alone, as suggested by the study of Corbella et al. [7], which reported similar efficacy of sulbactam alone or combined with ampicillin in 42 patients with nosocomial multiresistant A. baumannii infections. Sulbactam is a synthetic b-lactam molecule, with structural, chemical, and pharmacokinetic properties similar to those of aminopenicillins. A feature that distinguishes sulbactam from other b-lactamase inhibitors is its direct in vitro antimicrobial activity against Acinetobacter species, which is related to its affinity for penicillin-binding proteins. Rates of susceptibility to sulbactam are high, ranging from 81 % to 100 % [8]. The minimal inhibitory concentration (MIC) breakpoint for sulbactam alone has never been decided, but the criterion for ampicillin/sulbactam combination (8/16 mg/l) is usually used [9]. The usual recommended dose (1 g every 6–8 h) may be insufficient in meningitis and might lead to therapeutic failure. Few clinical studies so far have reported the use of sulbactam at higher doses, particularly in meningitis [6]: in the study of Cawley et al., the daily dose was ampicillin 2 g/sulbactam 1 g every 3 h. In our case, the high dose of ampicillin/ sulbactam administered (3/1.5 g IV every 4 h) may have resulted in strain eradication. That the combination of ampicillin/sulbactam with rifampicin also contributed to strain eradication is another hypothesis. Although rifampicin has been shown to have in vitro and in vivo bactericidal activity against carbapenemresistant A. baumanii, it must be noticed that its combination with ampicillin/sulbactam may be efficient in meningitis only when the MIC of sulbactam against the responsible strain does not exceed 32 mg/l [10], which was not the case in our patient. For fosfomycin, a bactericidal antibiotic with a broadspectrum activity against both gram-positive and gramnegative bacteria, reported MIC against A. baumannii is very high. In a review on fosfomycin for the treatment of infections caused by multidrug-resistant nonfermenting gram-negative bacilli, among multiresistant A. baumanii, only 3.5 % were susceptible to fosfomycin [11]. Nevertheless, the addition of fosfomycin may increase the probability of therapeutic success. However, the combination of fosfomycin with other antibiotics, such as aminoglycosides, has been reported to be synergistic in A. baumannii infections [12]. In conclusion, this case report suggests that a combination of ampicillin/sulbactam (high doses), rifampicin,
123
960
J Infect Chemother (2012) 18:958–960
and fosfomycin may be an effective therapeutic option in the treatment of multiresistant A. baumannii meningitis. 8.
References 1. Bergogne-Berezin E, Towner KJ. Acinetobacter spp. as nosocomial pathogens: microbiological, clinical, and epidemiological features. Clin Microbiol Rev. 1996;9:148–65. 2. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993;328:21–8. 3. Seifert H, Richter W, Pulverer G. Clinical and bacteriological features of relapsing shunt-associated meningitis due to Acinetobacter baumannii. Eur J Clin Microbiol Infect Dis. 1995;14: 130–4. 4. Kim BN, Peleg AY, Lodise TP, Lipman J, Li J, Nation R, et al. Management of meningitis due to antibiotic-resistant Acinetobacter species. Lancet Infect Dis. 2009;9:245–55. 5. Jimenez-Mejias ME, Pachon J, Becerril B, Palomino-Nicas J, Rodriguez-Cobacho A, Revuelta M. Treatment of multidrugresistant Acinetobacter baumannii meningitis with ampicillin/ sulbactam. Clin Infect Dis. 1997;24:932–5. 6. Cawley MJ, Suh C, Lee S, Ackerman BH. Nontraditional dosing of ampicillin-sulbactam for multidrug-resistant Acinetobacter baumannii meningitis. Pharmacotherapy. 2002;22:527–32. 7. Corbella X, Ariza J, Ardanuy C, Vuelta M, Tubau F, Sora M, et al. Efficacy of sulbactam alone and in combination with
123
9.
10.
11.
12.
ampicillin in nosocomial infections caused by multiresistant Acinetobacter baumannii. J Antimicrob Chemother. 1998;42: 793–802. Murray PR, Cantrell HF, Lankford RB. Multicenter evaluation of the in vitro activity of piperacillin-tazobactam compared with eleven selected beta-lactam antibiotics and ciprofloxacin against more than 42,000 aerobic gram-positive and gram-negative bacteria. In Vitro Susceptibility Surveillance Group. Diagn Microbiol Infect Dis. 1994;19:111–20. Jones RN, Dudley MN. Microbiologic and pharmacodynamic principles applied to the antimicrobial susceptibility testing of ampicillin/sulbactam: analysis of the correlations between in vitro test results and clinical response. Diagn Microbiol Infect Dis. 1997;28:5–18. Pachon-Ibanez ME, Docobo-Perez F, Lopez-Rojas R, Dominguez-Herrera J, Jimenez-Mejias ME, Garcia-Curiel A, et al. Efficacy of rifampin and its combinations with imipenem, sulbactam, and colistin in experimental models of infection caused by imipenem-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2010;54:1165–72. Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrugresistant non-fermenting gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009;34:111–20. Martinez-Martinez L, Rodriguez G, Pascual A, Suarez AI, Perea EJ. In vitro activity of antimicrobial agent combinations against multiresistant Acinetobacter baumannii. J Antimicrob Chemother. 1996;38:1107–8.