The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in millions of deaths worldwide. While the World Health Organization declared an end to the public health emergency in May 2023, COVID-19 remains a significant health threat due to factors such as insufficient vaccination rates, viral mutations leading to immune escape, and uneven distribution of medical resources. Receding viral infections like influenza and COVID-19 can weaken antibacterial immunity, increasing susceptibility to secondary bacterial or viral pneumonias. Co-infections are a significant factor influencing the severity and mortality of COVID-19. The most frequently identified bacterial co-infections include *Klebsiella pneumoniae*, *Streptococcus pneumoniae*, *Staphylococcus aureus*, and *Haemophilus influenzae*, while common viral co-infections include influenza A virus, influenza B virus, respiratory syncytial virus (RSV), and other coronaviruses. Concerns exist regarding antibiotic overuse during the pandemic, potentially leading to increased antibiotic resistance. This study aimed to investigate the prevalence of co-infections among COVID-19 patients in China after the relaxation of epidemic prevention policies in December 2022, focusing on the rationality of antibiotic use and identifying risk factors for poor prognosis.

Existing literature highlights the substantial contribution of co-infections to increased disease severity and mortality in COVID-19 patients. Studies report varying proportions of co-infections, often exceeding 50% in deceased patients. While some research exists on bacterial and viral co-infections in COVID-19, further investigation, particularly in the context of China's post-policy adjustment surge in cases, is crucial. The review of existing literature underscores the need for a deeper understanding of co-infection prevalence, antibiotic usage patterns, and risk factors to guide effective management strategies for COVID-19.

This retrospective study included 716 COVID-19 inpatients admitted to the Affiliated Hospital of Youjiang Medical University for Nationalities in Guangxi, China, between December 14, 2022, and January 30, 2023. Patient data, including clinical manifestations, laboratory results, and treatment details, were collected. Throat swabs were used to detect 12 common respiratory pathogens (6 bacteria, 5 viruses, and *Mycoplasma pneumoniae*) using quantitative real-time polymerase chain reaction (qPCR). SARS-CoV-2 detection was performed using a separate PCR kit. Statistical analysis involved descriptive statistics, Wilcoxon rank-sum test, Pearson's Chi-squared test, Fisher's exact test, and Cox regression analysis to identify risk factors associated with mortality. The study received ethics approval, and consent was waived due to the anonymized nature of the data.

A high prevalence of co-infections (76.82%) was observed among the 716 COVID-19 patients. Bacterial co-infections were significantly more common (74%) than viral co-infections (15%). *Streptococcus pneumoniae* and *Haemophilus influenzae* were the most prevalent bacterial co-infection agents. Influenza A virus and respiratory syncytial virus were the dominant viral co-infections. About 12% of patients had both bacterial and viral co-infections. There was a significant difference in the length of hospital stay and leukocyte counts between patients with and without co-infection. Analysis of antibiotic usage showed that 65.5% of COVID-19 patients received antibiotics, with some inappropriate antibiotic use. Cox regression analysis identified dyspnea, hypoproteinemia, low lymphocyte counts, and *Mycoplasma pneumoniae* co-infection as significant risk factors for mortality. Chi-square tests revealed associations between lymphopenia and *H. influenzae* co-infection, and between hypoproteinemia and *S. pneumoniae*, *H. influenzae*, and *P. aeruginosa* co-infections. Elevated C-reactive protein levels correlated with co-infections involving *S. pneumoniae* and *P. aeruginosa*. No significant association was found between antibiotic use and mortality.

The high prevalence of co-infections (77%) in this study is notable compared to previous reports, potentially due to the study focusing on moderate to severe cases, the sensitivity of the qPCR method, and the high patient density during the epidemic peak. The findings support the established link between bacterial co-infections and poor prognosis in viral pneumonia. The identification of *S. pneumoniae*, *H. influenzae*, and *K. pneumoniae* as the most common bacterial co-infections aligns with previous research. The prevalence of viral co-infections, especially influenza A and RSV, highlights the complex interplay of respiratory pathogens during COVID-19. The study's findings on antibiotic usage indicate a need for improved antibiotic stewardship to prevent the emergence of antibiotic resistance and minimize potential negative effects on gut microflora. The identified risk factors for mortality—dyspnea, hypoproteinemia, low lymphocyte counts, and *M. pneumoniae* co-infection—emphasize the importance of comprehensive patient management.

This study reveals a high prevalence of co-infections among hospitalized COVID-19 patients in China during an epidemic peak. The findings highlight the need for improved antibiotic stewardship and comprehensive management strategies focusing on respiratory support, nutrition, and vigilance for co-infections, particularly *M. pneumoniae*. Vaccination against common co-infecting pathogens is an effective preventive measure. Future research should focus on larger, more diverse cohorts to further validate these findings and explore the complex interactions between different pathogens.

The study's limitations include the limited scope of the respiratory PCR panel, which might have missed some co-infections (e.g., fungal); qPCR results indicating potential risk rather than confirmed active infection; difficulty in differentiating community-acquired from nosocomial bacterial infections; lack of data on pneumococcal, Hib, and influenza vaccination status; and the absence of healthy or mildly affected COVID-19 groups as controls.