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Fiscon, Marta (2017) Validazione di un percorso diagnostico rapido per l'analisi del fenotipo di sensibilitĂ  dei batteri Gram negativi. [Ph.D. thesis]

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Abstract (english)

The multidrug-resistant bacterial infections represent a global and complex problem because of the increase in their prevalence and the lack of new antibiotics. In this context, the antimicrobial stewardship programs are based on the collaboration between the infectious disease specialist and the microbiologist, which must merge their competencies to optimize antimicrobial therapy, implement surveillance and control the spread of MDR epidemic in health-care facilities. Moreover, they should create specific diagnostic procedures to obtain a prompt diagnosis of sepsis, with the species-identification of the pathogen and its sensitivity profile to antibiotics.
Our research evaluated a new diagnostic approach for the early determination of the phenotypic antimicrobial susceptibility in Gram-negative bacteria.
The first study aimed to validate an innovative rapid procedure for bacterial antibiogram in sepsis, which is 24 hours quicker than the traditional one. Nowadays indeed, the laboratory can use new technologies molecular biology techniques as a support in sepsis diagnostics; however, culture and microbroth diluition are still the gold standards in sepsis’ microbiological diagnosis. Unfortunately, they require a long time to be finalized, and this is more and more a severe limit since patients’ survival depends on a rapid and correct therapy start. Many authors studied new pathways of identification of resistances, but until now, nobody was able to establish a shared procedure based on evidence. For this reason, in the real-life laboratory, operational protocols are based on the responsibility and the expertise of the single professional.
In our study, we included 145 strains of E. coli, K. pneumoniae and P. aeruginosa, with different phenotypic profiles. They were analyzed with both the gold standard method and the rapid one, comparing the values of Minimal Inhibitory Concentration. The procedure included haemocolture’s bottles inoculum, spot streaking on an agar plate, 5 hours incubation at 37°C, and finally microbroth diluition test preparation (Sensititre® method). MIC data and their interpretation (susceptible, intermediate or resistant) were collected and compared to ones obtained with the gold standard test, and agreement index was calculated together with sensitivity, specificity and prediction parameters.
The aggregate data analysis showed a good performance, regarding precision, the Categorical Agreement (97.9%), the Essential Agreement (99.1%), the sensitivity (96%) and specificity (99%). Furthermore, the errors related to the evaluation of both the single antibiotic and the total of the MIC resulted in being acceptable. However, we observed the presence of some significant Very Major and Major Errors concerning Ampicillin/Sulbactam, Piperacillin/Tazobactam e Fosfomycin: these results suggested us to exclude the three drugs from the new rapid susceptibility test, without precluding the utility in guiding the so called “first line therapy”.
In the second study, we evaluated the application of mass spectrometry to the rapid detection of quinolones’ resistance, with particular attention to the expression of the aminoglycoside acetyltransferase variant AAC(6’)-Ib-cr. We included in the study 72 strains of E. coli, which were spot streaked on an agar plate, incubated for 5 hours at 37°C with norfloxacin disk and finally collected for the MALDI-TOF analysis. For the study, we used the Saramis® software, Vitek® MS (Biomerieux), which allows examining separately every single detected spectrum. In particular, we investigated the presence of spectra related to the native and the acetylated norfloxacin spectra (“indirect” method) and the AAC(6’)-Ib-cr spectra (“direct” method). In both the cases, the analysis did not show satisfactory results, regarding both agreements with the reference test and sensitivity/specificity.
In conclusion, our study demonstrated that the new rapid procedure for the bacterial antimicrobial susceptibility test has an acceptable agreement with the traditional one regarding the major part of the antibiotics that are used in practice as a first line therapy in sepsis. On the contrary, our method for the evaluation of quinolone with mass spectrometry did not show any clinical and microbiological viability. Further studies might be designed in this topic, but they should always consider the need to guarantee a precise and rapid result, together with a targeted diagnosis and care that never neglect expertise, caution, and clinical monitoring.

Abstract (italian)

Il problema delle infezioni da germi multiresistenti è complesso e di gravità sempre crescente, a causa dell’incremento della loro diffusione e del mancato sviluppo di nuove opzioni terapeutiche. Un’efficace soluzione è rappresentata dai programmi di antimicrobial stewardship, che prevedono una stretta collaborazione interdisciplinare allo scopo di ottimizzare la terapia antimicrobica, contenere le epidemie da germi multiresistenti e creare iter diagnostici mirati, specie nel caso delle infezioni invasive.
L’attività di ricerca svolta ha avuto lo scopo di validare un percorso diagnostico innovativo per l’analisi rapida del fenotipo di sensibilità dei batteri Gram negativi. Ad oggi, infatti, nella diagnosi microbiologica di sepsi, l’antibiogramma secondo brodo-diluizione rappresenta ancora il gold-standard; tuttavia sussiste la necessità di fornire il risultato in tempi sempre più brevi, per consentire al clinico di perfezionare la terapia iniziata empiricamente. Per questo motivo, il limite dato dalle lunghe tempistiche attuali è sempre più gravoso, seppur le tecnologie attuali consentano di integrare nella routine di laboratorio metodi veloci ed efficaci, come le analisi in biologia molecolare. Vari autori hanno indagato nuovi percorsi di identificazione rapida del fenotipo di sensibilità, ma ad oggi non è ancora presente nessuno studio conclusivo e nessuna indicazione ufficialmente validata e riconosciuta per l’uso delle metodiche rapide di rilevazione delle resistenze nella real-life, lasciando alla responsabilità e all’esperienza del medico microbiologo l’adozione di protocolli operativi e la loro integrazione nel work-flow del laboratorio.
Nel primo studio, pertanto, è stata validata una procedura innovativa di esecuzione dell’antibiogramma, in grado di anticiparne il risultato di circa 24 ore, grazie all’analisi dopo semina a spot, che permette di ottenere la rapida crescita di una patina batterica. Sono stati inclusi in questa analisi 145 ceppi di E. coli, K. pneumoniae e P. aeruginosa, con differenti profili di sensibilità, che sono stati analizzati sia secondo il metodo di riferimento che secondo il metodo rapido per la determinazione della MIC. Nel complesso, i dati ottenuti hanno evidenziato una performance soddisfacente, per quanto riguarda la ripetibilità, la concordanza tra le due metodiche, la sensibilità e la specificità. Anche gli errori rilevati, analizzando i singoli antibiotici e il totale delle MIC complessivamente determinate, sono risultati entro il limite di accettabilità del metodo; tuttavia, sono state osservate alcune criticità, soprattutto riguardo all’attendibilità dei risultati per Ampicillina/Sulbactam, Piperacillina/Tazobactam e Fosfomicina, che potrebbero essere escluse dalla refertazione dell’antibiogramma “rapido” senza precluderne l’utilità per l’aggiustamento della prima linea terapeutica.
Il secondo studio, invece, ha valutato l’applicazione della spettrometria di massa alla rilevazione rapida della resistenza ai fluorchinoloni, con particolare attenzione all’espressione della variante della aminoacetiltrasferasi AAC(6’)-Ib-cr. A tale scopo, sono stati inclusi nella ricerca 72 ceppi di Escherichia coli, seminati a spot su piastre di agar sangue, incubati per 5 ore con disco di norfloxacina ed infine raccolti per l’analisi dello spettro proteico tramite MALDI-TOF. Per lo studio è stato utilizzato il software Saramis™ dello strumento Vitek-MS® (BioMerieux), che ha consentito l’analisi scorporata dei singoli spettri rilevati. In particolare, sono stati ricercati gli spettri corrispondenti alle forme di norfloxacina native e acetilate (metodo “indiretto”) e il picco corrispondente all’enzima aac(6’)-Ib-cr (metodo “diretto”). In entrambi i casi, la valutazione non ha dato risultati soddisfacenti, sia in termini di concordanza con il metodo tradizionale, che di specificità e sensibilità.
In conclusione, il percorso diagnostico rapido per la determinazione della MIC è risultato valido in termini di riproducibilità e affidabilità e può essere applicato, seppur con alcune riserve, nella diagnosi microbiologica di sepsi. Al contrario, la rilevazione della resistenza ai chinoloni tramite spettrometria di massa con il metodo indagato non ha dimostrato alcuna applicabilità nella pratica clinica. Ulteriori approfondimenti potranno essere presi in considerazione, tenendo sempre conto della necessità di garantire un risultato rapido e preciso, che non tralasci la centralità di una diagnosi e cura sempre guidate da expertise, prudenza e monitoraggio clinico.

EPrint type:Ph.D. thesis
Tutor:Parisi, Saverio
Ph.D. course:Ciclo 27 > scuole 27 > BIOMEDICINA
Data di deposito della tesi:07 September 2017
Anno di Pubblicazione:07 September 2017
Key Words:antibiogramma, Gram-negativi, sepsi, fenotipo di sensibilitĂ  antimicrobial susceptibility testing
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/07 Microbiologia e microbiologia clinica
Area 06 - Scienze mediche > MED/17 Malattie infettive
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:10515
Depositato il:25 Oct 2018 16:51
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