Infection Associated with COVID-19: A Case Series and Literature Review

Background

Stenotrophomonas maltophilia, a multidrug resistant, gram-negative bacterial rod is found in aquatic environments, such as water, soil, and plants. Owing to its ability to form biofilms on medical equipment and to grow in disinfectants, it is an emerging opportunistic pathogen known to cause bacteremia, pneumonia, endocarditis, and meningitis, as well as urinary tract, ocular, bone and joint, skin and soft tissue, and gastrointestinal infections in hospitals settings [1]. S. maltophilia infections include ventilator-associated pneumonia (VAP) and central venous catheter (CVC)-related bacteremia [2]. S. maltophilia bacteremia has a mortality rate of over 20%, and risk factors include Intensive Care Unit (ICU) admission, indwelling devices such as CVC and ventilators, exposure to carbapenems and anti-Pseudomonas aeruginosa cephalosporins within 14 days prior to bacteremia, and S. maltophilia isolation within 30 days [3]. S. maltophilia pneumonia has been reported to cause opportunistic infections in some patients, such as those with hematologic malignancy [4]. S. maltophilia colonizes the sputum, and a high sequential organ failure assessment score is seen in patients who are immunocompromised and exposed to broad-spectrum antimicrobial agents [5]. It is difficult to determine whether S. maltophilia simply colonizes the lungs or causes true infection leading to pulmonary inflammation. Despite a few reports of S. maltophilia pneumonia in patients with COVID-19, the risk factors for S. maltophilia infection in COVID-19-positive patients are unknown. Herein, we aimed at identifying the risk factors for S. maltophilia infection in patients with COVID-19 based on the information available in the literature and on our cases in St Luke’s International Hospital between January 1, 2020, and August 31, 2021.

Case Reports

CASE 1:

A 52-year-old woman using prednisolone (PSL) and baricitinib (BARI) with a medical history of systemic lupus erythematosus, rheumatoid arthritis, liver cirrhosis, and interstitial pneumonia was admitted to our Emergency Department with high fever and headache. On admission, her vital signs were as follows: clear consciousness; temperature, 37.2°C; blood pressure, 101/77 mmHg; pulse rate, 100 beats/min; respiratory rate, 22 breaths/min; and oxygen saturation, 94% on room air. The patient’s COVID-19 polymerase chain reaction (PCR) test result was positive. Chest computed tomography (CT) revealed bilateral, non-segmental, ground-glass opacities in the diffuse area, and honeycomb appearance associated with interstitial pneumonia in the bilateral dorsal aspects of the inferior lung lobe (Figure 1A–1C). We initiated administration of remdesivir (RDV) and methylprednisolone (mPSL) 1000 mg/day for 3 days followed by mPSL 40 mg/day, BARI 4 mg/day, and ceftriaxone (CTRX) 1 g intravenously (i.v.) every 24 h. On day 4 of hospital admission, her respiratory status worsened, she was moved to the ICU, and a nasal high flow cannula was inserted. We switched the antibiotics to meropenem (MEPM). On day 8, the patient developed a fever of 37.9°C with 90% oxygen saturation with FIO2 60% and nasal high flow gas 40 L/min, and was intubated. Blood and sputum cultures were positive for S. maltophilia (Figure 2A, 2B). Mucoid-type S. maltophilia was detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Biotyper, Bruker Daltonics, Germany). Adjustment to 0.5 McFarland in the mucoid-type S. maltophilia was difficult; thus, susceptibility testing could not be performed. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX) (equivalent to 15 mg/kg/day TMP) was initiated. Her respiratory status improved; however, the Aspergillus galactomannan antigen level was 1.1. We administered voriconazole to treat COVID-19-associated invasive aspergillosis. The patient’s respiratory condition stabilized, although the duration of intubation was extended; consequently, tracheostomy was performed. Sputum culture revealed elimination of S. maltophilia. At the time of writing this review, the patient’s clinical status had improved (Figure 3).

CASE 2:

An 80-year-old man with a medical history of hypertension and acute myocardial infarction status after coronary artery bypass graft was admitted to our Emergency Department with high fever. On admission, the vital signs were as follows: clear consciousness; temperature, 37.6°C; blood pressure, 101/77 mmHg; pulse rate, 98 beats/min; respiratory rate, 22 breaths/min; and oxygen saturation, 96% (10 L/min on reservoir mask). The patient’s COVID-19 PCR result was positive. Chest CT revealed bilateral ground-glass opacity and reticulation with subpleural distribution (Figure 4A, 4B). We initiated administration of RDV, dexamethasone (DEXA) 6.6 mg/day, BARI 4 mg/day, and CTRX 1 g i.v. every 24 h. Owing to severe hypoxemia, he was transferred to the ICU and mechanically intubated, and a CVC was inserted. On day 4 of hospital admission, he developed a fever of 38°C, and antibiotics were switched to piperacillin/ tazobactam (PIPC/TAZ). A sputum culture on day 8 revealed the presence of Candida glabrata (mold) and S. maltophilia; however, we did not administer any treatment for these as we assumed them to be colonizing organisms. The minimum inhibitory concentrations were measured using the MicroScan WalkAway 96 Plus and NC-NF2J panel (Beckman Coulter Inc). Levofloxacin (LVFX), minocycline (MINO), TMP-SMX, and ceftazi-dime were all effective (Table 1). The patient had persistent prominent fever; however, and a blood culture on day 11 indicated C. glabrata infection. We administered micafungin and replaced the CVC. Follow-up blood cultures were negative for C. glabrata; however, the fever did not abate, and on day 18 the patient showed increased hypoxia. Switching antibiotics from PIPC/TAZ to MEPM did not improve the clinical symptoms.

Therefore, we administered TMP-SMX (equivalent to 15 mg/ kg/day TMP) for treating S. maltophilia-associated pneumonia, and the fever resolved. Owing to acute kidney injury, we switched from TMP-SMX to LVFX and MINO. Aspergillus galactomannan sputum antigen was >5.0, and we administered voriconazole. However, the patient’s respiratory status worsened. He died on day 28 of hospital admission due to COVID-19-associated invasive aspergillosis (Figure 5).

CASE 3:

A 48-year-old man with COVID-19 and a medical history of hypertension, diabetes, and obesity was admitted to another hospital, where he was treated with RDV and DEXA. His respiratory condition deteriorated, and he was mechanically intubated and treated with mPSL 1000 mg/day for 3 days. On day 7 following COVID-19 onset, his PaO2/FiO2 ratio was about 80. He was transferred to our hospital for COVID-19 treatment with extracorporeal membrane oxygenation (ECMO). Chest CT revealed bilateral diffuse consolidation (Figure 6). He was treated with RDV, mPSL 125 mg/day, and PIPC/TAZ. His respiratory status stabilized; therefore, ECMO was discontinued, and he was extubated on day 9. On day 10 of hospital admission, he had increased sputum production and his C-reactive protein level increased to 23.7 mg/dL. Chest radiography revealed consolidation in the right lower lung field (Figure 6). The sputum culture revealed the presence of S. maltophilia; therefore, he was treated with TMP-SMX (equivalent to 15 mg/kg/day TMP). By the time of this report, the patient was clinically stable and preparing for transfer to a rehabilitation hospital (Figure 7).

CASE 4:

An 80-year-old man with a medical history of dementia developed COVID-19 four days before admission. The patient was medically monitored at a health care institute. When his O2 saturation level gradually decreased, he was admitted to our hospital. Chest CT revealed ground-glass opacity with subpleural distribution (Figure 8). We started RDV, DEXA 6.6 mg/day, AZM 500 mg/day, and CTRX 1 g i.v. every 24 h. Owing to severe hypoxemia, he was transferred to the ICU and mechanically intubated on day 6 after hospital admission. On day 9, his sputum culture revealed S. maltophilia, Klebsiella aerogenes, and Enterococcus faecalis. Although susceptible to LVFX, MINO, and TMP-SMX, the bacteria were resistant to ceftazidime (Table 2). The patient was treated with LVFX 500 mg/day. On day 18 of hospital admission, he was extubated. However, his sputum production increased, and he was re-intubated on day 34. He was treated with TMP-SMX (equivalent to 15 mg/kg/day TMP) and MEPM. His respiratory status improved, although a tracheostomy had to be performed because of CO2 retention. He was finally transferred to a rehabilitation hospital on day 56 of hospital admission (Figure 9).

Discussion

Two authors independently reviewed the relevant titles and abstracts in the database records, retrieved full texts for eligibility assessment, and extracted the information from these cases. We performed a search using the keywords “Stenotrophomonas maltophilia” and “COVID-19” in the electronic databases PubMed, Embase, and Ichushi from January 1, 2020, to April 4th, 2022 (Table 3).

We found 68 articles and 8 case reports on COVID-19-associated S. maltophilia infection (Figure 10). The clinical characteristics of the patients in the 8 published cases, including the 4 in this review, are shown in Table 4. Furthermore, we extracted 13 retrospective studies on COVID-19-associated S. maltophilia infections, which are shown in Table 5.

We extracted the data of 8 patients with COVID-19 and positive S. maltophilia cultures at St. Luke’s International Hospital, a 520-bed teaching hospital in Tokyo (Figure 10). Four patients were diagnosed with S. maltophilia colonization, while the other 4 had COVID-19-associated S. maltophilia infection (Table 4).

The median age of the 12 patients, including the 4 patients in this review, with COVID-19-associated S. maltophilia infection was 64 years (Table 4). Among them, 10 (83%) were men. Eleven patients (92%) were admitted to the ICU, and 12 (100%) were mechanically intubated. Immunosuppressants such as steroids, BARI, and tocilizumab were used in 9 (75%) patients; however, only DEXA, a short-term steroid used for COVID-19, was administered in 2 patients. Antimicrobial agents were administered to almost all patients, including MEPM to 5 patients, PIPC/TAZ to 2 patients, and cefepime to 1 patient. The treatment against S. maltophilia was TMP-SMX in 7 patients, and 2 were switched from TMP-SMX to LVFX owing to acute renal injury; LVFX was used in 5 patients, including 2 patients who were switched from TMP-SMX, as mentioned above. There were 3 deaths. In our hospital, there were 4 patients with S. maltophilia colonization, all of whom were admitted to the ICU, 3 who were administered steroids, and 3 who were administered broad-spectrum antibiotics such as cefepime, PIPC/TAZ, or MEPM. Two patients had positive sputum cultures; however, they were resolved without treatment. Autopsy blood cultures from 2 patients were positive for S. maltophilia, although their antemortem blood cultures were negative.

Among the 13 observational studies (Table 5), 4 were from China, 2 from Italy, 2 from Spain, and 5 from the United States. Nine of the 13 studies were conducted in the ICU (2 studies had mixed ICU and non-ICU patients). Eleven studies included respiratory infections, such as VAP and hospital-acquired pneumonia (HAP). Mortality rates ranged from 15.4% to 52.4%, although we did not find any mortality rate for S. maltophilia-associated VAP or HAP. In addition to S. maltophilia, the organisms Acinetobacter spp., P. aeruginosa, and Enterobacter spp. were the causative or isolated organisms in VAP and HAP.

Here, we report 4 cases of COVID-19-associated S. maltophilia infection. To the best of our knowledge, this is the first literature review on COVID-19-associated S. maltophilia infection. It may help clinicians make treatment choices by presenting clinical data on patient backgrounds, treatment choices, and outcomes of COVID-19-associated S. maltophilia infection, for which no consensus has been reached.

S. maltophilia can form small colony variants [6], and the one detected in Case 1 was considered to be of the mucoid type as it was a large, viscous colony with a positive string test. Reports of mucoid-type S. maltophilia are rare: only 1 case from Japan has been previously reported [7]. Further studies are needed to clarify the mechanism of mucoid-type S. maltophilia.

Among patients without COVID-19, the risk of S. maltophilia infection was higher in patients who were admitted to the ICU, intubated, and had exposure to broad-spectrum antimicrobials and used immunosuppressants [3,5]. In this review, patients with COVID-19 had similar risk factors for S. maltophilia infection. In our observational study at St Luke’s International Hospital, S. maltophilia colonization was 50% in 8 patients. It is difficult to distinguish between patients with S. maltophilia colonization and infection as they have similar baseline characteristics. The previous study reported that VAP caused by S. maltophilia is associated with high morbidity and mortality [6]. Another study reported a mortality rate due to S. maltophilia bacteremia ranging from 12.5% to 41% [7]. According to the Infectious Diseases Society of America guideline, the overall VAP mortality rate is 20% to 50% [8]. Therefore, the mortality rate for S. maltophilia is also high enough. Owing to the high mortality rate of COVID-19-associated S. maltophilia infection, we believe that this condition should be treated in clinically unstable patients. In general, S. maltophilia-associated pneumonia was diagnosed 11 days after intubation and 11 days after ICU admission [8]. In the present study, COVID-19-associated S. maltophilia was either isolated from the culture immediately after ICU admission or was positive in the PCR test for S. maltophilia if not detected in the culture [9,10]. Therefore, S. maltophilia infection should be considered immediately after ICU admission in patients with COVID-19. Chest CT imaging abnormalities in COVID-19-associated pneumonia manifest as rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities that progress to or co-exist with consolidations within 1 to 3 weeks [11]. Chest CT imaging abnormalities in S. maltophilia infections also appear as ground-glass opacity [12,13], which is difficult to distinguish from that of COVID-19. In the 4 patients in this review, we did not find any new ground-glass opacity when the S. maltophilia culture was positive. In these 4 patients, S. maltophilia was susceptible to TMPX-SMX, LVFX, and MINO. S. maltophilia is a multidrug-resistant organism exhibiting intrinsic metallo-beta-lactamases, cephalosporinases, and efflux pumps [14]. Therefore, S. maltophilia is resistant to penicillin, cephalosporins, and carbapenems. It is important for the clinician to note that beta-lactams such as carbapenems target extended-spectrum beta-lactamase-producing Enterobacteriaceae and is not effective for S. maltophilia. We have to administer TMP-SMX or LVFX to treat S. maltophilia infection.

There is limited evidence on effective antimicrobials against S. maltophilia. TMP-SMX is the most commonly used drug showing good susceptibility [15]. In the presence of TMP-SMX-induced hypersensitivity reactions and acute kidney injury, LVFX is an alternative; however, 1 study showed no difference in its efficacy compared to that of TMP-SMX [16]. Moreover, LVFX-resistant S. maltophilia has emerged worldwide [17]. The aforementioned study showed that a history of fluoroquinolone use, previous ICU stay, and the number of previous exposures to different classes of antibiotics were significantly associated with LVFX-resistant S. maltophilia. Another study described the antimicrobial susceptibility of COVID-19-related S. maltophilia [18], and the resistant strains were ceftazidime (90%), LVFX (30%), TMP-SMX (0%), and MINO (0%). In our review, S. maltophilia infection was associated with higher mortality; therefore, we suggest empirically administering TMX-SMP. Further studies are needed to confirm this hypothesis.

This study had some limitations. As VAP and HAP definitions differed among the studies, it was not possible to discern whether S. maltophilia was colonizing or infectious. In addition, no retrospective studies have analyzed the risk factors and mortality associated with S. maltophilia. However, this case review suggested that a history of broad-spectrum antimicrobial use, steroid use, and ICU admission are risk factors for COVID-19-associated S. maltophilia infection.

Conclusions

S. maltophilia is detected in sputum cultures of clinically unstable ICU patients with COVID-19 who are receiving immunosuppressive drugs, are intubated, or are on broad-spectrum antimicrobial agents. We suggest administering treatment for S. maltophilia-associated pneumonia.