Comparison of Intravenous Ampicillin–sulbactam Plus Nebulized Colistin with Intravenous Colistin Plus Nebulized Colistin in Treatment of Ventilator Associated Pneumonia Caused by Multi Drug Resistant Acinetobacter Baumannii: Randomized Open Label Trial

Document Type : Research article

Authors

1 Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Department of Infectious Diseases, Imam Hossein Teaching and Educational Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Department of Critical Care Medicine, Imam Hossein Medical and Educational Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

The purpose of this study was evaluating the efficacy and safety of intravenous (IV) ampicillin–sulbactam plus nebulized colistin in the treatment of Ventilator-Associated Pneumonia (VAP) caused by MDR Acinetobacter (MDRA)in ICU patients as an alternative to IV plus nebulized colistin. In this single-blinded RCT, one group received IV colistin and another group IV ampicillin–sulbactam (16 and 12 patients from total 28 patients, respectively) for 14 days or since clinical response. Both groups received nebulized colistin by mesh nebulizer. There were no statistically significant differences between the 2 groups in baseline characteristics and previous antibiotic therapy. In follow up period, no significant difference was observed between 2 groups in rate of microbiological eradication, clinical signs of VAP improvement, survival rate and length of hospital as well as ICU stays. Although we have found no significant differences in Acute Kidney Injury (AKI) incidence between two groups, comparison of cumulative patient-days with stages 2 and 3 AKI with days with no or stage 1 AKI, according to AKIN criteria, revealed significant difference in IV colistin versus IV ampicillin–sulbactam group (p = 0.013). The results demonstrated that the high dose IV ampicillin–sulbactam plus nebulized colistin regimen has comparable efficacy with IV plus nebulized colistin in the treatment of VAP caused by MDRA,withsensitivity to colistin only, with probably lower incidence of kidney injury.

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Main Subjects


(1) Ranzani OT, Prina E and Torres A. Nosocomial
pneumonia in the intensive care unit: how should
treatment failure be predicted? Rev. Bras. Ter.
Intensiva (2014) 26: 208-11.
(2) Grief SN and Loza JK. Guidelines for the evaluation
and treatment of pneumonia. Prim. Care (2018) 45:
485-503.
(3) Othman AA and Abdelazim MS. Ventilatorassociated pneumonia in adult intensive care unit
prevalence and complications. Egypt. J. Crit. Care
Med. (2017) 5: 61-3.
(4) Chung DR, Song JH, Kim SH, Thamlikitkul V, Huang
SG, Wang H, So TM, Yasin RM, Hsueh PR, Carlos
CC, Hsu LY, Buntaran L, Lalitha MK, Kim MJ, Choi
JY, Kim SI, Ko KS, Kang CI and Peck KR. High
prevalence of multidrug-resistant nonfermenters in
hospital-acquired pneumonia in Asia. Am. J. Respir.
Crit. Care Med. (2011) 184: 1409-17.
(5) da Silveira F, Nedel WL, Cassol R, Pereira PR,
Deutschendorf C and Lisboa T. Acinetobacter
etiology respiratory tract infections associated
with mechanical ventilation: what impacts on the
prognosis? A retrospective cohort study. J. Crit.
Care (2019) 49: 124-8.
(6) Djordjevic ZM, Folic MM and Jankovic SM.
Distribution and antibiotic susceptibility of
pathogens isolated from adults with hospitalacquired and ventilator-associated pneumonia in
intensive care unit. J. Infect. Public Heal. (2017) 10:
740-4.
(7) Garnacho-Montero J and Timsit JF. Managing
Acinetobacter baumannii infections. Curr. Opin.
Infect. Dis. (2019) 32: 69-76.
(8) Bailey KL and Kalil AC. Ventilator-associated
pneumonia (VAP) with multidrug-resistant (MDR)
pathogens: optimal treatment? Curr. Infect. Dis. Rep.
(2015) 17: 494.
(9) Jung SY, Lee SH, Lee SY, Yang S, Noh H, Chung
EK and Lee JI. Antimicrobials for the treatment of
drug-resistant Acinetobacter baumannii pneumonia
in critically ill patients: a systemic review and
Bayesian network meta-analysis. Crit. Care (2017)
21: 319.
(10) Lu Q, Girardi C, Zhang M, Bouhemad B, Louchahi
K, Petitjean O, Wallet F, Becquemin MH, Le Naour
G, Marquette CH and Rouby JJ. Nebulized and
intravenous colistin in experimental pneumonia
caused by Pseudomonas aeruginosa. Intensive
Care Med. (2010) 36: 1147-55.
(11) Mendelman PM, Smith AL, Levy J, Weber
A, Ramsey B and Davis RL. Aminoglycoside
penetration, inactivation, and efficacy in cystic
fibrosis sputum. Am. Rev. Respir. Dis. (1985) 132:
761-5.
(12) Ehrmann S, Chastre J, Diot P and Lu Q. Nebulized
antibiotics in mechanically ventilated patients:
a challenge for translational research from
technology to clinical care. Ann. Intensive Care.
(2017) 7: 78.
(13) Jeong IB, Na MJ, Son JW, Jo DY and Kwon SJ.
High-dose sulbactam treatment for ventilatorassociated pneumonia caused by carbapenemresistant Acinetobacter baumannii. Korean J. Crit.
Care Med. (2016) 31: 308-16.
(14) Mosaed R, Haghighi M, Kouchek M, Miri MM,
Salarian S, Shojaei S, Javadi A, Taheri S, Nazirzadeh
P, Foroumand M and Sistanizad M. Interim study:
Comparison of safety and efficacy of Levofloxacin
plus Colistin regimen with Levofloxacin plus high
dose Ampicillin/Sulbactam infusion in treatment of
Ventilator-Associated Pneumonia due to multi drug
resistant Acinetobacte. Iran. J. Pharm. Res. (2018)
17: 206-13.
(15) Jang JY, Kwon HY, Choi EH, Lee WY, Shim H
and Bae KS. Efficacy and toxicity of high-dose
nebulized colistin for critically ill surgical patients
with ventilator-associated pneumonia caused by 
280
Pourheidar E et al. / IJPR (2019), 18 (Special Issue): 269-281
multidrug-resistant Acinetobacter baumannii. J.
Crit. Care (2017) 40: 251-6.
(16) Rouby JJ, Bouhemad B, Monsel A, Brisson H,
Arbelot C, Lu Q and Nebulized Antibiotics Study
Group. Aerosolized antibiotics for ventilatorassociated pneumonialessons from experimental
studies. Anesthesiology (2012) 117: 1364-80.
(17) Kalil AC, Metersky ML, Klompas M, Muscedere
J, Sweeney DA, Palmer LB, Napolitano LM,
O’Grady NP, Bartlett JG, Carratala J, El Solh
AA, Ewig S, Fey PD, File TM Jr, Restrepo MI,
Roberts JA, Waterer GW, Cruse P, Knight SL and
Brozek JL. Management of adults with hospitalacquired and ventilator-associated pneumonia:
2016 clinical practice guidelines by the infectious
diseases society of America and the American
thoracic society. Clin. Infect. Dis. (2016) 63:
e61-e111.
(18) Dulhunty JM, Roberts JA, Davis JS, Webb SA,
Bellomo R, Gomersall C, Shirwadkar C, Eastwood
GM, Myburgh J, Paterson DL and Lipman J.
Continuous infusion of beta-lactam antibiotics
in severe sepsis: a multicenter double-blind,
randomized controlled trial. Clin. Infect. Dis.
(2013) 56: 236-44.
(19) Falagas ME, Tansarli GS, Ikawa K and Vardakas
KZ. Clinical outcomes with extended or
continuous versus short-term intravenous infusion
of carbapenems and piperacillin/tazobactam: a
systematic review and meta-analysis. Clin. Infect.
Dis. (2013) 56: 272-82.
(20) Makris D, Petinaki E, Tsolaki V, Manoulakas E,
Mantzarlis K, Apostolopoulou O, Sfyras D and
Zakynthinos E. Colistin versus colistin combined
with ampicillin-sulbactam for multiresistant
Acinetobacter baumannii ventilator-associated
pneumonia treatment: an open-label prospective
study. Indian J. Crit. Care Med. (2018) 22: 67-77.
(21) Zalts R, Neuberger A, Hussein K, Raz-Pasteur A,
Geffen Y, Mashiach T and Finkelstein R. Treatment
of carbapenem-resistant Acinetobacter baumannii
ventilator-associated pneumonia: retrospective
comparison between intravenous colistin and
intravenous ampicillin-sulbactam. Am. J. Ther.
(2016) 23: e78-85.
(22) Falagas ME and Karageorgopoulos DE. Pandrug
resistance (PDR), extensive drug resistance
(XDR), and multidrug resistance (MDR) among
Gram-negative bacilli: need for international
harmonization in terminology. Clin. Infect. Dis.
(2008) 46: 1121-2.
(23) Wisplinghoff H, Paulus T, Lugenheim M, Stefanik
D, Higgins PG, Edmond MB, Wenzel RP and
Seifert H. Nosocomial bloodstream infections due
to Acinetobacter baumannii, acinetobacter pittii
and Acinetobacter nosocomialis in the United
States. J. Infect. (2012) 64: 282-90.
(24) Song JH and Group AHW. Treatment
recommendations of hospital-acquired pneumonia
in Asian countries: first consensus report by the
Asian HAP Working Group. Am. J. Infect. Control
(2008) 36: S83-S92.
(25) Betrosian AP, Frantzeskaki F, Xanthaki A and
Douzinas EE. Efficacy and safety of high-dose
ampicillin/sulbactam vs. colistin as monotherapy
for the treatment of multidrug resistant
Acinetobacter baumannii ventilator-associated
pneumonia. J. Infect. (2008) 56: 432-6.
(26) Betrosian AP, Frantzeskaki F, Xanthaki A and
Georgiadis G. High-dose ampicillin-sulbactam as
an alternative treatment of late-onset VAP from
multidrug-resistant Acinetobacter baumannii.
Scand. J. Infect. Dis. (2007) 39: 38-43.
(27) Valcke YJ, Rosseel MT, Pauwels RA, Bogaert
MG and Van der Straeten ME. Penetration of
ampicillin and sulbactam in the lower airways
during respiratory infections. Antimicrob. Agents
Chemother. (1990) 34: 958-62.
(28) Wildfeuer A, Ruhle KH, Bolcskei PL and
Springsklee M. Concentrations of ampicillin and
sulbactam in serum and in various compartments
of the respiratory tract of patients. Infection (1994)
22: 149-51.
(29) Khalili H, Shojaei L, Mohammadi M,
Beigmohammadi MT, Abdollahi A and Doomanlou
M. Meropenem/colistin versus meropenem/
ampicillin-sulbactam in the treatment of
carbapenem-resistant pneumonia. J. Comp. Eff.
Res. (2018) 7: 901-11.
(30) Ferrari F, Lu Q, Girardi C, Petitjean O, Marquette
CH, Wallet F and Rouby JJ. Nebulized ceftazidime
in experimental pneumonia caused by partially
resistant Pseudomonas aeruginosa. Intensive Care
Med. (2009) 35: 1792-800.
(31) Wood GC and Swanson JM. Aerosolised
antibacterials for the prevention and treatment of
hospital-acquired pneumonia. Drugs (2007) 67:
903-14.
(32) Markou N, Fousteri M, Markantonis SL,
Boutzouka E, Tsigou E and Baltopoulo G. Colistin
penetration in the alveolar lining fluid of critically
ill patients treated with IV colistimethate sodium.
Chest (2011) 139: 232-3.
(33) Markou N, Markantonis SL, Dimitrakis E,
Panidis D, Boutzouka E, Karatzas S, Rafailidis P,
Apostolakos H and Baltopoulos G. Colistin serum
concentrations after intravenous administration
in critically ill patients with serious multidrug-
281
Treatment of VAP Caused by MDR Acinetobacter
resistant, gram-negative bacilli infections: a
prospective, open-label, uncontrolled study. Clin.
Ther. (2008) 30: 143-51.
(34) Wood GC and Boucher BA. Aerosolized
antimicrobial therapy in acutely ill patients.
Pharmacotherapy (2000) 20: 166-81.
(35) Burdette SD, Limkemann AJ, Slaughter JB, Beam
WB and Markert RJ. Serum concentrations of
aerosolized tobramycin in medical, surgical, and
trauma patients. Antimicrob. Agents Chemother.
(2009) 53: 4568.
(36) Cikman A, Ceylan MR, Parlak M, Karahocagil MK
and Berktas M. [Evaluation of colistin-ampicillin/
sulbactam combination efficacy in imipenemresistant Acinetobacter baumannii strains].
Mikrobiyol. Bul. (2013) 47: 147-51.
(37) Kalin G, Alp E, Akin A, Coskun R and Doganay M.
Comparison of colistin and colistin/sulbactam for
the treatment of multidrug resistant Acinetobacter
baumannii ventilator-associated pneumonia.
Infection (2014) 42: 37-42.
(38) Pongpech P, Amornnopparattanakul S, Panapakdee
S, Fungwithaya S, Nannha P, Dhiraputra C
and Leelarasamee A. Antibacterial activity
of carbapenem-based combinations againts
multidrug-resistant Acinetobacter baumannii. J.
Med. Assoc. Thai. (2011) 93: 161.
(39) Kempf M, Djouhri-Bouktab L, Brunel JM, Raoult
D and Rolain JM. Synergistic activity of sulbactam
combined with colistin against colistin-resistant
Acinetobacter baumannii. Int. J. Antimicrob.
Agents (2012) 39: 180-1.