Nosocomial septicemia in COVID-19 nosocomial K. pneumoniae, A. baumannii, and Elizabethkingia meningoseptica septicemia in a patient of COVID-19.

To the Editor:

We read with interest the paper by Kwok and colleagues to highlight the antibiotic overuse among hospitalized coronavirus disease 2019 (COVID-19) cases. Although the reported antibiotic prescription rate (29.1%) was lower than previously reported, it still remarkably exceeded that of the confirmed bacterial co-infections (1.8%). However, for patients who develop severe hypoxemia, immune modulation with corticosteroids and anti-IL6 are suggested to limit the collateral damage of the cytokine storm. Aggressive supportive care such as central venous catheterization, mechanical ventilation, and extracorporeal membrane oxygenation may be needed for those with respiratory failure and hemodynamic instability. These invasive procedures and immune modulators render these patients vulnerable to nosocomial infections, negatively impacting treatment outcomes. It could be a dilemma whether antibiotics should be used for those with deteriorating multiorgan dysfunctions. Herein, we reported a patient of COVID-19 associated acute hypoxemic respiratory failure who was initially treated with broad-spectrum antibiotics, corticosteroids, tocilizumab, and remdesivir and was successfully liberated from mechanical ventilation. Yet, bacteremia and osteomyelitis of multidrug-resistant nosocomial pathogens ensued, leading to a protracted course of hospitalization.

A 65-year-old man visited the emergency room due to productive cough, lightheadedness, weakness, and shortness of breath for one week during an outbreak of domestic COVID-19. The patient was a teacher of physical education who was in his usual state of health before this episode. He had a past medical history of alcoholism with alcoholic liver cirrhosis and was inconsistently followed up.

He was 176 cm tall and weighed 70 kg. He was febrile, tachypneic, and cyanotic (saturation of peripheral oxygen, SpO2 87%). His-laboratory data showed abnormal liver function tests (aspartate aminotransferase 119 U/l, alanine aminotransferase 89 U/l, and total bilirubin 2.4 mg/dl), elevated infection parameters (C-reactive protein 3.1 mg/dl, procalcitonin 1.07 ng/ml, d-dimer 1.02 mcg/ml and ferritin 4298 ng/ml), and lactic acidosis (pH 7.308, HCO3 19.1 mmol/l, lactate 8.7 mmol/l). High hemoglobin A1c (9.0%) was noted, but he was previously unaware of a diagnosis of diabetes mellitus. The SARS-CoV-2 reverse transcriptase-polymerase chain reaction was positive. The chest X-ray showed bilateral ground-glass opacities.

After being admitted, he was empirically treated with intravenous ertapenem and levofloxacin (Table. 1 ). Dexamethasone and remdesivir therapy were started on the first and third days. On the third day, one dose of tocilizumab 600 mg was given alongside. Enoxaparin 40 mg QD was prescribed to prevent thromboembolism.

Table 1

Summary of the admission course, antimicrobial agents, and culture results.

Time (day)	Event	Antibiotics	Culture
−7	Cough, shortness of breath
1	Admission, dexamethasone given	Ertapenem, levofloxacin	Sputum: normal flora; Blood: negative
3	Tocilizumab and remdesivir used	Ertapenem, levofloxacin
6	Mechanical ventilation (MV)	Doripenem, levofloxacin, teicoplanin	Sputum: normal flora and Candida albicans; Blood: negative
9	Liberation from MV
19	Jaundice, sepsis	Meropenem, fluconazole	Blood: A. baumannii, K. pneumoniae, Elizabethkingia meningoseptica
22		Cefoperazone/sulbactam, tigecycline
23	Spiking fever jaundice progressed	Ceftazidime/avibactam, amikacin	Blood: E. meningoseptica
26		Piperacillin/tazobactam, tigecycline	Blood: E. meningoseptica
31			Blood: E. meningoseptica
44	Spine MRI: osteomyelitis	Cefoperazone/sulbactam, tigecycline	Blood: negative
58	Discharge	Minocycline, sulfamethoxazole/trimethoprim	Blood: negative

On the 6th day of admission, with the support of an O2 mask using a fraction of inspiration oxygen (FiO2) of 0.6, the partial pressure of oxygen (PaO2) of arterial blood was 102.1 mmHg (PaO2/FiO2 = 170 mmHg). He fainted while briefly leaving the oxygen support, attempting to go to the toilet. Mechanical ventilation was initiated through an endotracheal tube.

Antibiotics were altered to doripenem, levofloxacin, and teicoplanin to cover suspected nosocomial infection. He improved and was liberated from mechanical ventilation three days later. The sputum culture grew normal flora and Candida albicans, and the antibiotics were discontinued. However, he became icteric and exhausted on the 19th day. Although he showed no fever or chillness, meropenem and fluconazole were used empirically. The blood culture yielded carbapenem-resistance Klebsiella pneumoniae, Acinetobacter baumannii, and Elizabethkingia meningoseptica. The antibiotics were changed to cefoperazone/sulbactam and tigecycline. Yet, spiking fever developed on the 23rd day and jaundice progressed (Total bilirubin 8.47 mg/dl). The antimicrobials were altered to ceftazidime/avibactam and amikacin. Later, the blood culture yielded Elizabethkingia meningoseptica. The antibiotics were changed to piperacillin/tazobactam and tigecycline. Jaundice and fever subsided, but the Elizabethkingia meningoseptica bacteremia persisted until the 31st day of admission. The antibiotics continued until two weeks after blood cultures converted to negative results.

He kept complaining about lower back pain, and abnormal alkaline phosphatase levels ranging from 110 to 220 U/l persisted. It raised the doubt of unresolved infection foci. A spine MRI revealed an abnormal enhancement in T2-weighted images, suggestive of osteomyelitis, at L3–4 endplates (Fig. 1 ). Intravenous cefoperazone/sulbactam and tigecycline were administered. Subsequent blood cultures yielded no positive results. After a 14-day course of intravenous antibiotics, oral minocycline and sulfamethoxazole/trimethoprim were used, and the patient was discharged. The oral antibiotics were continued for four months in the outpatient department until the erythrocyte sedimentation rate declined to be within normal limits.

Fig. 1

Contrast enhancement at L3–4 endplate in T2-weighted images of the spine magnetic resonance imaging.

As pointed out by Kwok et al., bacterial co-infection is rare among hospitalized COVID-19 patients, and antibiotics should not be prescribed as a routine upon admission. Imprudent use of antibiotics predisposes the patients to multi-resistant nosocomial infections, especially for those with comorbid conditions, advanced age, using immunosuppressants, indwelling invasive devices, and prolonged hospitalizations. On the other hand, delay in adequate antibiotic coverage for patients with sepsis due to bacterial etiologies leads to catastrophic organ dysfunctions and increases the risk of mortality. Procalcitonin, widely used as an indicator for bacterial septicemia, also increases in a severe COIVD-19 cytokine storm. As illustrated in the present case, the usefulness of procalcitonin to guide antibiotics therapy was eclipsed in patients with severe COVID-19.

Multiple factors contributed to the increased risk of secondary infection in severe COVID-19. Patients with underlying medical conditions are more likely to progress to severe disease. Suppression of type 1-interferon production by the SARS-CoV2 infection compromises macrophage recruitment and phagocytic function, creating a positive environment for secondary bacterial infections , . Contamination of these multidrug-resistant K. pneumoniae, A. baumannii, and Elizabethkingia meningoseptica frequently found in the environment of intensive care units could be translocated to patients’ mucosa or skin surface during daily care. The use of broad-spectrum antibiotics, especially the carbapenems, decreases the diversity and shifts the equilibrium of microbial flora, favoring these resistant strains. The combination of underlying comorbidities, immune dysfunction, immunosuppressive therapy, and invasive procedures breaching the natural skin and mucosal barriers makes patients of severe COVID-19 prone to secondary nosocomial infections.

Elizabethkingia meningoseptica septicemia and osteomyelitis, although uncommon, is highly resistant to antibiotics and carries a high risk of mortality. Judicious use of antibiotics is suggested to avoid the expansion of multi-drug resistant pathogens, and agile microbiological study is advised if clinical clues of sepsis arise.

Funding

No funding source to report

Ethical statement

The Joint Institutional Review Board of Taipei Medical University approved this report (N202203030). The consent for publication was obtained from the patient.

CRediT authorship contribution statement

Jie Ywi Ong: Writing – original draft, Visualization. Cheng-Hui Wang: Writing – original draft, Resources. Yi-San Tsai: Data curation, Conceptualization, Writing – review & editing. Fu-Lun Chen: Writing – review & editing, Resources. Chih-Hsin Lee: Writing – review & editing, Conceptualization. Tsong-Yih Ou: Writing – review & editing, Supervision, Project administration.

Conflict of Interest

The authors declare no conflict of interest.