Multidrug-Resistant and Methicillin-Resistant Co-Infection in a Nigerian Patient with COVID-19: A Case Report

Background

The Coronavirus Disease 2019 (COVID-19), an acute and highly infectious respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a problem globally since its first report in 2019. Fatalities due to this disease has been reported worldwide, with a higher risk of severe infection and, consequently, mortality observed in the elderly, immunocompromised, and patients with co-morbidities and co-infections such as chronic kidney disease, pulmonary disease, cardiovascular diseases, and diabetes [1–3]. The increased risk of mortality seen in this demographic has been associated with the onset of opportunistic infections, which further complicates COVID-19 treatment.

Bacterial co-infection has been reported as a substantial impediment to the management of viral respiratory tract infections, resulting to a large increase in morbidity and mortality [4]. In the early cases of COVID-19, attention was not paid to bacterial co-infection in COVID-19 mortality. This may be because most reports do not focus on the prevalence and etiology of bacterial co-infection in COVID-19 patients. However, bacteria co-infection with COVID-19 has been linked to an increased risk of shock, respiratory failure, and longer hospital stay. About 3.5% of patients have been reported to have bacterial co-infection at the time of COVID-19 diagnosis, while 14.3% are classified as secondary bacterial co-infections (SBI), which are bacterial infections contracted after admission with COVID-19 [5]. Most of the bacterial co-infection seen in COVID-19 cases are secondary bacterial co-infections. However, Staphylococcus aureus was the most common pathogen causing respiratory co-infections, secondary bacterial co-infection, and bloodstream infection among COVID-19 patients [6–8]. In addition, reports have shown that bacterial co-infections are responsible for 0.6–50% of COVID-19 deaths [3,4]. Hence, there is a need for proper diagnosis and treatment of patient with bacterial co-morbidities to prevent or reduce complications associated with bacterial co-infection in COVID-19 patients. The aim of this case report is to present the case of a male diabetic patient with bacterial co-infection of methicillin-resistant Staphylococcus aureus and Kocuria rosea with COVID-19, and the impact of diagnosis and treatment on his COVID-19 outcome.

Case Report

On August 20, 2021, during the third COVID-19 wave in Nigeria, a 72-year-old male Nigerian presented with symptoms of cough, chest pain, urinary incontinence, respiratory distress, sore throat, fever, diarrhea, loss of taste, and anosmia (loss of smell), all characteristics of COVID-19. The patient was confirmed and diagnosed with COVID-19 at the Infectious Diseases Hospital, Lagos, Nigeria. This hospital is a renowned hospital where the index case of COVID-19 was detected in Nigeria.

The hospital uses the Sansure Novel Coronavirus (2019-nCoV) Nucleic Acid Diagnostic Kit for COVID-19 diagnosis coupled with symptoms. The kit has been reported to have high sensitivity and has also been endorsed for the diagnosis of COVID-19 [9].

A review of the medical history of the patient showed that he had hypertension and diabetes mellitus but did not have a record of any indwelling devices. He had received a dose of the COVID-19 vaccine 1 week before admission. However, information was not available on which brand of the vaccine and how many doses of the vaccine he had received. There was also no information on how well the patient managed his diabetes, his travel history, or if he had been in contact with someone who travelled into Nigeria.

Physical examination at the time of admission showed he had an oxygen saturation level of 94% with a non-rebreathing face mask (NRFM) at 15 liters per minute (L/min), blood pressure of 170/89 millimeter mercury (mmHg), pulse rate of 108 beats per minute, respiratory rate of 22 cycles per minute, temperature of 37°C, and elevated fasting blood and random blood sugar values of 257 milligram per deciliter (mg/dL) and 365 nanogram per deciliter (ng/dL), respectively. Apart from this, blood examination showed that he also had septicemia, with an elevated white blood cell count of 17×109/L, a neutrophil percentage of 83%, lymphocytes 12%, and an elevated erythrocyte sedimentation rate (ESR) level of 98 mm/h, but all other blood parameters, including platelet counts, were normal. He also had normal electrolytes, urea, and creatinine levels. The patient was catheterized on admission, but it was indicated in the case note that this was later removed. A blood sample was collected for blood culture; however, the results of the blood culture were not available before treatment commenced.

Upon admission, the patient was managed for COVID-19 and associated symptoms with IV ceftriaxone 1g every 12 hours; IV metronidazole 500 milligrams (mg) every hour; IV dexamethasone 8 mg and then 4 mg every 12 hours; subcutaneous enoxaparin 40 mg every 12 hours; Ivermectin tablet 12 mg on days 1, 3, 6, and 7; Zinc tablet 100 mg daily; vitamin C Tablet 1000 mg daily; and vitamin D Tablet 1000 International units (IU) daily. For other co-morbidities, the patient received subcutaneous insulin 10 IU every 8 hours a day and a tablet of amlodipine 10 mg daily. The treatment regimen was well adhered to as the nurses were responsible for instituting the intervention and frequent checks were done on the patients in the isolation wards by the health team to assess tolerability to the interventions. No significant adverse effects were reported throughout the patient’s management.

Follow-up tests during his stay at the center included regular monitoring of vital signs and fasting and random blood sugar level evaluation. At follow-up, the white blood cell count had increased to 19.23×109/L, the neutrophil percentage increased to 89.2%, and the ESR level increased to 105 mm/h.

The fasting and random blood sugars also remained elevated, but all other hematological parameters remained normal. Due to poor glycemic and blood pressure control, the dosage of the subcutaneous insulin was increased, and Glucophage, glibenclamide, Moduretic, and losartan tablets were added to the patient’s regimen. Also, due to the increasing WBC counts and the blood culture results that showed the presence of a presumptive Staphylococcus species, intravenous ciprofloxacin was given. Nebulized high-flow oxygen delivery with salbutamol and budesonide was also given to help with poor oxygen saturation.

On September 9, 2021, as part of an on-going study on the nasal bacteria carriage among COVID-19 patients, the nasopharyngeal sample of the patient was collected. The swabs were placed in a tryptone soy broth (TSB) enriched with sodium chloride and a skimmed milk, tryptone soy broth, glycerol, and glucose (STGG) transport medium. The sample in the sodium chloride-enriched TSB was incubated aerobically overnight at 37°C, while the sample in the STGG was incubated microaerophilically overnight at 37°C. The broth was plated on mannitol salt agar, MacConkey agar, blood agar, and nutrient agar. The isolated growth showed a mixed culture of Staphylococcus aureus and a mannitol-negative strain which was similar but had morphological differences from Staphylococci. The Staphylococcus aureus was identified based on mannitol fermentation and confirmed using the API Staph V4.0 system (bioMérieux, France) and amplification of the nuc gene using polymerase chain reaction.

Based on the exhibited morphological characteristics as identified in the literature [10], the second bacterial isolate was suspected to be a Kocuria species.

The isolate presented as non-mannitol fermenting, pale-cream growth on mannitol salt (Figure 1A, 1B), small, smooth, pale-cream colonies on nutrient agar that were indistinguishable from Staphylococcus aureus (Figure 1C). Unlike the Staphylococcus aureus which appeared as a dense golden, weak beta hemolytic colonies that were about 1–4 mm in diameter on blood agar (Figure 1D), the Kocuria isolate presented as a dense growth of pale-pink, non-hemolytic colonies that were 1–2 mm in size on blood agar (Figure 1E). Gram staining analysis of the strain showed small gram-positive cocci arranged in pairs, tetrads, or clusters (Figure 2).

The suspected Kocuria species was misidentified as the coagulase-negative Staphylococci, Staphylococcus epidermidis, with a 99.9% probability using the BD BioMic V3, a semi-automated bacteriological identification system, with its corresponding gram-positive identification kit (BBL Crystal Gram-Positive; Becton Dickinson, USA). The same isolate, however, was identified with an 83.5% probability as Staphylococcus hominis with the API Staph V4.0 system (bioMérieux, France). Identification of the isolate was confirmed using 16S rRNA sequencing (SeqStudio Genetic Analyzer, Applied Biosystems, USA). Analysis of the nucleotide sequence with the basic local alignment search tool (BLAST) program showed 97.87% DNA sequence homology with K. rosea (GenBank accession number FN357178.1). A phylogenetic tree produced using the Fast Minimum Evolution (FME) method in the BLAST pairwise alignment tool is presented in Figure 3.

After bacterial identification, both the MRSA strain and the Kocuria strain were subjected to antibiotic susceptibility testing using the disc diffusion method on Muller-Hinton agar according to Clinical and Laboratory Standards Institute (formerly NCCLS) guidelines for Staphylococcus [11]. Both isolates were found to be highly multi-drug resistant, with resistance seen to various classes of antibiotics. The results of the antimicrobial susceptibility testing are presented in Table 1.

However, 5 days after collection of the specimen and while bacteria characterization was still on-going, the patient died of complications on September 14, 2021.

Discussion

This case report presents an interesting case of bacterial co-infection in a COVID-19 patient who was living with diabetes as a comorbidity. The 2 bacteria identified in this case were Methicillin-resistant Staphylococcus aureus (MRSA) and Kocuria rosea (K. rosea), which is a gram-positive bacterium and a normal flora of the skin, but capable of causing nosocomial infection, infection in patients with underlying co-morbidities, and causing central line-associated bloodstream infections in catheterized and immunocompromised patients [12]. The major symptoms associated with Kocuria infection include recurrent sepsis, increased platelets and white blood cell counts, and febrile neutropenia [2,13].

The association of Staphylococcus aureus with COVID-19 co-infection has been documented [7–10], with Staphylococcus aureus being the most frequently isolated bacteria in co-infection with COVID-19 and responsible for early-onset bacterial infection symptoms in COVID-19 patients. However, to the best of our knowledge, there are no reports of K. rosea co-infection in COVID-19 cases, even in those with other co-morbidities. This is probably because infections due to Kocuria species are very rare and the bacteria are sometimes misidentified as Staphylococci [12]. There are, nonetheless, a few reports of this bacteria in the literature, causing or associated with peritonitis, brain abscesses, meningitis, endocarditis, bacteremia/ sepsis, and acute cholecystitis [10,16].

One important feature of the case in this report was that the patient was initially catheterized, and the catheter was later removed at admission. Kocuria infection has been mostly reported in patients with indwelling devices. The infections associated with the presence of indwelling devices has been termed central line-associated or catheter-related bloodstream infections [12–14]. These types of infection have been reported to significantly affect patient outcome [12–14]. The case in our study is quite similar to the case reported in Colombia [17]. Both patients were elderly (71 and 72 years old), had diabetes mellitus, hypertension, and had an history of indwelling device placement, with the main difference being that the patient in our case was infected with COVID-19. COVID-19 may or may not have any correlation with the Kocuria infection, but the presence of the COVID-19 influenced the treatment approach of this case, with little priority given to the bacterial infection.

The MRSA and K. rosea isolate reported in this study was recovered from the nasopharyngeal sample at the research laboratory of the Nigerian Institute of Medical Research. The blood culture, which was done at the hospital diagnostic laboratory at the time of presentation of the patient, showed the presence of Staphylococcus aureus with an antimicrobial susceptibility pattern similar to that found in the research laboratory. The antimicrobial susceptibility result showed that the MRSA was susceptible to ceftriaxone and ciprofloxacin, which were the main antibiotics used in the management of this patient. In contrast, the isolated K. rosea was resistant to both ceftriaxone and ciprofloxacin. As infection due to K. rosea is rare, there is no definite antibiotic sensitivity profile for this bacterium. Susceptibility of K. rosea has been reported to piperacillin/tazobactam and clarithromycin [17], penicillin, oxacillin, erythromycin, clindamycin, ciprofloxacin, levofloxacin, trimethoprim/sulfamethoxazole, vancomycin, teicoplanin, and linezolid [18], and to ampicillin, cefotaxime, ciprofloxacin, cloxacillin, gentamicin, erythromycin, amikacin, imipenem, linezolid, teicoplanin, and vancomycin [10]. In this study, the isolated K. rosea was highly multi-drug-resistant, with susceptibility only seen to imipenem, meropenem, vancomycin, nitrofurantoin, rifampicin, and tetracycline. Similarly, a recent case report in 2022 showed the isolation of K. rosea from the blood of a sickle cell patient with bacteria [12]; as in our study, the isolated K. rosea was also susceptible to vancomycin and meropenem. The K. rosea in our patient was resistant to all the macrolides and ciprofloxacin, which further substantiates the ineffectiveness of the ceftriaxone and ciprofloxacin used for the management of this patient, even though the MRSA was sensitive to these antibiotics. It can thus be inferred that K. rosea was a major cause of the bacteremia/sepsis and treatment complication associated with this case.

It is believed that one of the problems that affected the management of this patient was the identification process after blood culture. This is because Kocuria are usually misidentified by phenotypic tests and sometimes ignored as laboratory contaminants [12]. Other reports have also mentioned that identification of Kocuria species using biochemical methods is often difficult due to their similarity to Staphylococci [10,16–19]. In this case report, we believe that the Kocuria rosea may have been missed or disregarded as a laboratory contaminant and only the Staphylococcus aureus was focused on as the cause of bacteremia in the treatment process. This resulted in suboptimal treatment of the patient, leading to his death, which was inadvertently reported as a COVID-19 mortality.

The main limitation of this study was that the case record and health history of the patient were not available to the clinicians. The Infectious Disease Hospital (IDH) was the first isolation center for COVID-19 patients in Lagos, Nigeria, and most of the patients admitted at the hospital did not use the hospital as their primary healthcare provider; therefore, their case records may not be available at the IDH. Hence, only information from COVID-19 diagnosis until discharge or otherwise are available.

Conclusions

This case report shows that the presence of multi-drug-resistant bacterial infections can be fatal in patients with COVID-19, especially in patients with other co-morbidities like diabetes. This case report also shows that biochemical testing may be inadequate in identifying rare and emerging bacterial infections and there is a need to include proper bacterial screening and treatment in the management of COVID-19, especially in those with other co-morbidities like diabetes, and for patients with indwelling devices.