key: cord-1018730-12izjt6p
authors: García-Meniño, Isidro; Forcelledo, Lorena; Rosete, Yaiza; García-Prieto, Emilio; Escudero, Dolores; Fernández, Javier
title: Spread of OXA-48-producing Klebsiella pneumoniae among COVID-19-infected patients: the storm after the storm
date: 2020-12-03
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2020.11.001
sha: 559b4a98d5a15e7fde0a465abbb52c2b3da1850b
doc_id: 1018730
cord_uid: 12izjt6p

The impact of secondary infections by multidrug-resistant bacteria in COVID-19- infected patients has yet to be evaluated. Here, we report the clinical and molecular features of an outbreak of seven patients carrying CTX-M-15- and OXA-48-producing Klebsiella pneumoniae belonging to ST326 during COVID-19 pandemic in an ICU in northern Spain. Those patients were admitted to beds close to each other, two of them developed ventilator-associated pneumonia (VAP), one exhibited primary bacteremia and the remaining four were considered to be colonized. None of them was colonized prior to admission to the ICU an all, except one of those who developed VAP, were discharged. Hydroxychloroquine and lopinavir/ritonavir were administered to all of them as COVID-19 therapy and additionally, three of them received tocilizumab and corticosteroids, respectively. Reusing of personal protective equipment due to its initial shortage, relaxation in infection control measures and negative-pressure air in ICU rooms recommended for the protection of health care workers (HCWs), could have contributed to this outbreak. Maximization of infection control measures is essential to avoid secondary infections by MDR bacteria in COVID-infected patients.

The impact of secondary infections by multidrug-resistant bacteria in COVID-19infected patients has yet to be evaluated. Here, we report the clinical and molecular features of an outbreak of seven patients carrying CTX-M-15-and OXA-48-producing Klebsiella pneumoniae belonging to ST326 during COVID-19 pandemic in an ICU in northern Spain. Those patients were admitted to beds close to each other, two of them developed ventilator-associated pneumonia (VAP), one exhibited primary bacteremia and the remaining four were considered to be colonized. None of them was colonized prior to admission to the ICU an all, except one of those who developed VAP, were discharged. Hydroxychloroquine and lopinavir/ritonavir were administered to all of them as COVID-19 therapy and additionally, three of them received tocilizumab and corticosteroids, respectively. Reusing of personal protective equipment due to its initial shortage, relaxation in infection control measures and negative-pressure air in ICU rooms recommended for the protection of health care workers (HCWs), could have Health systems worldwide are confronted by COVID-19, one of the most serious challenges in modern medicine. The most complex struggle is happening in intensive care units (ICUs), where the use of personal protective equipment (PPE) including respiratory protection, long-sleeved water-resistant gown, eye protection (goggles or face shield), and gloves is considered essential for health care workers (HCWs) and is now widespread [1, 2] . However, PPE shortages means items are commonly being reused on the same working day when HCWs move from one patient to another. This issue, together with other aspects such as i) the huge overload of work, that may result in a certain relaxation of infection control measures, ii) the hiring of unqualified personnel in ICUs, and iii) the impaired immune system of patients infected with COVID-19, could cause an increase in outbreaks of multidrug-resistant (MDR) bacteria among such patients in ICUs.

Our hospital (Hospital Universitario Central de Asturias, northern Spain), and specifically the ICU, was recently battling the COVID-19 pandemic. Since admitting the first patient to the ICU on February 29 th , a total of 62 patients have passed through the unit. In recent weeks, seven ICU patients with clinical and/or surveillance samples that have tested positive for carbapenem-resistant Klebsiella pneumoniae have been detected (see source of colonization/infection and clinical data in Table 1 ). Bacterial identification was performed by MALDI TOF/MS (Bruker Daltonics, Bremen, Germany) and antimicrobial susceptibility testing carried out by the Microscan System (Beckman Coulter, Brea, CA, USA), and the results interpreted according to EUCAST (www.eucast.org). Bacterial DNA was extracted by boiling lysis method and extended-J o u r n a l P r e -p r o o f spectrum β-lactamase (ESBL) and carbapenemase encoding genes were screened by the AMR Flow Chip system (Máster Diagnóstica, Granada, Spain), conventional PCR and further sequencing as previously described [3] , and all were positive for the bla CTX-M-15 and bla OXA-48 genes . Pulsed-field gel electrophoresis (PFGE) was carried out as described elsewhere using endonuclease XbaI and similarities evaluation was performed by the Dice coefficient using MVSP (Multivariate Statics Package for PCs, RockWare Inc.) [3] , showing two similar pulsotypes (Supplementary Figure 1) with a coefficient of similarity higher than 0.85 suggesting that all isolates were the same clone. Multilocus sequence typing (MLST) performed according to Pasteur guidelines (https://pubmlst.org/) revealed that isolates belonged to sequence type (ST) 326 (gapA 1, infB 1, mdh 1, pgi 1, phoE 1, rpoB 1, tonB 64) a clone previously related to OXA-48 dissemination in Spain [3, 4] .

Since all patients were admitted to beds close to each other, and the relationship between their isolates was clonal (almost equal PFGE profiles with Dice similarities higher than 0.85), cross-transmission through the contaminated PPE of HCWs could be the main hypothesis of likely spread, considering that transmission via contaminated gowns and gloves has been described to be important in the nosocomial spread of K. pneumoniae strains [5] . It is of note that none of the patients were previously [5] . Already some studies have described that patients hospitalized with COVID-19 have acquired dangerous secondary bacterial infections, which appear strongly linked to death, (up to 50% of the total number of fatalities having such infections) [7, 8] . In other viral pandemics scenarios, such as the 1918-1919 influenza pandemic, is hypothesized that most of the deaths were caused by secondary bacterial infections [9] . In those days, medicine was in the pre-antibiotic era, but nowadays the high pressure of MDR bacteria in some environments like ICUs, could also bring on serious problems during the COVID-19 pandemic.

Diagnosis of secondary MDR bacterial infections is tricky since they could be masked by alterations in acute infection markers caused by COVID-19 itself. Furthermore, it is J o u r n a l P r e -p r o o f important to distinguish between colonization and infection especially in non-sterile samples, while at the same time noting that when these bacteria are detected in sterile fluids such as blood cultures, it may be too late for optimal treatment to be implemented. In our series, two patients developed ventilator-associated pneumonia, one exhibited primary bacteremia and the remaining four were considered to be colonized ( Table 1 ). The three infected patients were treated with meropenem (MICs to this antibiotic were of 1 mg/L), but in two patients treatment had to be escalated to ceftazidime/avibactam due to an increase in meropenem MIC (32 mg/L) during therapy.

All except one of those who developed VAP, was successfully discharged from ICU (Table 1) .

Only a few antimicrobials are available for the treatment of infections caused by MDR bacteria in general and particularly for carbapenemase-producing Enterobacteriaceae [10] . In COVID-19-affected patients this situation is aggravated by factors such as organ disruption (renal and liver impairment) and potential interactions with immunomodulators or other drugs used in their treatment (antiretrovirals, macrolides, hydroxychloroquine, etc.). As such, new drugs such as new ß-lactams and ß-lactamase inhibitors (ceftazidime/avibactam, ceftolozane/tazobactam, ceftaroline…) could play an important role in the treatment of secondary infections caused by MDR bacteria in these patients.

There is still much to learn about the role and prevention of secondary infections by MDR bacteria and specifically carbapenemase-producing 

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