Document 6479614

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Treatment of Multidrug-Resistant Acinetobacter baumannii Meningitis with
Ampicillin/Sulbactam
M. E. Jimenez-Mejias, J. Pachon, B. Becerril,
J. Palomino-Nicas, A. Rodriguez-Cobacho,
and M. Revuelta
From the Infectious Diseases Unit, the Service of Microbiology, and the
Neurosurgery Department, University Hospital Virgen del Rocio,
Seville, Spain
Nosocomial infections caused by Acinetobacter species have
been increasing in frequency over the past years [1]. These
bacteria cause several types of nosocomial infections, such as
bacteremia, pneumonia, meningitis, urinary tract, and surgical
wound infections [1]. Nosocomial Acinetobacter baumannii
infections have a high related mortality; the case fatality rate
ranges between 19% and 44% in cases of bacteremia [2, 3].
In addition, ventilator-associated pneumonia in hospitalized patients that is caused by Acinetobacter species, among other
etiologies, is associated with high mortality [4, 5].
Acinetobacter meningitis is a severe nosocomial infection
caused by A. baumannii and is associated with a mortality rate
of20%-27% [6, 7]. Most of the reported cases have occurred in
a neurosurgical setting and have been associated with indwelling
ventriculostomytubes, CSF fistulae, or head trauma [6-9]. Nosocomial acinetobacter meningitis has been caused by the intrathecal administration of contaminated methotrexate solution to children with leukemia, with a mortality of 37.5% [10].
Most of the reported cases of acinetobacter meningitis have
been treated with imipenem, leading to recovery in 11 of 13
cases (84.6%) [8, 9, 11, 12]. However, the extensive use of
imipenem may induce the appearance of acinetobacter infections caused by strains resistant to imipenem [13, 14], leaving
few therapeutic options, especially for the management of CNS
infections. This article describes the clinical features and the
Received 14 August 1996; revised 23 October 1996.
Reprints or correspondence: M. E. Jimenez-Mejias, Unit of Infectious Diseases, Hospital Universitario Virgen del Rocio, Avda. Manuel Siurot sin, 41013
Seville, Spain.
Clinical Infectious Diseases 1997;24:932-5
© 1997 by The University of Chicago. All rights reserved.
1058--4838/97/2405 -0028$02.00
outcome of nosocomial A. baumannii meningitis treated with
ampicillin/sulbactam.
Methods
We performed a retrospective clinical study to evaluate the
outcome of eight cases of postneurosurgical meningitis caused
by multiresistant A. baumannii during the period between January 1993 and December 1995.
All patients met the following inclusion criteria: (1) clinical
signs of meningitis (fever, meningeal signs, low consciousness
level); (2) pleocytosis, low glucose level, and elevated protein
level in the CSF; (3) isolation of A. baumannii from CSF; and
(4) treatment with ampicillin/sulbactam.
All CSF cultures were processed by the hospital laboratory
with use of the Bactec NR860 system (Becton Dickinson,
Cockeysville, MD). A. baumannii was identified by the
MicroScan system (Baxter Health Care, West Sacramento,
CA), the API 20 NE system (bieMerieux, Marcy l'Etoile,
France), and temperature growth tests [15]. Susceptibility to
antimicrobial agents was determined by the MicroScan system,
with use ofthe Neg Breakpoint Combo Panel 21(Baxter Health
Care), according to the norms established by the National Committee for Clinical Laboratory Standards [16]. Susceptibility to
sulbactam was also determined by microdilution in MuellerHinton broth [16].
Clinical cure was considered to be the disappearance of fever
and meningeal signs, improvement of consciousness level (in
cases of low consciousness directly related to meningitis), and
remission of CSF alterations at the time the therapy was discontinued. Bacteriologic cure was defined as elimination of
A. baumannii from CSF during therapy. Death was considered
to be related to meningitis if it occurred during treatment for
meningitis.
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The clinical features and the outcomes of eight cases of nosocomial Acinetobacter baumannii
meningitis treated with ampicillinlsulbactam are reported. All the patients had fever, neck stiffness
or meningeal signs, and a low consciousness level, and in their cerebrospinal fluid (CSF), pleocytosis,
a low glucose level, and an elevated protein level were noted. For all CSF isolates of A. baumannii,
the MIC of ampicillinlsulbactam was :%;8/4 p,glmL. The MICs of sulbactam by microdilution in two
cases were 4 p,glmL. All isolates were resistant to cefotaxime, ceftriaxone, ceftazidime, ureidopenicillins, ciprofloxacin, and gentamicin. Seven isolates were resistant to imipenem. A. baumannii was
isolated from other samples in seven episodes. All patients were treated with ampicillinlsulbactam
(seven with 2 gil g every 6 hours and one with 2 gil g every 8 hours). Six patients were cured and
two patients died of meningitis. There were no side effects with the ampicillinlsulbactam treatment.
In conclusion, ampicillinlsulbactam may be effective as therapy for meningitis caused by A. baumanii
resistant to imipenem and other p-Iactam drugs.
em
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SulbactamlAmpicillin for Acinetobacter Meningitis
1997;24 (May)
Table 1. Clinical characteristics of the eight patients with nosocomial A. baumannii meningitis, as well as microbiological findings, treatment,
and outcome.
Patient no.
Age (y)1
sex
74/F
Underlying condition(s)
53/F
40/M
5
6
65/M
43/M
Intraventricular hemorrhage
Cerebellar hematoma
7
30/F
8
351M
Head trauma, cranial
fracture, subdural
hematoma
Syringomyelia
55/F
Dosage (gig) of
ampicillin!
sulbactam
Duration
(d) of
therapy
Outcome
Burr holes drilled
Blood, surgical wound
211 q6h
8*
Cured
External CSF shunt placed
External CSF shunt placed
Posterior fossa craniotomy,
external CSF shunt
External CSF shunt exchanged
Posterior fossa craniotomy,
external CSF shunt
Burr holes drilled, external CSF
and VP§ shunts placed
External CSF shunt
None
Surgical wounds
2/1 q6h
2/1 q6h
2/1 q6h
14
21 t
16t
Cured
Cured
Died
Blood, bronchial aspirate
Blood, bronchial aspirate
2/1 q6h
211 q6h
21
19t
Cured
Cured
Bronchial aspirate,
VP shunt
2/1 q6h
21
Cured
Posterior fossa craniotomy
Bronchial aspirate
2/1 q8h
5
Died
* He was switched to imipenem therapy on day 8 of treatment (see Results).
Intraventricular netilmicin (15 - 20 mg qd) also was given during the same time period.
t Intraventricular amikacin (15 mg qd) also was given during the same time period.
§ Ventriculoperitoneal.
t
A. baumannii meningitis was considered to be related to a
CSF shunt if it appeared following placement of the CSF shunt,
if the CSF at the time of placement was sterile, and if there
were no other neurosurgical procedures in the period of time
between the shunt placement and the onset of meningitis.
The results of analyses of continuous variables are expressed
herein as mean ± SD.
Results
Eight patients (four men and four women) between 30 and
74 years of age were included. The most common underlying
condition was intracerebral or subarachnoid hemorrhage (six
cases) (table 1). All patients underwent surgical procedures,
involving 3 craniotomies, 2 burr hole drillings, and 6 placements of external CSF shunts, which were in place for 3-17
days (10.5 ± 6.3 days) before onset of meningitis. The external
CSF shunt was directly related to A. baumannii meningitis in
five cases (83%). Four patients had CSF fistulae at the craniotomy and/or burr hole sites. One case had A. baumannii surgical
wound infection prior to meningitis. Seven patients had been
in the intensive care unit and seven had received antimicrobial
treatment prior to onset of meningitis.
All the patients had fever (39.06 ± 0.69°C), neck stiffness
or meningeal signs, and a low consciousness level (coma in
six cases and stupor and somnolence in one case each). Five
patients had nausea and/or vomiting and three suffered seizures.
The neurological deficits and the headaches were difficult to
evaluate because of the underlying conditions.
Leukocytosis (18,817 ± 6,lOlIpL) with a polymorphonuclear predominance was noted in seven patients. In all CSF
specimens, pleocytosis (4,383 ± 6,927 cells/ul.) with a polymorphonuclear predominance, an elevated protein level (415
± 219 mg/dl.), and a low glucose level (14 ± 15 mg/dL) were
noted.
In seven episodes, additional A. baumannii isolates were
recovered from other samples (table 1). All A. baumannii isolates were susceptible to ampicillin!sulbactam (MIC, ~8/4
p,glmL, per MicroScan system) and resistant to cefotaxime,
ceftriaxone, ceftazidime, ureidopenicillins, ciprofloxacin, and
gentamicin. Seven isolates were also resistant to imipenem.
The microdilution MICs of sulbactam in two cases (cases 2
and 3) were 4 tLg/mL.
The dosages and the duration of treatment with ampicillin!
sulbactam appear in table 1. Three patients also received intraventricular aminoglycosides. Three patients received dexamethasone (4 mg t.i.d.) for cerebral edema and/or anticonvulsant drugs (two received phenytoin and one received
phenobarbital). All the ventriculoperitoneal or external CSF
shunts were removed.
Two patients (25%) died of meningitis. Resolution of the
symptoms and signs of meningitis and improvement of CSF
findings on day 8 of treatment with ampicillin!sulbactam were
noted in case 1; however, the CSF culture remained positive
and the patient was switched to imipenem therapy for 14 more
days. There were no side effects with the ampicillin!sulbactam
treatment. Furthermore, there were neither recurrences nor superinfections.
Discussion
The cases of acinetobacter meningitis in this study were
related to head trauma or neurosurgical procedures, including
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2
3
4
Head trauma, subdural
hematoma
Intracerebral hemorrhage
Subarachnoid hemorrhage
Choroid plexus papilloma
Neurosurgical procedure(s)
Sources of other
Acinetobacter isolates
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Jimenez-Mejias et al.
vivo, in mice models of intraperitoneal infection [27]. In another study, of 20 Acinetobacter strains that were resistant to
imipenem and most probably of clonal origin, the MIC90 of
sulbactam was ~4 }1g/mL and the MIC90 of ampicillin!sulbactam was ~8/4 }1g/mL, while the MIC90 of ampicillin was> 128
}1g/mL [13].
The mortality rate in our study (25%) was similar to those
previously reported with regard to acinetobacter meningitis [6,
7] and slightly higher than the mortality of 15.4% among 13
cases treated with imipenem [8, 9, 11, 12]. Seven of the patients
in the present study had another acinetobacter infection, such
as tracheobronchitis or pneumonia and bacteremia, which are
associated with high mortality [3-5]. Eradication of Acinetobacter species from the CSF in shunt-associated meningitis
required complete removal of ventricular devices plus administration of bactericidal antibiotics. In this study, all external or
ventriculoperitoneal CSF shunts were removed. There were
neither recurrences nor superinfections.
In conclusion, the results of this study suggest that administration of ampicillin!sulbactam may be an effective therapy for
meningitis caused by A. baumanii resistant to imipenem and
other (3-lactam drugs.
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. Seifert H, Strate A, Pulverer G. Nosocomial bacteremia due to Acinetobacter baumannii: clinical features, epidemiology and predictors of
mortality. Medicine (Baltimore) 1995; 74:340-9:
3. Cisneros JM, Reyes MJ, Pachon J, et al. Bacteremia due to Acinetobacter
baumannii: epidemiology, clinical findings, and prognostic features.
Clin Infect Dis 1996;22:1026-32.
4. Kollef MH, Silver P, Murphy DM, Trovilion E. The effect of late-onset
ventilator-associated pneumonia in determining patient mortality. Chest
1995; 108:1655-62.
5. Fagon J-Y, Chastre J, Hance AJ, Montravers P, Novara A, Gibert C.
Nosocomial pneumonia in ventilated patients: a cohort study evaluating
attributable mortality and hospital stay. Am J Med 1993; 94:281-8.
6. Siegman-Igra Y, Bar-Yosef S, Gorea A, Avram 1. Nosocomial acinetobacter meningitis secondary to invasive procedures: report of 25 cases
and review. Clin Infect Dis 1993; 17:843-9.
7. Jimenez-Mejias ME, Lopez-Cortes L, Becerril B, Palomino J, del Nozal
M, Pachon J. Acinetobacter meningitis. Risk factors and clinical features
[abstract no 1182]. In: Abstracts of the 7th European Congress on
Clinical Microbiology and Infectious Diseases (Vienna). Taufkirchen,
Germany: European Society of Clinical Microbiology and Infectious
Diseases, 1995.
8. 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.
9. Nguyen MH, Harris SP, Muder RR, Pasculle AW. Antibiotic-resistant
Acinetobacter meningitis in neurosurgical patients. Neurosurgery 1994;
35:851-5.
10. Kelkar R, Gordon SM, Giri N, et al. Epidemic iatrogenic Acinetobacter
spp. meningitis following administration of intrathecal methotrexate. J
Hosp Infect 1989; 14:233-43.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
placement of external ventricular devices (present for > 5
days), factors which have previously been associated with this
infection [6-9, 17]. The excessive administration of antimicrobial agents to neurosurgical patients may facilitate the appearance of acinetobacter meningitis [6, 9], as probably occurred
in seven of the cases in the present study.
Nosocomial A. baumannii infections have a high related
mortality, with a case fatality rate of 20%-27% for acinetobacter meningitis [6, 7]. The mortality is related to inappropiate
treatment of bacteremias due to A. baumannii [3], a finding
which stresses the importance of correct empirical treatment.
Many nosocomial A. baumannii strains are resistant to a
wide variety of antimicrobial agents. Imipenem, tetracycline,
ampicillin!sulbactam, polymyxin B, and (according to some
studies) ceftazidime and ciprofloxacin are among the more active antimicrobial agents against A. baumannii [3, 18-20].
However, antimicrobial susceptibility patterns may change
from hospital to hospital. Thus, the use of imipenem for acinetobacter infections caused by strains that are only imipenemsusceptible may induce the appearance of imipenem-resistant
acinetobacter infections.
Urban et al. [13] referred to an outbreak of acinetobacter
infections that necessitated widespread use of ceftazidime and
later the use of imipenem. Subsequently, they observed Acinetobacter strains resistant to all antimicrobial agents tested, including imipenem, ceftazidime, and amikacin [13]. We have
observed a steady increase in the incidence of multiresistant
A. baumannii infections in our hospital, including those resistant to imipenem, after extensive use of this antimicrobial
agent. For instance, only 43%, 26%, and 38% of A. baumannii
isolates from the same building of the hospital were susceptible
to imipenem in 1993, 1994, and 1995, respectively.
In the treatment of imipenem-resistant acinetobacter infections, ampicillin!sulbactam has been useful for patients with
respiratory tract infections and bacteremia [13]. Ampicillin!
sulbactam was also useful in the treatment of uncomplicated
urinary tract infections [21]. There are few clinical data on the
treatment of meningitis with ampicillin!sulbactam. These (31actam drugs have been effective in the treatment of bacterial
meningitis caused by Haemophilus infiuenzae, Streptococcus
pneumoniae, Neisseria meningitidis, and Staphylococcus species in infants, children, and adults [22-24].
Only one patient with acinetobacter posttraumatic meningitis
was treated and cured with ampicillin!sulbactam [22]. Sulbactam penetrates into the CSF of patients with bacterial meningitis in a pattern similar to that of ampicillin [23]. One gram of
sulbactam administered intravenously achieved CSF concentrations as high as 32% of serum concentrations (8.5 }1g/mL) in
patients with meningitis [25] but < 1% of those in patients
without meningitis [26].
There are data indicating thatsulbactam is responsible for
the bactericidal effect of ampicillin/sulbactam on Acinetobacter
species. Sulbactam was more active than ceftazidime and clavulanate on Acinetobacter calcoaceticus, both in vitro and in
CID 1997;24 (May)
cm
1997;24 (May)
SulbactamJAmpicillin for Acinetobacter Meningitis
19. Seifert H, Baginski R, Schulze A, Pulverer G. Antimicrobial susceptibilityof
Acinetobacter species. Antimicrob Agents Chemother 1993;37:750-3.
20. Traub WM, Sporh M. Antimicrobial drug susceptibility of clinical isolates
of Acinetobacter species (A. baumannii, A. haemolyticus. Genospecies
3, and genospecies 6). Antimicrob Agents Chemother 1989;33:
1617-9.
21. Telenti Asensio M, Moreno Torrico A, Ruiz Palomar J, Fernandez Bernaldo de Quiros J. Eficacia de sulbactam-ampicilina en la infeccion
urinaria por Acinetobacter calcoaceticus var. anitratus. Med Clin (Bare)
1995; 105:48-9.
22. Baltas I, Tsoulfa S, Sakellariou P, Vogas V, Fylaktakis M, Kondodimou
A. Posttraumatic meningitis: bacteriology, hydrocephalus, and outcome.
Neurosurgery 1994;35:422-7.
23. Stahl JP, Bru JP, Fredj G, Brammer KW, Malleret MR, Micoud M. Penetration of sulbactam into the cerebrospinal fluid of patients with bacterial
meningitis receiving ampicillin therapy. Rev Infect Dis 1986; 18(suppl
5):S612-6.
24. Rodriguez WJ, Khan WN, Puig J, et al. Sulbactamlampicillin vs. chloramphenicol/ampicillin for the treatment of meningitis in infants and children. Rev Infect Dis 1986; 8(suppl 5):S620-9.
25. Campoli-Richards DM, Brogden RN. Sulbactamlampicillin: a review of
its antibacterial activity, pharmacokinetic properties, and therapeutic
use. Drugs 1987;33:577-609.
26. Hanninen P, Rossi T. Penetration of sulbactam into cerebrospinal fluid of
patients with viral meningitis or without meningitis. Rev Infect Dis
1986; 8(suppl 5):S609-11.
27. Obana Y, Nishimo T. In-vitro and in-vivo activities of sulbactam and
YTR830H against Acinetobacter calcoaceticus. J Antimicrob Chemother 1990;26:677-82.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
11. Sanchez JF, Sanz-Hospital J, Guerrero A, Martinez-Beltran J, Quereda C.
Curacion con imipenem-cilastatino de una meningitis por Acinetobacter
calcoaceticus. EnfInfec Microbiol Clin 1991;9:512-3.
12. Rouveix E, Bure AM, Regnier B, et al. Experience with imipenemlcilastatin in the intensive care unit. J Antimicrob Chemother 1986; 18(suppl
E):153-60.
13. Urban C, Go E, Mariano N, et al. Effect of suibactam on infections caused
by imipenem-resistant Acinetobacter calcoaceticus biotype anitratus. J
Infect Dis 1993; 167:448-51.
14. Go ES, Urban C, Bums J, et al. Clinical and molecular epidemiology of
acinetobacter infections sensitive only to polymyxin Band sulbactam.
Lancet 1994; 344:1329-32.
15. Bouvet PJM, Grimont PAD. Taxonomy of the genus Acinetobacter with
the recognition of Acinetobacter baumannii sp. nov., Acinetobacter
haemolyticus sp. nov., Acinetobacter johnsonii sp. nov., and Acinetobacter junii sp. nov. and emended descriptions of Acinetobacter calcoaceticus and Acinetobacter lwoffii. J Syst Bacteriol1986; 36:228-40.
16. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility testing for bacteria that grow aerobically. 2nd ed. NCCLS document M7-A2. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1990.
17. Mayhall CG, Arched NH, Lamb VA, et al. Ventriculostomy-related infections: a prospective epidemiologic study. N Engl J Med 1984;310:
553-9.
18. Vila J, Marcos A, Marco F, et al. In vitro antimicrobial production of {3lactamases, aminoglycoside-modifying enzymes, and chloramphenicol
acetyltransferase by and susceptibility of clinical isolates of Acinetobacter baumannii. Antimicrob Agents Chemother 1993; 37:138-41.
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