Infección asociada a implante por Pseudomonas aeruginosa

Infección asociada a implante por

Pseudomonas aeruginosa

Ateneo

Asistente. Dra Tenaglia

Prof Adjunto Dr Henry Albornoz

Caso 1

59 años.

AP: tabaquista. Hepatopatía OH. PTC (prótesis cadera) derecha 30/08/16, PTC izquierda 02/17.

07/18: ingresa por signos fluxivos y fístula a nivel de cadera derecha.

Planteo de infección protésica tardía, tratamiento médico-quirúrgico.

02/08 Limpieza quirúrgica: pus, tallo, cotilo y cemento flojo. Retiran el cotilo y tallo, colocan cotilo de cemento y tallo nuevo.

Cultivo intraoperatorio: 4 de 4 muestras (+) P. Aeruginosa. (S) CAZ, IMI,

TZP), (R) AMK, CIP, GEN.

Plan ATB: ceftazidime y colistin, se rota a ceftazidime por falla renal

completando 4 semanas. Alta v/o ciprofloxacina 500 mg c/8 +rifampicina 300 mg c/8 por 1 mes, seguido de ciprofloxacina vo.

2º ingreso 03/19: luxación PTC dcha, sin actividad infecciosa PCR (-).

Reducción en block: retiran cotilo colocan nuevo cementado con vancomicina y

gentamicina, se mantiene tallo. Cultivo profundo (-). Tratamiento supresivo

con ciprofloxacina.

3º ingreso 05/19: dolor y fístula sobre cicatriz Q. Planteo diagnóstico infección

protésica tardía. Cultivo de trayecto fistuloso (+) P. aeruginosa. (S) CAZ, IMI,

MEM, TZP (R) AMK, CIP, GEN. Equipo quirúrgico tratante decide tratamiento

medico. Se inicia ATB parenteral prolongado: colistin + ceftazidime 6 semanas.

Actualmente control ambulatorio bajo plan supresivo con ciprofloxacina vo.

Diagnóstico: Infección peri-protésica crónica a P. aeruginosa MR, tratada con

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Caso 2

65 años.

AP. tabaquista. OH en abstinencia. Prótesis de cadera derecha 06/2016. Fractura peri prótesis 10/2016- estabilizada con osteosíntesis con placa.

07/2017: ingresa por dolor, impotencia funcional y fístula en cadera derecha.

Planteo diagnóstico infección de osteosíntesis y peri-protésica. Tratamiento médico-quirúrgico. LQ: pus al abrir la cápsula, retiran el material de OS y los componentes articulares (tallo y cotilo). Recambio en 1 tiempo.

Cultivo profundo: P aeruginosa (S) CAZ, MEM, IMI, PTZ , (R) CIP, GEN,

02/18: Punción articular ambulatoria de cadera cultivo (-).

08/18: retiro de PTC dcha. por dolor crónico y limitación funcional. LQ: colección supurada y membranas, retiran el tallo, cotilo.

Cultivo profundo: P. aeruginosa (S) CAZ, IMI, MEM, PTZ, (R) CIP, AMK, CIP, GEN.

Plan ATB: colistin+ ceftazidime 4 d, luego ceftazidime 3 semanas.

Alta con ciprofloxacina 500 mg vo c/8 hs+ rifampicina 300 mg vo c/8 hs por 1 mes, luego ciprofloxacina 500 mg vo c/8 hs.

Actualmente deambula con apoyo, sin dolor, sitio quirúrgico sin elementos inflamatorios y RFA (-)

Diagnóstico: Infección peri-protésica crónica a P. aeruginosa MR, tratada con retiro del implante.

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Preguntas

1. ¿Qué conducta tomar frente a un paciente con una infección crónica

asociada a implante por P. aeruginosa MR, cuando no es posible el retiro del implante y carecemos de opción de tratamiento vía oral?

2. En cuanto a la MIC a antimicrobianos, ¿el resultado obtenido en

condiciones controladas en el laboratorio es la misma que dentro del biofilm o intracelular?

3. ¿P. aeruginosa selecciona poblaciones resistentes durante su tratamiento? 4. ¿Opciones para consolidar el plan con antimicrobiano vo?

5. ¿La ciprofloxacina tiene algún lugar?

6. ¿Que rol tiene la asociación de antimicrobianos inmunomoduladores y acción intracelular?

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Ferry T, et al. The CRIOAc healthcare network in France: A nationwide Health Ministry program to improve the management of bone and joint infection. Orthop Traumatol Surg Res (2018)

Evolución anual del número de implantes articulares

Uruguay 2000-2017

0 1000 2000 3000 4000 5000

2000 2002 2004 2006 2008 2010 2012 2014 2016

Cad. Artrosis Cad. Fractura Cad. Revisión

Rodilla Rodilla Revisión Total Implantes

Etiología

• Los microorganismos más frecuentemente son cocos gram (+) en

55-60% (ECN, Staphylococcus aureus y Enterococcus sp.).

• BGN representan 10-30% (aumentando principalmente MR).

• Las infecciones causadas por P. aeruginosa representan el 5-20%

de los BGN y preocupan por las escasas opciones de tratamiento disponible.

• Anaerobios y hongos representan <1%.

Clasificación Tsukayama

Infección protésica precoz: ocurre dentro del primer mes del implante.

Infección crónica: pasado el primer mes.

Infección hematógena: cualquier período de tiempo, inicia en forma aguda y en presencia de un foco de origen a distancia.

Cultivos intra-operatorios positivos: cultivos (+) obtenidos de un recambio aséptico.

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Diagnóstico

Sección 2

365

2.1. DIAGNÓSTICO: DEFINICIONES

Autores:Noam Shohat, Thomas Bauer, Martin Buttaro, Nicolaas Budhiparama, James Cashman, Craig J. Della Valle, Lorenzo Drago, Thorsten Gehrke, Luiz S. Marcelino Gomes, Karan Goswami, Nils P. Hailer, Seung Beom Han, Carlos Higuera, Yutaka Inaba, Jean≠Y ves Jenny, Per Kjaersgaard≠A ndersen, Mel Lee, Adolfo Llin·s , Alex Mclaren, Konstantinos Malizos, Michael A. Mont, Rhidian Morgan Jones, Javad Parvizi, Patricia Peel, Salvador Rivero≠Bos chert, Carlo Romano, John Segreti, Alex Soriano, Ricardo Sousa, Mark Spanghel, Timothy L. Tan, Rashid Tikilov, Ibrahim Tuncay, Heinz Winkler, Eivind Witso, Marjan Wouthuyzen≠B akker, Simon Young, Xianlong Zhang, Yixin Zhou, Wer Zimmerli

PREGUNTA 1: ø Cu· l es la de niciÛ n de infecciÛ n en la articulaciÛ n periprotÈ sica (IAP) de rodilla y

cadera? ø Se pueden utilizar los mismos criterios para ambas articulaciones?

RECOMENDACIÓN:Consulte la Tabla 1, criterios propuestos para la ReuniÛ n de Consenso Internacional (ICM) de 2018 para IAP.

TABLA 1. Criterios de ICM propuestos para 2018 para IAP

Criterios mayores (al menos uno de los siguientes) Decisión

Dos crecimientos positivos del mismo organismo utilizando mÈ todos de cultivo est· ndar.

Infectado Tracto stuloso con evidencia de comunicaciÛ n a la articulaciÛ n o visualizaciÛ n de la prÛ tesis.

Criterios menores Tiempo de evolución Puntuación Decisión

Agudo1 _Crónico

PCR sÈ rica (mg/L) o

DÌ mero D (ug/L)

100 desconocido 10 860 2 PuntuaciÛ n combinada preoperatoria y postoperatoria:

≥ 6 infectado

3 a 5 no concluyente* < 3 no infectado

VSG elevada (mm/h) No relevante 30 1

Contaje leucocitario sinovial elevado o

Esterasa leucocitaria o

Alfa≠ defensina positiva (seÒ al/limite de corte)

10.000 ++ 1,0 3.000 ++ 1,0 3

PMN sinoviales elevados (%) 90 70 2

1 cultivo positivo 2

HistologÌ a positiva 3

Purulencia intraoperatoria positiva2 ₃

1 _{Este criterio nunca fue validado en infecciones agudas.} 2 _{No juega ning˙n papel en la sospecha de reacciÛn adversa local al tejido.}

* Considere otros diagnÛs ticos moleculares tales como la secuenciaciÛn nueva generaciÛn .

NIVEL DE EVIDENCIA:Moderado

VOTO DEL DELEGADO: De acuerdo: 68%; en desacuerdo: 28%; abstenciÛ n: 4% (supermayorÌa, co nsenso dÈ bil).

JUSTIFICACIÓN

La introducciÛ n de los criterios de la Sociedad de InfecciÛ n Muscu≠ loesquelÈ tica (MSIS) para IAP en 2011, que luego fue modi cada por la ICM de 2013, dio como resultado relevantes mejoras en la con a≠

bilidad del diagnÛ stico y su colaboraciÛ n en las investigaciones [1]. En los ˙ ltimos aÒ os, se han evaluado numerosos marcadores sÈ ri≠ cos y sinoviales que se encuentran ampliamente disponibles [2≠ 14]. /"&.%%)#,+' &0($1% 2,$%",*$#&,*3(!&,'%,'4' 5%%$#,+(&, /%"#6"&'$1%$#. 7&#,$ 2,0%.$#&,8(9:;<(

Tratamiento de Infección protésica

Limpieza quirúrgica

Antimicrobianos Retiro del

implante

Infección hematógena

Si Si No

Infección aguda

Si Si No

Infección crónica

Si Si Si

CIOPP No Si No

Tratamiento

Médico-quirúrgico.

Estrategia debe considerar:

1. Huésped: comorbilidad, accesos vasculares, disponibilidad de antibióticos.

2. Microorganismo: patrón de sensibilidad.

3. Fármaco dinamia y cinética de la molécula a usar. 4. Biofilm: relación con el microorganismo responsable. 5. Tolerancia a los ATB dentro del biofilm.

6. Resistencia y heterorresistencia dentro del biofilm. 7. Variantes de colonias pequeñas.

Biofilm

• Es el agregado de células microbianas embebidas en una matriz de polímeros, que son adherentes entre si y/o a una superficie natural o artificial. Es un complejo ecosistema.

• El 10-20% de la estructura son bacterias, el resto es matriz de

gluco-polisacáridos y agua. En su interior viven poblaciones

bacterianas: fase estacionaria, formas persistentes.

740 Current Protein and Peptide Science, 2012, Vol. 13, No. 8 Garnett and Matthews

gies and materials. In this review we will be concentrating on the architectural protein components of these bacterial accre-tions and how they mediate persistent host-pathogen interac-tions. We will then give a brief discussion of therapeutic targets with the aim of dismantling and/or removing prob-lematic biofilms.

2. INITIAL SURFACE ADHESION

The initial attachment of prokaryotes to abiotic and bio-logical surfaces is by far the most understood process of biofilm development. The bacterial surface is decorated with an arsenal of diverse and often multifunctional macromole-cules. Adhesive structures are projected away from the cell surface with sufficient distance to sample the surrounding environment and recognize appropriate interactions. At the time of this review, a search of the protein data bank (PDB: www.pdb.org) revealed 140 ‘adhesin’ structures from bacte-ria, many of which are unique proteins. In this section a number of different fibres from a range of bacteria will be discussed, although the focus will be on those structures that contribute to a well-defined understanding of surface at-tachment. For example, whilst type IV pili (T4P) are very important factors leading to surface attachment in many bac-teria, no receptor complexes are available and so they will not be discussed here. In addition, although the chaperone-usher (CU) assembled type I and P pili are important lectins from Escherichia coli, a wealth of both structural and bio-chemical information has already been amassed and a num-ber of excellent articles and reviews are already available [18-22], so again these will not be described.

2.1. MSCRAMMs

Staphylococcus aureus is a regular commensal of the skin and anterior nares of animals and humans [23]. Whilst harmless in these environments, S. aureus may become a dangerous pathogen if it crosses the epithelial barrier where it can infect almost any organ and cause abscesses, pneumo-nia, endocarditis, sepsis and infections associated with medi-cal implants [24]. A number of surface components of S. aureus have been implicated in biofilm formation. The exopolysaccharide biofilm matrix is composed of a polymer of poly-N-acetyl- -(1-6)-glucosamine, termed polysaccha-ride intercellular adhesin (PIA) or poly-N-acetylglucosamine (PNAG) and mediates intercellular adhesion events [25,26].

S. aureus biofilms can also form independently of PIA and the composition of this proteinaceous matrix includes SasG [27], Protein A (Spa) [28,29], fibronectin binding proteins (FnBPs) [30,31] and biofilm associated protein (Bap) [32]. SasG can bind desquamated nasal epithelial cells [31] and promotes inter-bacterial aggregation [33]. Spa binds immu-noglobulin’s which enables S. aureus to evade in-nate/adaptive immune responses [34] and can promote mul-ticellular adherence [28]. FnBPs have been shown to mediate intercellular biofilm interactions [30] [31], recognize fi-bronectin and fibrinogen [35,36] and can also promote the invasion of epithelial cells [37]. Bap is involved in the initial attachment to inert surfaces/interbacterial interactions [32] and also prevents cellular internalization of S. aureus

through binding the GP96 host receptor, which interferes with the FnBP mediated invasion pathway [38].

Fig. (1). Schematic representation of the biofilm life cycle. (1) Free swimming bacteria (2) adhere to a surface using cell surface displayed

adhesin molecules. (3) Bacteria begin to divide and the expression of further macromolecules allows them to stick together in small micro-colonies. (4) As these colonies grow they begin to secrete a complex mixture of carbohydrates, protein and lipids that encapsulates the bacte-ria. This biofilm matrix (fuzzy outline) provides protection and stability for the maturing biofilm. (5) When the biofilm reaches maturity, a number of factors will have developed a heterogeneous arrangement of cells and molecules within the biofilm, and given rise to solvent filled cavities and channels. This can lead to dispersal of cells from the cellular mass. (6) Upon signal from the environment (waste build up or demand for nutrients, for example), molecules are released that cause cell lysis and matrix dissemination. Many planktonic cells are now released and can find a new habitat.

Biofilm y quorum sensing:

los microorganismos cambian su

estilo de vida censando las condiciones ambientales, señales

químicas (nutrientes, oxigeno, ATB, etc) y eléctricas

expresando genes que modifican su fenotipo.

Un biofilm inmaduro permite la entrada de antimicrobianos

con mayor facilidad que uno maduro.

La entrada de neutrófilos y macrófago es limitada en todas

las etapas.

Gradiente O2 Gradiente

nutrientes

Células activas

Crecimiento estacionario Células persistentes

Anaerobios Aerobios

Fermentadores

Heterogeneidad poblacional: ecosistema complejo y biodiverso

1. Gradiente de nutrientes, metabolitos, oxígeno 2. Microorganismos en múltiples estados fisiológicos

Logarítmico

Estacionario

Persistente

Parsek. Annu. Rev. Microbiol. 2003

Biofilm y tolerancia a los antimicrobianos

• Fenómeno que permite la sobrevida de bacterias sensibles frente a dosis de ATB bactericidas (1% de la población dentro de la

biopelícula). Se manifiesta a 48 hs de formado

• Bacterias con MIC bajas a los ATB recuperan la sensibilidad cuando se desprenden del biofilm (fase planctónica).

Lin, Zhenyu Cheng , Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. Jba (2018),

Fenómeno de tolerancia

1. Física: entrada y difusión de ATB restringida, moléculas cargadas como los AMG quedan atrapados en la matriz, es un fenómeno saturable superado aumentando la dosis. Las FQ neutras pueden difundir con facilidad.

2. Fenotípica: existen subpoblaciones con diferente actividad metabólica, en la capas superficiales son activas y en capas profundas metabolismo reducido (latente y persistente).

3. Expresión de genes: hiperproducción de bombas de eflujo por estímulo del estrés oxidativo y el escaso contenido de nutrientes.

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Concentración bactericida dentro del biofilm

La MIC define los niveles de ATB a los que el microorganismo es susceptible en su estado planctónico, no se puede usar para guiar el tratamiento de bacterias en biofilm.

La MBEC (concentración bactericida dentro del biofilm) es una medida de la susceptibilidad a los ATB in vitro de los organismos productores de biopelículas.

Aun no estandarizados.

non-slime-producing strains (p<0.0001). In contrast, for the same antimicrobials the CV biofilm biomass scores showed contradictory results, where biofilm biomass score 1 showed higher MBEC/MIC ratios than biomass score 2 and 3 (p<0.05).

The MBECs were high and uniform for all enterococcal strains showing the highest MBEC/MIC ratios compared to staphylococci, which showed more interstrain variability depending on the antimicrobial agent. The MBEC/MIC ratios for E. faecalis ranged from 64–2,048 (median 512) for VAN, CIP, LZD, AMP, and RIF (Table IV). The range of the MBEC/ MIC ratios for the ten antibiotics in S. aureus was 1–2048 (median 9) and for the S. epidermidis strains was 0.0038–64 (median 1). Furthermore, the S. aureus strain that caused a

relapse in a patient exerted a 459-fold increase in MBEC versus a 63-fold MBEC by the nonrelapse causing staphylo-cocci. Nineteen percent of all the strains were susceptible to VAN, CIP, LZD, and RIF according to MIC whereas 77% were resistant according to MBEC evaluation (Figure 4).

DISCUSSION

This study represents the first report on the biofilm proper-ties of bacteria causing deep infections associated with bone-anchored femoral amputation prostheses. In the present study, the biofilm-forming ability of bacterial isolates from orthopaedic implant-associated osteomyelitis was determined with both phenotypic and genotypic methods. A major obser-vation was that the majority of the clinical strains (11 out of 13) formed biofilm in vitro and most of them were classified as moderate or strong biofilm producers.

In agreement with observations on prosthetic joint infec-tions,8 _{biofilm-producing S. aureus and S. epidermidis strains}

from infected percutaneous osseointegrated amputation pros-theses showed significantly higher MBEC/MIC ratios than the non-biofilm-producing strains. Since also the slime-producing strains had higher MBEC/MIC ratios compared with the non-slime-producing ones, the ability to produce slime may have contributed to the observed higher tolerance to antimicro-bials. However, biofilm tolerance to antimicrobials is

multifac-torial and not only caused by slime.38,39 Restricted

antimicrobial diffusion, slow growing persister cells, and altered physiological activity of the bacteria constitute addi-tional alternative mechanism for the observed findings.38,40

Planktonic and biofilm antibiograms differed for VAN, LZD, CIP and RIF, commonly used for the treatment of

TABLE IV. Ratios Between the MBEC and MIC Values for Ten Antimicrobial Agents

Strain code CLI GEN VANa LZDa CIPa OXA FA AMPa SXT RIFa CFU/peg

Biofilm production classificationa

E. faecalis strains

CCUG 64515 N/A N/A 512 128 512 N/A N/A 1024 N/A 256 9.8 3103 Moderate

CCUG 64517 N/A N/A 1024 128 512 N/A N/A 1024 N/A 256 4.6 3103 Weak

CCUG 64519 N/A N/A 1024 128 256 N/A N/A 2048 N/A 256 7.5 3104 Strong

CCUG 64524 N/A N/A 512 128 512 N/A N/A 1024 N/A 64 4.7 3104 Moderate

CCUG 64526 N/A N/A 1024 128 512 N/A N/A 1024 N/A 512 1.4 3104 Moderate

CCUG 64527 N/A N/A 1024 128 512 N/A N/A 2048 N/A 256 2.7 3104 _Weak

S. epidermidis strains

CCUG 64518 1 4 1 16 8 0.5 4 2 4 0.12 1.2 3104 _Moderate

CCUG 64521 1 1 0.5 2 2 0.125 64 1 0.125 4 8.8 3103 _Strong

CCUG 64523 0.016 0.016 2 4 0.125 0.25 4 0.25 0.5 0.0038 8.8 3103 _Non-producer

S. aureus strains

CCUG 64514 2.08 1 1 256 2 1 2048 1 1 2 2.2 3103 _Moderate

CCUG 64516 1 1 16 128 1 1 2 1 1 1 4.8 3104 Moderate

CCUG 64520 64 32 1 32 2 128 2048 1 32 533 2.7 3105 Non-producer

CCUG 64522 1024 1024 1024 128 32 1024 2048 2 32 533 7.9 3105 Weak

The ratios were calculated dividing the MBEC value by the MIC value for each strain and antimicrobial agent. The ratios show the increased/equal resistance factor of the biofilm susceptibility versus its equivalent planktonic susceptibility (approximately equal final amount of CFU in the planktonic culture as in the biofilm).

MIC (minimum inhibitory concentration), MBEC (minimum biofilm eradication concentration), CLI (clindamycin), GEN (gentamycin), VAN (vancomycin), LZD (linezolid), OXA (oxacillin), FA (fusidic acid), AMP (ampicillin), SXT (trimethoprim/sulfamethoxazole), RIF (rifampin).

a_{Biofilm production versus MBEC/MIC ratio: MBEC/MIC ratios from strains with biofilm production scores of 3, 4, and 5 (weak, moderate, and}

strong biofilm producers, respectively) were significantly higher than the MBEC/MIC ratios of non-biofilm producing strains (score 2) (p<0.0001) for VAN, LZD, CIP, AMP, and RIF.

FIGURE 4. Distribution of the susceptibility testing to four common

antimicrobial agents: vancomycin, linezolid, ciprofloxacin, and rifam-pin according to (a) MIC5minimum inhibitory concentration and (b) MBEC5minimum biofilm eradication concentration for the 13 clinical strains.

•

Bacterias persistentes:

no tienen cambios genéticos, son

metabólicamente inactivas (fenotipo durmiente). Viables,

no crecen, no se dividen, retoman crecimiento al cesar

noxa. Responsables de las recurrencia.

•

Variantes de colonia pequeña:

microorganismos de

crecimiento lento, intracelular, excelentes formadores de

biopelículas e importantes productores de

exopolisacáridos.

•

Heterorresistencia:

variación poblacional de la resistencia

a los ATB, subpoblaciones muestran diversas

susceptibilidades a un agente ATB particular.

-Ciofu O and Tolker-Nielsen T. Tolerance and Resistance of Pseudomonas aeruginosa Biofilms to Antimicrobial Agents how P. aeruginosa Can Escape Antibiotics. Microbiol 2019; 10:913.

El-Halfawy and Valvano. Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity.Clinical Microbiology Reviews

ries. Confusion regarding this phenomenon precludes establish-ing its clinical significance and implementestablish-ing proper therapeutic interventions and guidelines. Therefore, in this review, we criti-cally assess the published literature on heteroresistance, expose contradictions and variations in its definition, and recommend an operational definition and uniform criteria for assessment of het-eroresistant bacteria.

MULTIPLE DEFINITIONS OF HETERORESISTANCE

Heteroresistance means that there are population-wide variable responses to antibiotics (6). Several reports, including the earliest studies describing the phenomenon, applied this definition with-out specifying a particular antibiotic concentration range (3, 4, 7,

8). In contrast, concentration ranges were indicated for

heterore-sistance in Acinetobacter baumannii, where subpopulations grew

in 3 to 10!g/ml colistin while the culture’s MIC ranged from 0.25 to 2!g/ml (9). Others described heteroresistance when a subset of the microbial population was resistant to an antibiotic and the rest of the population was susceptible based on the concentration breakpoints of traditional in vitro susceptibility testing (10). This definition excludes cases where the bacterial culture comprises subpopulations with various levels of resistance but the entire population is either sensitive (Fig. 1D) or resistant (Fig. 1F) to the antibiotic.

Other definitions of heteroresistance contributed to miscon-ceptions about the nature of the phenomenon. Some of them were based on single cutoff concentrations, which did not describe the variation in resistance among members of a bacterial population.

For example, heteroresistance was defined by growth of A.

bau-mannii colonies on plates containing 8 !g/ml of colistin, with

confirmation of a MIC of 8!g/ml by a subsequent broth

microdi-lution method (11). Similarly, heterogeneously resistant

staphy-lococci were defined as any culture containing subpopulations at a frequency of 1 in 106 CFU/ml or higher, with a MIC of "4 !g/ml for vancomycin or!16!g/ml for teicoplanin (12), or simply with a MIC above those specified in the CLSI guidelines for breakpoints

of vancomycin or teicoplanin (13). A similar definition was

ad-opted by setting a cutoff diameter of 10 mm in disc diffusion assays, below which the strain was considered heteroresistant

rather than merely resistant (14). Another approach defined

het-eroresistance as a high MIC of Enterococcus faecium against

van-comycin ("256 !g/ml) by broth dilution but a low MIC (1.8

!g/ml) by Etest (15).

Other forms of heterogeneous bacterial behavior against antibiot-ics were reported as heteroresistance. CertainStaphylococcus aureus

strains displayed methicillin resistance at high antibiotic concen-trations (64 to 512!g/ml) and susceptibility at low concentrations

(2 to 16 !g/ml) (16). This phenomenon, termed “Eagle-type”

resistance, was similar to the Eagle killing by penicillin described earlier, in which the bactericidal action of penicillin paradoxically decreased at high antibiotic concentrations (17). Similar patterns of bimodal growth in population analysis profiles were observed forA. baumannii with cefepime, where growth inhibition after an initial peak of growth at a low antibiotic concentration was

fol-lowed by another peak of growth at a higher concentration (18).

Certain S. aureus strains displayed “thermosensitive”

heteroresis-tance, where cultures growing at high methicillin concentrations at 30°C lost this ability within 30 min after shifting of the growth

temperature to 37°C (19). A temperature shift in the reverse

di-rection caused an equally rapid expression of methicillin resis-tance (19).

Adding to the confusion, the term “heteroresistance” has been applied to describe infections with bacterial strains having differ-ent levels of resistance to an antibiotic. Amoxicillin-resistant and -susceptibleHelicobacter pyloriisolates (MICs of 2!g/ml and 0.06

!g/ml, respectively) were observed in different biopsy specimens

from one patient, displaying what was described as “interniche” heteroresistance (20). More recently, pairs of H. pylori isolates obtained from the same patients had different levels of resistance to levofloxacin, metronidazole, and (in only one case) clarithro-mycin; the antibiotic-resistant strains were mostly derived from a preexisting sensitive strain rather than from infection with different strains of H. pylori having different levels of anti-biotic resistance (21). Similarly, heteroresistance in Mycobacte-rium tuberculosis was defined as coexistence of antituberculosis drug-susceptible and -resistant bacteria in the same patient (22,

23). More recently, heteroresistance in M. tuberculosis was

rede-fined as coexistence of populations with different mutations in a

drug resistance locus within a sample of organisms (24).

There-fore, heteroresistance does not have a uniformly consistent defi-nition, making retrospective comparisons to assess its true clinical significance impossible.

MEASURING HETERORESISTANCE Population Analysis Profiling

The population analysis profiling (PAP) method is considered the gold standard for determining heteroresistance. In this method, the bacterial population is subjected to a gradient of antibiotic concentrations (either on plates or in liquid medium), and bacte-rial growth at each of these concentrations is quantified. PAP is typically performed using the format of standard MIC

determina-FIG 1 Heteroresistant versus homogeneous responses to antibiotics. Dotted lines represent breakpoints for resistance. Homogeneous bacterial cultures can be either susceptible (A), of intermediate susceptibility (B), or resistant (C) to an antibiotic according to traditional in vitro susceptibility testing. Heterore-sistant bacteria may be any of the following. (D) Bacteria are completely sus-ceptible to an antibiotic, whereby the different subpopulations respond to antibiotic concentrations extending below the breakpoints. This form is less likely to be detected and is probably the least clinically important (unless the least responsive subpopulations develop resistance to the antibiotic). (E) Bac-teria exhibit the more classical form of heteroresistance, in which the majority of the bacterial population is susceptible to an antibiotic, with a highly resistant minority. Antibiotic treatment guided by the traditional susceptibility testing breakpoints would select for the resistant subpopulation, leading to therapeu-tic failure. (F) The entire bacterial population, including the least resistant subpopulations, is resistant to the antibiotic. Chemical communication of antibiotic resistance from the more resistant members of the population protecting less resistant bacteria is the major concern of such bacterial populations.

El-Halfawy and Valvano

192 cmr.asm.org Clinical Microbiology Reviews January 2015 Volume 28 Number 1

on September 5, 2019 by guest

http://cmr.asm.org/

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Comportamiento de ATB en el biofilm

Ciprofloxacina: difunde rápidamente dentro de la biopelícula y la CIMB es

similar a las formas plantónicas.

Betalactámicos: CIM >1000 veces que las formas planctónicas, frente a

la exposición P aeruginosa aumenta la producción de AmpC, para contrarrestar el efecto se aumenta la dosis del B-lactámico.

AMG: su carga positiva favorece la unión a la matriz glicoproteica, dejando

• Fosfomicina: actividad bacteriostática, tiempo dependiente,

influenciada por el efecto inóculo. La heteroresistencia es frecuente, no usar en monoterapia.

• Colistin: actividad bactericida independiente de la formación y consumo de radicales hidroxilo, mayor destrucción de bacterias ubicadas dentro del biofilm en las capas más profundas.

• Rifampicina: acción intracelular, afecta poblaciones estacionarias, alta concentración intracelular.

• Azitromicina: elevadas concentraciones dentro del biofilm e intracelular, inmunomodulador.

Tratamiento de infecciones por P. aeruginosa

• Bajar la carga bacteriana y de biopelícula.

• Combinado (fase estacionaria y planctónica).

• Infusión prolongada o altas dosis intermitentes,

En cepas MDR se ha demostrado sinergia de:

1. β-lactámico en casos resistentes (MIC 2-4 veces mayores) asociado a otro ATB.

2. Ciprofloxacina (resistente) protege de la aparición de mutantes resistentes al MEM.

3. Imipenem + rifampicina (R a carbapenémicos mediado por porinas).

• Rodriguez Pardo et al. Gram-negative prosthetic joint infection: outcome of a debridement, antibiotics and implant retention approach. A large multicentre study. Clin Microbiol Infect 2014; Vol 20 Number 11,

• M.C. Farin ̃as, L. Martínez-Martínez. Infecciones causadas por bacterias gramnegativas multirresistentes: enterobacterias, Pseudomonas aeruginosa, Acinetobacter baumannii y otros bacilos gramnegativos no fermentadores. Enferm Infecc Microbiol Clin. 2013;31(6):402–409

En Infecciones Protésicas Agudas con implante estable y sensiblidad a ciprofloxacina se recomienda desbridamiento y retención del implante (éxito 79% vs 41% cuando es resistente).

En IPT crónicas retirar el implante evitar la recurrencia.

Duración del tratamiento no definido, se recomienda prolongado y en casos en los que no puede retirarse el implante terapia supresiva.

Tratamiento de infecciones asociadas a

implantes por

P. aeruginosa

• J. Mensa, et al. Antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the Spanish Society of Chemotherapy. Rev Esp Quimioter 2018;31(1): 78-100

• Hu et al. In vitro antibacterial activity of rifampicin in combination with imipenem, meropenem and doripenem against multidrug-resistant clinical isolates of Pseudomonas aeruginosa . BMC Infectious Diseases (2016) 16:444

Experiencia grupo CRIOac Francia

Estudio de cohorte retrospectiva de los pacientes con infección por P. Aeruginosa

asociadas a implantes.

Objetivo: analizar el impacto de un tratamiento quirúrgico óptimo sumado a un

plan antimicrobiano parenteral 3 semanas seguido de vía oral con ciprofloxacina.

Período 2012-2017, todos con 1 o más cultivos profundos a P. Aeruginosa.

Seguimiento de 20 meses.

Definiciones:

Tratamiento antibiótico inicial efectivo: uso de un fármaco betalactámico iv activo dirigido por antibiograma.

Implant-associatedP. aeruginosa bone and joint infections: experience in a regional reference center in france. http://www.crioac-lyon.fr

Falla del tratamiento: a) persistencia (nueva cirugía + P. aeruginosa), b)

superinfección (cirugía nueva o punción articular con aislamiento de otro

organismo), o c) cualquier otra causa de recaída, como la necesidad de

una cirugía posterior.

Tratamiento quirúgico adecuado:

1. Desbridamiento y retención: <1 mes del implante, estable sin fístula o

tejido blando dañado.

2. Recambio en 1 tiempo: > 1 mes del implante, sin fístula y buen estado

del paciente.

3. Recambio en 2 tiempos: > 1 mes del implante, tracto sinusal,

microorganismo difícil de tratar, mal estado del huésped.

Implant-associatedP. aeruginosabone and joint infections: experience in a regional reference center in france. http://www.crioac-lyon.fr

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Resultados

Factores independientes de buen pronóstico (análisis multivariado):

1. tratamiento quirúrgico óptimo p: 0,045

2. antibiótico parenteral 3 semanas p:0,003

3. ciprofloxacina por 3 meses p: 0,015

Fallo terapéutico: 25,6%

- 7,5% fue por persistencia de P aeruginosa y

- 17,8% superinfección.

Conclusión: la infección peri-protésica por P. aeruginosa es una de las más

difíciles de tratar, y la estrategia quirúrgica tiene un fuerte impacto en el pronóstico. Es efectivo un tratamiento antibiótico intravenoso inicial durante al menos 3

semanas, seguido de ciprofloxacina oral por una duración total de 3 meses.

Implant-associatedP. aeruginosabone and joint infections: experience in a regional reference center in france. http://www.crioac-lyon.fr

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Objetivo describir el manejo de infección ósea (IO) por P. aeruginosa

MDR y opciones terapéuticas.

Métodos: retrospectivo, período 2004-13. Se definieron 2 grupos: A

retiene el implante, B retiro del implante. Todos recibieron ATB de acuerdo

a criterio clínico. Resultados: 34 pacientes, 15 PJI y 19 OI (8

relacionados con un dispositivo ortopédico). Se retiro el implante en 14 casos, asociado a ATB monoterapia 19 y combinado 15. La tasa de

curación general fue del 50% (39% y 63% grupos A y B, respectivamente).

Osteoarticular infection caused by MDR Pseudomonas aeruginosa: the benefits of combination therapy with colistin plus b-lactams

Alba Ribera1_{*, Eva Benavent}1_{, Jaime Lora-Tamayo}1_{, Fe Tubau}2,3_{, Salvador Pedrero}4_,

Xavier Cabo4_{, Javier Ariza}1_{and Oscar Murillo}1

1_{Infectious Diseases Department, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain;}2_{Microbiology Department,}

IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain;3_{Ciber de Enfermedades Respiratorias ISCIII, Madrid, Spain;} 4_{Orthopaedic Surgery Department, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain}

*Corresponding author. E-mail: [email protected]

Received 17 June 2015; returned 16 July 2015; revised 7 August 2015; accepted 11 August 2015

Objectives:In the era of emergence of MDRPseudomonas aeruginosa, osteoarticular infections (OIs) add more difficulties to its treatment. The role ofb-lactams (BLs) is questioned and older drugs need to be reconsidered. The objective of this study was to describe our experience in the management of OIs caused by MDRP. aeruginosa

and evaluate different therapeutic options.

Methods:This was a retrospective analysis of a prospectively collected cohort (2004–13) of patients with OI caused by MDRP. aeruginosa. We created two groups: (i) Group A (more difficult to treat), prosthetic joint infections (PJIs) and osteoarthritis (OA) managed with device retention; and (ii) Group B (less difficult to treat), OA managed without device retention. Antibiotic treatment was administered according to clinician criteria: monotherapy/combined therapy; and BL used by intermittent bolus (IB)/continuous infusion.

Results:Of 34 patients, 15 (44.1%) had PJI and 19 (55.9%) had OA (8 related to an orthopaedic device). Twenty-three cases (68%) were caused by XDRP. aeruginosa. The initial management included removal of an orthopaedic device in 14 cases, together with antibiotic [alone, 19 (55.9%; 4 colistin, 14 BL-IB and 1 BL continuous infusion); and in combination, 15 (44.1%; 5 BL-IB and 10 BL continuous infusion)]. The overall cure rate was 50% (39% and 63% in Groups A and B, respectively), ranging from 31.6% with monotherapy to 73.3% with combined therapy (P¼0.016), with special interest within Group A (cure rate with combined therapy 71.4%,P¼0.049). After rescue therapy, which included removal of remaining devices, the cure rate reached 85.3%.

Conclusions:We suggest that the BL/colistin combination is an optimized therapy for OI caused by MDR

P. aeruginosa, together with an appropriate surgical treatment.

Introduction

Gram-positive bacteria are the most frequent infective agents in osteoarticular infection (OI), whereas Gram-negative bacteria (GNB) may be responsible of 10%–23% of cases.1–3_{In particular}

settings, such as prosthetic joint infections (PJIs),4–7_Pseudomonas

aeruginosamay cause up to 20% of these GNB infections.7While current antibiotic recommendations for the treatment of OIs caused by GNB areb-lactams and ciprofloxacin,8,9_{there is no}

stand-ard of treatment for MDR GNB infection.

The progressive emergence of MDR GNB represents a new challenge in the treatment of nosocomial infection. In the field of PJI, a recent study showed that the percentage of MDR GNB almost tripled from 3.3% in 2003 to 9.4% in 2012.10Among these pathogens,P. aeruginosais particularly problematic, with few therapeutic options.11_{Some strains are resistant or not fully}

susceptible tob-lactams, and the only active antimicrobials are polymyxins and aminoglycosides.12

Moreover, the pathology of OIs, especially when an ortho-paedic device is present, adds further complexity to the clinical and surgical management of these infections.3,13–16

It is well known that bacteria involved in OIs can live in a sta-tionary phase or non-growing condition, either intracellularly or within biofilms around the orthopaedic device.17Inside the com-plex glycoproteic matrix of the biofilm, the low concentration of oxygen and nutrients leads to heterogeneous phenotypic changes in the bacteria. In turn, this results in different antimicro-bial tolerances to different families of antibiotics.17,18_{Indeed, the}

use ofb-lactams to treat PJIs caused by quinolone-resistant GNB was associated with a poor cure rate,7_{since the role of antibiotics}

was even more complicated by the reduced susceptibility or resistance tob-lactams.

#The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

For Permissions, please e-mail: [email protected] J Antimicrob Chemother2015;70: 3357–3365

doi:10.1093/jac/dkv281 Advance Access publication 28 September 2015

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infection; (ii) amputation of the affected limb; or (iii) persistence of clinic-ally relevant MDRP. aeruginosa(i.e. signs/symptoms of infection and/or positive cultures) despite appropriate initial therapy. Rescue therapy was evaluated as part of the outcome assessment.

Statistical analysis

Continuous variables were expressed as medians with the IQR and were compared using the Mann –WhitneyU-test. Categorical variables were expressed as number (percentage) and were compared using thex2test or Fisher’s exact test, as appropriate. Statistical significance was defined as a two-tailedPvalue,0.05. Predictor parameters of failure were analysed by logistic regression. In addition, Kaplan–Meier curves and the log-rank test were used to compare the cumulative likelihood of failure between patients treated with combined therapy or monotherapy. Data were ana-lysed using IBM SPSS for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA).

Results

We included 34 patients: 15 (44%) with PJI, 11 (32%) with OA not related to an orthopaedic device and 8 (24%) with OA related to an orthopaedic device. The median age was 68.7 years (IQR 59.5 – 78) and 59% were men, with.70% having at least one comorbidity. Polymicrobial infection was initially present in 16 (47%) patients and 20 (59%) had a super-infection caused by MDRP. aeruginosa(Table1).

Of the 34 patients, 31 (92%) initially underwent surgery. Three patients with OA (without device) were managed conservatively with antibiotics alone: two had post-surgical pubic symphysis

osteomyelitis following a prostatic resection, and one had sacroi-liitis because of a sacral pressure sore. Among the 23 patients with OI related to an orthopaedic device (8 OA plus 15 PJI), surgery

Table 2. Initial management of patients with OI caused by MDR PA;N_¼34

n(%) orn

Antibiotic

monotherapy 19 (55.9)

colistin 4

BL-IB 14

BL continuous infusion 1

combined therapy 15 (44.1)

colistin+BL-IB 3

colistin+BL continuous infusion 10

amikacin+BL-IB 2

Surgery

no surgery 3 (8.8)

surgery without device maintenancea _{22 (64.7)}

debridement with device retention 9 (26.5)

BL,b-lactam; IB, intermittent bolus.

Monotherapy: BL-IB, ceftazidime (4), cefepime (1), aztreonam (1), pipera-cillin/tazobactam (4) and carbapenem (4); and BL continuous infusion, piperacillin/tazobactam (1).

Combined therapy: colistin+BL-IB: ceftazidime (1), aztreonam (1) and carbapenem (1); colistin+BL continuous infusion: ceftazidime (5), aztreonam (2), piperacillin/tazobactam (2) and carbapenem (1); and amikacin+BL-IB: cefepime (1) and piperacillin/tazobactam (1).

a_{Includes patients with OI without a device managed by debridement and}

patients in which the involved devices were removed.

Table 3. Prognostic factors for persistence of infection after the initial therapy; analysis of risk of failure considering main characteristics and antibiotic treatment;N¼34

Cured infection,

n¼17

Non-cured infection,

n¼17 P

Main characteristics

age (years), median (IQR) 71 (59–76) 67 (51–79) 1

male,n(%) 12 (70.6) 8 (47.1) 0.163

polymicrobial infection,n(%) 6 (35.3) 10 (58.8) 0.169

super-infection,n(%) 11 (64.7) 9 (52.9) 0.486

MDR PA,n(%) 3 (17.6) 8 (47.1)

0.067

XDR PA,n(%) 14 (82.4) 9 (52.9)

related to an orthopaedic device,n(%)

10 (58.8) 13 (76.5) 0.271

Antibiotic

monotherapy,n(%) 6 (35.3) 13 (76.5)

0.016

combined therapy,n(%) 11 (64.7) 4 (23.5)

BL-IB,n(%) 8 (53.3) 11 (73.3)

0.256 BL continuous infusion,n(%) 7 (46.7) 4 (26.7)

PA,P. aeruginosa; BL,b-lactam; IB, intermittent bolus.

Table 1. Main characteristics of patients with OI caused by MDR PA;N¼34

Median (IQR) orn(%)

Age (years) 68.7 (59.5–78)

Male 20 (58.8)

Comorbidities

diabetes mellitus 6 (17.6)

immunosuppressive therapy 8 (23.5)

autoimmune disease 5 (14.7)

chronic renal failure 6 (17.6)

malignancy 4 (11.8)

othersa _{6 (17.6)}

no comorbidityb _{10 (29.4)}

Type of infection

PJI 15 (44.1)

OA (without related device) 11 (32.4)

OA (related to an orthopaedic device) 8 (23.5)

Polymicrobial infection 16 (47.1)

Super-infection 20 (58.8)

MDR PA/XDR PA 11 (32.4)/23 (67.6)

PA,P. aeruginosa.

a_{Includes patients with chronic pulmonary disease, chronic heart disease}

or advanced dementia.

b_{Includes patients without any of the previously defined comorbidities.}

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involved debridement and device removal in 14 (60.9%; 9 PJI and 5 OA), while the device was retained in 9 (39.1%; 6 PJI and 3 OA). Monotherapy was used in 19 (56%) patients, mainly with inter-mittent boluses ofb-lactams (14/19), but 4 patients received colistin alone. When the clinician used combination therapy (15, 44%), it was mostly with continuous infusion of ab-lactam plus colistin (10/15). Overall, 30 patients receivedb-lactams: in 12 patients,P. aeruginosastrains were susceptible (6 to anti-pseudomonal cephalosporins, 2 to piperacillin/tazobactam and 4 to carbapenems), but the other 18 were not susceptible: 2 inter-mediate (1 to aztreonam and 1 to carbapenem) and 16 resistant (6 to anti-pseudomonal cephalosporins, 6 to piperacillin/tazobac-tam, 1 to aztreonam and 3 to carbapenems). The median dose of colistin was 5 MIU/day (IQR 2.8–6), for a median of 40.5 days (IQR 26–43). Amikacin was administered only in two patients, where it was combined with intermittent boluses ofb-lactams (Table2).

After initial therapy, the cure rate reached 50%. Among the remaining patients, 15 (44%) had persistent infection caused by MDRP. aeruginosaand 2 died during the initial treatment. The fac-tors predicting treatment failure were therefore evaluated, focus-ing on the host, the type of infection and the therapeutic plan. No significant difference was seen in the prognosis when comparing polymicrobial and monomicrobial infections or the presence of

P. aeruginosasuper-infection. XDRP. aeruginosawas present in 23 patients and MDRP. aeruginosain 11 patients, with no differ-ences in management (surgical or antibiotic regimen) between the groups (data not shown). Of the 11 patients with OI caused by MDRP. aeruginosa, just three (27%) were cured after the first therapeutic plan; but the cure rate more than doubled when the pathogen was an XDRP. aeruginosastrain (cure rate 14/23, 61%,

P¼0.067) (Table3).

Combination therapy (mainly with colistin plusb-lactams) was significantly more effective than monotherapy (with either

b-lactams or colistin), with cure rates of 11/15 (73%) and 6/19 (32%), respectively (P¼0.016) (Table3). Figure1illustrates the likelihood of failure according to the antibiotic treatment and follow-up period (log-rank¼0.079). In our case series, colistin was well tolerated, and although 10 patients presented renal impairment during the treatment, creatinine was normalized after reducing the dose. The use ofb-lactams in continuous infu-sion was safe and seemed to offer more benefits thanb-lactams in an intermittent bolus (cure rates of 64% and 42%, respectively,

P¼0.256) (Table3).

The failure rate was also analysed between the two groups by the difficulty of treatment. Patients in Group A had a higher failure rate (61.1%) compared with patients in Group B (37.5%). Focusing on those patients managed with implant retention (n¼9), three patients were cured after initial debridement (3/9, 33%), but six required further surgery for device removal (Table4). Combined anti-biotic treatment (mainly with colistin plusb-lactams) also appeared to be associated with better outcomes than monotherapy in patients with infections considered more difficult to treat (Group A), despite the added management difficulties, with cure rates of 5/7 (71%) and 2/11 (18%), respectively (P¼0.049) (Figure2).

Details of the treatment received by the 17 (50%) patients in whom initial therapy was not curative are summarized in Table5. Two patients died (Table5, cases 16 and 17). Among the patients who were not cured by initial therapy, one had a PJI that was retained with a persistent infection [Table5, case 7, managed conservatively with careful follow-up of a persistent fis-tula, but without antibiotics (no oral option was possible)]. Another 14 patients required second-line treatment (7 PJIs and 0.0

0 500 1000 1500

Time (days)* 2000 2500 0.2

0.4

Cumulativ

e lik

elihood of f

ailur e 0.6 0.8 1.0 Antibiotic treatment Combined therapy (CT) Monotherapy (MT) CT-censored MT-censored

Figure 1.Likelihood of failure according to the antibiotic treatment (combined therapy or monotherapy). *Time from the start of antibiotic therapy to the end of follow-up or to failure (in cases not initially cured). Grey continuous line, combined therapy; black broken line, monotherapy. Log-rank¼0.079.

Table 4.Prognostic factors for persistence of infection after the initial therapy; analysis of risk of failure according to the difficulty of treatment;N¼34 Type of infection Surgical management Failuren/N(%), 17/34 (50%) P

PJI implant retention 4/6 (66.7%)

more difficult-to-treat OI (Group A), 11/18 (61.1%)

0.169 PJI implant removala _{5/9 (55.6%)}

OA (with device) implant retention 2/3 (66.7%)

OA (with device) implant removal 2/5 (40%) _{less difficult-to-treat OI (Group B), 6/16 (37.5%)} OA (no device) no surgery or debridement 4/11 (36.4%)

a_{Management: 3 Girdlestone (2 failures), 5 two-step revision (3 failures) and 1 arthrodesis.}

Riberaet al.

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infection; (ii) amputation of the affected limb; or (iii) persistence of clinic-ally relevant MDRP. aeruginosa(i.e. signs/symptoms of infection and/or positive cultures) despite appropriate initial therapy. Rescue therapy was evaluated as part of the outcome assessment.

Statistical analysis

Continuous variables were expressed as medians with the IQR and were compared using the Mann –WhitneyU-test. Categorical variables were expressed as number (percentage) and were compared using thex2test or Fisher’s exact test, as appropriate. Statistical significance was defined as a two-tailedPvalue,0.05. Predictor parameters of failure were analysed by logistic regression. In addition, Kaplan–Meier curves and the log-rank test were used to compare the cumulative likelihood of failure between patients treated with combined therapy or monotherapy. Data were ana-lysed using IBM SPSS for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA).

Results

We included 34 patients: 15 (44%) with PJI, 11 (32%) with OA not related to an orthopaedic device and 8 (24%) with OA related to an orthopaedic device. The median age was 68.7 years (IQR 59.5 – 78) and 59% were men, with.70% having at least one comorbidity. Polymicrobial infection was initially present in 16 (47%) patients and 20 (59%) had a super-infection caused by MDRP. aeruginosa(Table1).

Of the 34 patients, 31 (92%) initially underwent surgery. Three patients with OA (without device) were managed conservatively with antibiotics alone: two had post-surgical pubic symphysis

osteomyelitis following a prostatic resection, and one had sacroi-liitis because of a sacral pressure sore. Among the 23 patients with OI related to an orthopaedic device (8 OA plus 15 PJI), surgery

Table 2. Initial management of patients with OI caused by MDR PA;N¼34

n(%) orn

Antibiotic

monotherapy 19 (55.9)

colistin 4

BL-IB 14

BL continuous infusion 1

combined therapy 15 (44.1)

colistin+BL-IB 3

colistin+BL continuous infusion 10

amikacin+BL-IB 2

Surgery

no surgery 3 (8.8)

surgery without device maintenancea _{22 (64.7)}

debridement with device retention 9 (26.5)

BL,b-lactam; IB, intermittent bolus.

Monotherapy: BL-IB, ceftazidime (4), cefepime (1), aztreonam (1), pipera-cillin/tazobactam (4) and carbapenem (4); and BL continuous infusion, piperacillin/tazobactam (1).

Combined therapy: colistin+BL-IB: ceftazidime (1), aztreonam (1) and carbapenem (1); colistin+BL continuous infusion: ceftazidime (5), aztreonam (2), piperacillin/tazobactam (2) and carbapenem (1); and amikacin+BL-IB: cefepime (1) and piperacillin/tazobactam (1).

a_{Includes patients with OI without a device managed by debridement and}

patients in which the involved devices were removed.

Table 3. Prognostic factors for persistence of infection after the initial therapy; analysis of risk of failure considering main characteristics and antibiotic treatment;N¼34

Cured infection,

n¼17

Non-cured infection,

n¼17 P

Main characteristics

age (years), median (IQR) 71 (59–76) 67 (51–79) 1 male,n(%) 12 (70.6) 8 (47.1) 0.163 polymicrobial infection,n(%) 6 (35.3) 10 (58.8) 0.169 super-infection,n(%) 11 (64.7) 9 (52.9) 0.486 MDR PA,n(%) 3 (17.6) 8 (47.1)

0.067 XDR PA,n(%) 14 (82.4) 9 (52.9)

related to an orthopaedic device,n(%)

10 (58.8) 13 (76.5) 0.271

Antibiotic

monotherapy,n(%) 6 (35.3) 13 (76.5)

0.016 combined therapy,n(%) 11 (64.7) 4 (23.5)

BL-IB,n(%) 8 (53.3) 11 (73.3)

0.256 BL continuous infusion,n(%) 7 (46.7) 4 (26.7)

PA,P. aeruginosa; BL,b-lactam; IB, intermittent bolus.

Table 1.Main characteristics of patients with OI caused by MDR PA;N¼34 Median (IQR) orn(%)

Age (years) 68.7 (59.5–78)

Male 20 (58.8)

Comorbidities

diabetes mellitus 6 (17.6)

immunosuppressive therapy 8 (23.5) autoimmune disease 5 (14.7) chronic renal failure 6 (17.6)

malignancy 4 (11.8)

othersa _{6 (17.6)}

no comorbidityb _{10 (29.4)}

Type of infection

PJI 15 (44.1)

OA (without related device) 11 (32.4) OA (related to an orthopaedic device) 8 (23.5)

Polymicrobial infection 16 (47.1)

Super-infection 20 (58.8)

MDR PA/XDR PA 11 (32.4)/23 (67.6)

PA,P. aeruginosa.

a_{Includes patients with chronic pulmonary disease, chronic heart disease}

or advanced dementia.

b_{Includes patients without any of the previously defined comorbidities.}

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Conclusiones: la combinación Betalactámico / colistina

es una terapia optimizada para la IO causada por P.

aeruginosa MDR junto con un tratamiento quirúrgico

Otras opciones

• En estudio:

1. Cámara hiperbárica: reportes de eficacia en casos de infección refractaria al tratamiento, sensibilizaría el efecto de la

ciprofloxacina.

2. Azitromicina: se extrapolan datos de su efecto inmunomodulador visto en pacientes con fibrosis quística, inhibe el quorum sensing y las células en fase estacionaria.

Propuesta de tratamiento en infecciones por

P. aeruginosa

asociada a implante

Es necesario el desbridamiento quirúrgico en todos los casos.

1º fase parenteral: 2 fármacos efectivos, betalactámicos +

aminoglucósidos o fosfomicina o colistin por 3 semanas o más.

Evitar el uso inicial de las quinolonas en caso de ser sensibles.

2º fase vía oral: quinolonas en casos sensibles, rifampicina opcional.

En casos resistentes considerar quinolonas + rifampicina. El objetivo sería tratar subpoblaciones tolerantes que persisten luego de erradicar las subpoblaciones resistentes que fueron tratadas con el plan

Conclusiones

• Las infecciones asociadas a implantes en hueso son difíciles de tratar.

• Incidencia está aumentando.

• El aumento de microorganismos MDR suma complejidad al tratamiento.

• Es necesario capacitarnos en su manejo, y formar equipos multidisciplinarios de trabajo.

• Debemos diseñar una pauta local de tratamiento ajustada a nuestra disponibilidad de moléculas.