High resistance of Pseudomonas aeruginosa to paromomycin, an agent used for selective bowel decontamination (SBD)

dgkh000204 10.3205/dgkh000204 urn:nbn:de:0183-dgkh0002040 Research Article High resistance of Pseudomonas aeruginosa to paromomycin, an agent used for selective bowel decontamination (SBD) Hohe Resistenz von Pseudomonas aeruginosa gegenüber Paromomycin, einem Wirkstoff für die selektive Darm-Dekontamination (SDD) Daxboeck Daxboeck Florian F

Clinical Institute for Hospital Hygiene, Medical University of Vienna, Austria

author Rabitsch Rabitsch Werner W

Department of Internal Medicine I, Bone Marrow Transplantation Unit, Medical University of Vienna, Austria

author Stadler Stadler Maria M

Clinical Institute for Hospital Hygiene, Medical University of Vienna, Austria

author Assadian Assadian Ojan O Univ.-Prof. Dr. DTMH

Clinical Institute for Hospital Hygiene, Medical University of Vienna, Vienna General Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Austria, Phone.: +43-1-40400-1904, Fax: +43-1-40400-1907Clinical Institute for Hospital Hygiene, Medical University of Vienna, Austria

ojan.assadian@meduniwien.ac.a author Leitgeb Leitgeb Johannes J

Department of Trauma-Surgery, Medical University of Vienna, Austria

author German Medical Science GMS Publishing House

Düsseldorf

610 paromomycin P. aeruginosa E. coli minimal inhibitory concentration (MIC) selective bowel decontamination (SBD) Paromomycin P. aeruginosa E. coli Minimale Hemmkonzentration (MHK) Selektive Darm-Dekontamination (SDD) 2013042920130710 engl 2196-5226 8 1 GMS Hygiene and Infection Control GMS Hyg Infect Control 04 20130710The ISSN has been corrected. Hintergrund: Paromomycin wird in zahlreichen Zentren bei Patienten, die vor einer Knochenmarktransplantation stehen, zur selektiven Darmdekontamination (SDD) eingesetzt. Dennoch findet sich in der Literatur keine Angaben der Resistenzlage Gram-negativer Bakterien gegenüber diesem Aminoglykosid-Antibiotikum. Ziel der vorliegenden Untersuchung war es, die In-vitro-Aktivität von Paromomycin gegen die typisch im Dickdarm habitierende Bakterien E. coli und P. aeruginosa zu bestimmen.Methoden: 94 E. coli-Isolate und 77 P. aeruginosa-Isolate, welche aus klinischem Probenmaterial isoliert wurden, wurden mittels Mikrodilutionsverfahren gegenüber Paromomycin und Amikacin getestet. Es wurden die CLSI Empfehlungen für Amikacin herangezogen. Ergebnisse: 86 von 94 E. coli-Isolaten (91%) und 71 von 77 P. aeruginosa-Isolaten (92%) zeigten In-vitro-Empfindlichkeit gegenüber Amikacin (MIC90 für beide Antibiotika: 16 µg/ml, range: 1–32 µg/ml für E. coli und 1–>128 µg/ml für P. aeruginosa). Paromomycin war aktiv gegenüber 83/94 E. coli-Isolaten (88%; MIC90: 32 µg/ml, range: 2–>128 µg/ml), zeigte aber schwache In-vitro-Wirksamkeit gegenüber P. aeruginosa (3/77 Isolate empfindlich [4%]; MIC90: >128 µg/ml, range: 2–>128 µg/ml).</PlainText></TextGroup></Pgraph><Pgraph><Mark1>Schlussfolgerung:</Mark1> Sollte eine SDD routinemäßig mit Einschluss eines Aminoglykosid Antibiotikums durchgeführt werden, sollte Paromomycin nicht eingesetzt warden, außer bei Vorliegen lokaler Resistenzkenntnis für die In-vitro-Effektivität von Paromomycin gegenüber <Mark2>P. aeruginosa</Mark2>.</Pgraph></Abstract> <Abstract language="en" linked="yes"><Pgraph><Mark1>Background:</Mark1> Paromomycin is used for selective bowel decontamination (SBD) in patients undergoing bone marrow transplantation in many hospitals, but there are no published resistance data for this compound in the recent medical literature. The aim of this study was to investigate the in vitro activity of paromomycin against the common intestinal bacteria <Mark2>E. coli</Mark2> and <Mark2>P. aeruginosa</Mark2>.</Pgraph><Pgraph><Mark1>Methods: </Mark1>94 <Mark2>E. coli</Mark2> isolates and 77 <Mark2>P. aeruginosa</Mark2> isolates derived from clinical specimens were tested by broth microdilution against paromomycin and amikacin, respectively, following the CLSI recommendations for testing amikacin.</Pgraph><Pgraph><Mark1>Results: </Mark1>86 of 94 <Mark2>E. coli</Mark2> isolates (91%) and 71 of 77 <Mark2>P. aeruginosa</Mark2> isolates (92%) showed in vitro susceptibility to amikacin (MIC90 for both compounds: 16 µg/ml, range: 1–32 µg/ml for <Mark2>E. coli</Mark2> and <TextGroup><PlainText>1–>128 µg/ml</PlainText></TextGroup> for<Mark2> P. aeruginosa</Mark2>). Paromomycin was active against 83/94 <Mark2>E. coli</Mark2> isolates (88%; MIC90: 32 µg/ml, range: 2–>128 µg/ml), but showed poor in vitro activity against <Mark2>P. aeruginosa</Mark2> (3/77 isolates susceptible [4%]; MIC90: >128 µg/ml, range: 2–>128 µg/ml).</Pgraph><Pgraph><Mark1>Conclusion:</Mark1> If SBD with inclusion of an aminoglycoside antibiotic is applied, paromomycin should not be used unless local resistance data provide evidence of a sufficient in vitro activity of this compound against <Mark2>P. aeruginosa</Mark2>.</Pgraph></Abstract> <TextBlock linked="yes" name="Introduction"> <MainHeadline>Introduction</MainHeadline><Pgraph>Infections remain a major cause of morbidity and mortality in neutropenic patients. Although recent data on the routes of infection are inconsistent, it is assumed that the majority of bacterial infections is caused by endogenous organisms or acquired Gram-negative bacteria which colonize the gastrointestinal tract <TextLink reference="1"></TextLink>. Therefore, prophylactic selective bowel decontamination (SBD) using non-absorbable antibacterial and antifungal agents is applied in patients undergoing bone marrow transplantation in some hospitals, although the value of this measure is controversial <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>. Like other aminoglycoside compounds, paromomycin (aminosidine) is poorly absorbed from the gastrointestinal tract <TextLink reference="4"></TextLink>. This compound is in use for SBD in some centers <TextLink reference="2"></TextLink>, <TextLink reference="5"></TextLink>, <TextLink reference="6"></TextLink>.</Pgraph><Pgraph>However, in vitro resistance data for paromomycin are lacking. Previously, we have published the observation that bacteremia with enterobacteriaceae is observed less frequently in neutropenic patients with previous SBD <TextGroup><PlainText>using</PlainText></TextGroup> paromomycin, whereas there is no difference with regard to bacteremia with non-fermenting Gram-negative bacilli <TextLink reference="6"></TextLink>. In this context, the aim of the present study was to investigate the in vitro activity of paromomycin against <Mark2>E. coli</Mark2> and <Mark2>P. aeruginosa</Mark2>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Material and methods"> <MainHeadline>Material and methods</MainHeadline><Pgraph><Mark2>E. coli </Mark2>isolates (n=94) were obtained from stool/rectal swabs (n=69), urine (n=10), respiratory tract (n=9), blood (n=4), and wound swabs (n=2). <Mark2>P. aeruginosa</Mark2> isolates (n=77) were derived from stool/rectal swabs (n=5), respiratory tract (n=6), blood (n=60), and wound swabs (n=6). Identification was performed with API™ 20E (BioMérieux, Marcy L’Etoile, France) for <Mark2>E. coli</Mark2>, and with culture on cetrimide agar plates (Pseudosal™; Becton Dickinson, Heidelberg, Germany) and inspection under UV-light combined with API™ 20NE (BioMérieux) for <Mark2>P. aeruginosa.</Mark2></Pgraph><Pgraph>Amikacin and paromomycin were purchased from Sigma Aldrich (Steinheim, Germany). The MICs for both compounds were determined according to the recommendations of the Clinical Laboratory Standards International (CLSI) for testing amikacin <TextLink reference="7"></TextLink>. Isolates with an MIC of ≤16 µg/ml were considered susceptible. The ATCC reference strains 25922 (<Mark2>E. coli</Mark2>) and 9027 (<Mark2>P. aeruginosa</Mark2>) were used for quality control.</Pgraph></TextBlock> <TextBlock linked="yes" name="Results"> <MainHeadline>Results</MainHeadline><Pgraph>The MICs for paromomycin and amikacin against <Mark2>E. coli</Mark2> and <Mark2>P. aeruginosa</Mark2>, respectively, are shown in Table 1 <ImgLink imgNo="1" imgType="table"/>.</Pgraph><Pgraph>Briefly, 86 of 94 <Mark2>E. coli</Mark2> isolates (91%) and 71 of 77 <Mark2>P. aeruginosa</Mark2> isolates (92%) showed in vitro susceptibility to amikacin (MIC90 for both compounds: 16 µg/ml, range: 1–32 µg/ml for<Mark2> E. coli</Mark2> and 1–>128 µg/ml for<Mark2> P. aeruginosa</Mark2>). Paromomycin was active against 83/94 <Mark2>E. coli</Mark2> isolates (88%; MIC90: 32 µg/ml, range: 2–>128 µg/ml), but showed poor in vitro activity against <Mark2>P. aeruginosa</Mark2> (3/77 isolates susceptible [4%]; MIC90: >128 µg/ml, range: 2–>128 µg/ml).</Pgraph></TextBlock> <TextBlock linked="yes" name="Discussion"> <MainHeadline>Discussion</MainHeadline><Pgraph>Paromomycin, which was first isolated in 1956, is a member of the aminoglycoside family. The agent inhibits protein synthesis and the assembly of the 30S ribosomal subunit <TextLink reference="8"></TextLink>. Paromomycin is indicated for the treatment of <Mark2>Entamoeba histolytica</Mark2> and <Mark2>Trichomonas</Mark2> spp. infections, and has been proposed as a treatment for <Mark2>Giardia lamblia</Mark2> in resistant infections and during pregnancy <TextLink reference="9"></TextLink>. Furthermore, it is used for prophylaxis of hepatic encephalopathy in patients with liver cirrhosis. Paromomycin is also used for SBD in patients undergoing bone marrow transplantation in some centers <TextLink reference="2"></TextLink>, <TextLink reference="5"></TextLink>, <TextLink reference="6"></TextLink>. In addition, paromomycin is frequently recommended for the use in SBD by non-peer reviewed media, at least in the German-speaking countries. Amikacin resistance in <Mark2>E. coli</Mark2> and <TextGroup><Mark2>P. aeruginosa</Mark2></TextGroup> was found to be in agreement with previously published data in the present study is. An analysis of more than 4,000 clinical isolates from patients with bloodstream infections in the United States revealed that 98.5% of <Mark2>E. coli</Mark2> isolates and 98.4% of <Mark2>P. aeruginosa</Mark2> isolates were susceptible to this agent <TextLink reference="10"></TextLink>. 94.4% of <TextGroup><Mark2>P. aeruginosa</Mark2></TextGroup> blood culture isolates in Vienna University Hospital are susceptible to amikacin <TextLink reference="11"></TextLink>.</Pgraph><Pgraph>Due to the lack of published in vitro resistance data for paromomycin, no trend in paromomycin resistance can be deduced from the present results. In addition, it is unknown which mechanisms lead to clinically relevant resistance against paromomycin. Generally, bacterial resistance to aminoglycosides may be due to decreased antibiotic uptake and accumulation, modification of the ribosomal target, and efflux of the antibiotic, but the enzymatic modification of aminoglycosides is thought to be the most important mechanism of aminoglycoside resistance in clinical isolates <TextLink reference="12"></TextLink>. Three families of enzymes that perform cofactor-dependent drug modification in the bacterial cytoplasm have been recognized; these are aminoglycoside phosphotransferases (APHs), aminoglycoside acetyltransferases (AACs), and aminoglycoside nucleotidyltransferases (ANTs). Some enzymes (i.e. APH(3')-I, APH(3')-III, and AAC(1)) have been shown to produce paromomycin resistance, while they are not implicated in amikacin resistance <TextLink reference="12"></TextLink>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Conclusions"> <MainHeadline>Conclusions</MainHeadline><Pgraph>In conclusion, if SBD with inclusion of an aminoglycoside antibiotic is applied, paromomycin should not be used unless local resistance data provide evidence of a sufficient in vitro activity of this compound against <Mark2>P. aeruginosa</Mark2>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Notes"> <MainHeadline>Notes</MainHeadline><SubHeadline>Competing interests</SubHeadline><Pgraph>The authors declare that they have no competing interests.</Pgraph></TextBlock> <References linked="yes"> <Reference refNo="1"> <RefAuthor>Schimpff SC</RefAuthor> <RefAuthor>Young VM</RefAuthor> <RefAuthor>Greene WH</RefAuthor> <RefAuthor>Vermeulen GD</RefAuthor> <RefAuthor>Moody MR</RefAuthor> <RefAuthor>Wiernik PH</RefAuthor> <RefTitle>Origin of infection in acute nonlymphocytic leukemia. 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DOI: 10.1128/CMR.16.3.430-450.2003</RefTotal> <RefLink>http://dx.doi.org/10.1128/CMR.16.3.430-450.2003</RefLink> </Reference> </References> <Media> <Tables> <Table format="png"> <MediaNo>1</MediaNo> <MediaID>1</MediaID> <Caption><Pgraph><Mark1>Table 1: Activities of amikacin and paromomycin tested against </Mark1><Mark1><Mark2>E. coli</Mark2></Mark1><Mark1> and </Mark1><Mark1><Mark2>P. aeruginosa</Mark2></Mark1></Pgraph></Caption> </Table> <NoOfTables>1</NoOfTables> </Tables> <Figures> <NoOfPictures>0</NoOfPictures> </Figures> <InlineFigures> <NoOfPictures>0</NoOfPictures> </InlineFigures> <Attachments> <NoOfAttachments>0</NoOfAttachments> </Attachments> </Media> </OrigData> </GmsArticle>