Efficacy and safety of carrimycin in ten patients with severe pneumonia following solid organ transplantation

Abstract

BACKGROUND

The number of patients undergoing solid organ transplantation has increased annually. However, infections in solid organ transplant recipients can have a severe effect on patient survival owing to the continued use of immunosuppressants. Carrimycin is a novel macrolide antibiotic produced by genetically engineered streptomyces spiramyceticus harboring a 4’’-O-isovaleryltransferase gene (ist) from streptomyces thermotoleran. Carrimycin has good antibacterial and antiviral effects. However, no relevant studies have been conducted on the efficacy and safety of carrimycin in patients with severe pneumonia (SP) after solid organ transplantation.

AIM

To explore the efficacy and safety of carrimycin in patients with SP after solid organ transplantation to provide a medication reference for clinical treatment.

METHODS

In March 2022, ten patients with SP following solid-organ transplantation were treated at our hospital between January 2021 and March 2022. When the condition was critical and difficult to control with other drugs, carrimycin was administered. These ten patients' clinical features and treatment protocols were retrospectively analyzed, and the efficacy and safety of carrimycin for treating SP following solid organ transplantation were evaluated.

RESULTS

All ten patients were included in the analysis. Regarding etiological agent detection, there were three cases of fungal pneumonia, two cases of bacterial pneumonia, two cases of Pneumocystis pneumonia, and three cases of mixed infections. After treatment with carrimycin, the disease in seven patients significantly improved, the course of the disease was significantly shortened, fever was quickly controlled, chest computed tomography was significantly improved, and oxygenation was significantly improved. Finally, the patients were discharged after curing. One patient died of acute respiratory distress syndrome, and two patients discontinued treatment.

CONCLUSION

Carrimycin is a safe and effective treatment modality for SP following solid organ transplantation. Carrimycin may have antibacterial and antiviral effects in patients with SP following solid organ transplantation.

Key Words: Carrimycin, Organ transplantation, Severe pneumonia, Immunosuppressant, Infection, Antiviral drugs

Core Tip: In this study, the clinical features and treatment projects of 10 cases of severe pneumonia (SP) after solid organ transplantation were retrospectively analyzed. It was conformed that carrimycin is a safe and effective modality in the treatment of SP after solid organ transplantation.

INTRODUCTION

The number of patients undergoing solid-organ transplantation (SOT) is increasing. Post-operative complications can severely affect patient survival[1]. Among these, pneumonia is a frequent infectious complication of SOT. It is considered the chief cause of morbidity and mortality in renal allograft recipients due to the continued use of immunosuppressants[2,3]. Pneumonia can lead to acute respiratory distress syndrome (ARDS)[4], with an occurrence rate ranging from 0.2% to 4.3%[5,6] and a mortality rate of 22.5%–67%[7-11]. The mortality rate has been reported to be nearly 100% in patients on ventilation[12]. However, the curative effect of conventional drugs is often poor and seriously puzzling for clinicians.

Carrimycin is a novel macrolide antibiotic produced by genetically engineered streptomyces spiramyceticus harboring a 4’’-O-isovaleryltransferase gene (ist) from streptomyces thermotolerans. Carrimycin is a broad-spectrum antibacterial agent and is effective against Gram-positive cocci, β-lactamase-producing bacteria, Mycoplasma, and Chlamydia, as well as some Gram-negative bacilli and fungi. Additionally, it has been reported that carrimycin can be used to treat Coronavirus disease 2019 (COVID-19) with good therapeutic effect[13]. Previous studies have verified the antitumor effects of carrimycin in vitro and in vivo[14].

However, no relevant studies have been conducted on the efficacy of carrimycin in patients with post-SOT infections. In this study, we investigated the efficacy and safety of carrimycin in SOT recipients in vitro and in vivo for the first time between January 2021 and March 2022; 10 patients with severe pneumonia (SP) following SOT were treated at our hospital. When the condition was critical and difficult to control with other drugs, carrimycin was administered. Through a retrospective analysis and summary of the clinical data of these patients, this study preliminarily discusses the efficacy and safety of carrimycin for treating SP following SOT to provide a medication reference for clinical treatment.

MATERIALS AND METHODS

Clinical characteristics

Among the ten patients, there were six males and four females, aged 27-63 years, all of whom underwent transplantation for the first time, including nine renal transplant recipients and one liver transplant recipient (Table 1).

Table 1 Clinical characteristics of 10 patients with severe pneumonia after solid organ transplantation.

Recipient	Gender	Age	Type of transplanted organ	Transplant time
1	Male	46	Renal transplantation	27 d
2	Male	63	Renal transplantation	5 months
3	Female	34	Renal transplantation	13 months
4	Male	55	Liver transplantation	7 d
5	Male	56	Renal transplantation	4 months
6	Female	27	Renal transplantation	5 months
7	Female	55	Renal transplantation	3 months
8	Male	60	Renal transplantation	16 yr
9	Male	27	Renal transplantation	4 months
10	Female	40	Renal transplantation	7 yr

Diagnostic criteria of SP after SOT

In this study, the diagnostic criteria of SP following SOT were based on the American Thoracic Society criteria and slightly adjusted in combination with the characteristics of SOT[15]: (1) Long-term application of immunosuppressants after SOT; (2) clinical symptoms of persistent fever, cough and progressive dyspnea; (3) an aspiratory rate > 30 per min; (4) an arterial oxygen partial pressure/oxygen inspiratory fraction (PaO₂/FiO₂) ratio < 250; and (5) chest film pneumonia showed and rapidly expanded by more than 50% in a short time. Diagnostic criteria of ARDS[16]: (1) Timing: Acute onset; (2) oxygenation: PaO₂/FiO₂ ≤ 200 mmHg regardless of positive end-expiratory pressure; (3) chest radiograph: Bilateral infiltrates seen on frontal chest radiograph; and (4) airway pressure: ≤ 18 mm Hg when measured or no clinical evidence of left atrial hypertension.

Immunosuppressive regimens

Eight patients (excluding cases 4 and 8), were treated with basiliximab or anti-thymocyte globulin for immunity induction therapy. Methylprednisolone (1000 mg) was administered intravenously during surgery, and methylprednisolone (500 mg/d) was administered intravenously for two consecutive d after transplantation. Methylprednisolone tablets were administered orally at 0.8 mg/kg·d on the fourth day after transplantation, decreasing by 4 mg per d to 16 mg/d and then by 4 mg per wk to 4 mg/d. After transplantation, except in case 8, cyclosporine + mycophenolate mofetil + methylprednisolone was administered; in the other 9 cases, tacrolimus + mycophenolate mofetil + methylprednisolone was administered. The blood tacrolimus and cyclosporine concentrations were maintained at 5-10 ng/mL, and the concentration of cyclosporine was maintained at 100-150 ng/mL. The dosage of mycophenolate mofetil used was 1000-1500 mg/d.

The time and clinical characteristics of infection

According to Rubinl's "infection schedule" stage[17], the time distribution of SP cases in this group is 2 cases (20%, 2/10) in the first month after surgery, 5 cases (50%, 5/10) in 2–6 months, and 3 cases (30%, 3/10) after 6 months. Clinical features: (1) Most patients have a regular temperature, but some present low or high fever. Fever was evident in the morning. The onset of fever is often delayed by 1–2 h daily. After sweating, the fever resolved. A few patients showed massive sweating, but their body temperatures were normal. When they developed a high fever, it was mostly persistent; and (2) there may be no obvious dyspnea symptoms in the early stage, followed by chest tightness, suffocation, accelerated heart rate, and other symptoms that worsen after activity, with or without coughing. No sputum was detected in the early or middle stages, and blood gas analysis indicated severe hypoxemia; (3) this disease progresses rapidly. After the symptoms of dyspnea and hypoxia, the disease progresses rapidly. Although noninvasive or invasive ventilation is used, some patients die from respiratory failure; and (4) it is often accompanied by multiple-organ dysfunction syndrome (MODS).

Treatment protocols

According to our center's experience, we summarized the "five early" scheme for treating pulmonary infection after SOT. (1) Early discontinuation of immunosuppressants. Immunosuppressants were discontinued immediately after the patient experienced symptoms of hypoxia. During this period, rejection generally does not occur due to patients' excessive immunosuppressive state; (2) early use of glucocorticoids. Glucocorticoids have anti-inflammatory and anti-rejection effects. The dose and frequency of methylprednisolone administration were determined based on the patient's body temperature. The dose was 40–80 mg every 12 h in the early stages. After the body temperature normalized for 3 d, methylprednisolone was gradually reduced to 40 mg qd and then changed to oral methylprednisolone tablets for maintenance; (3) early use of human immunoglobulin. The dosage of human immunoglobulin is 0.5 g/(kg/d), which is usually treated for 3-5 d. The course of treatment and dosage should be adjusted according to the patient’s situation; (4) early combined use of multiple drugs. It can be seen from the ten patients in this study that before the pathogen is determined, the treatment needs to include gram-positive bacteria, gram-negative bacteria, fungi, viruses, and Pneumocystis yersiniae. After identifying the pathogen, select the appropriate anti-infective drugs according to the pathogen (Table 2); and (5) early use of noninvasive ventilation. For patients with hypoxemia on blood gas analysis, the early use of non-invasive ventilation is conducive to reducing respiratory muscle fatigue, improving ventilation function, reducing lung injury, and reducing oxygen consumption. Delayed treatment may aggravate the patient's disease and lead to the use of invasive ventilation, resulting in complications such as ventilator-associated pneumonia. In addition, attention should be paid to increasing the patients' nutrition and treating hypoproteinemia, which is conducive to maintaining blood pressure stability and improving immunity. For those who had used the above measures and were still worsening, carrimycin was used for treatment. The dose of carrimycin was 400 mg orally on the first day and 200 mg orally every d for seven d.

Table 2 Treatment protocols of 10 patients with severe pneumonia after solid organ transplantation.

Recipient	Treatment protocols
1	Carrimycin + Vancocin + Levofloxacin
2	Carrimycin + Amphotericin B
3	Carrimycin + Caspofungin + Trimethoprim-sulfamethoxazole
4	Carrimycin + Meropenem + Linezolid + Caspofungin
5	Carrimycin + Ganciclovir + Moxifloxacin + Trimethoprim-sulfamethoxazole + Peramivir
6	Carrimycin + Caspofungin + Piperacillin sodium and tazobactam sodium + Imipenem + Trimethoprim-sulfamethoxazole
7	Carrimycin + Meropenem + Azithromycin + Caspofungin
8	Carrimycin + Moxifloxacin + Ganciclovir + Peramivir + Imipenem + Piperacillin sodium and tazobactam sodium + Tigecycline + Linezolid + Fluconazole
9	Carrimycin + Caspofungin + Trimethoprim-sulfamethoxazole + Imipenem + Moxifloxacin
10	Carrimycin + Imipenem + Ganciclovir + Voriconazole

RESULTS

Pathogens

There were three cases of fungal pneumonia, two cases of bacterial pneumonia, two cases of pneumocystis pneumonia, and three cases with mixed infections (Table 3).

Table 3 Pathogens of 10 patients with severe pneumonia after solid organ.

Recipients	Pathogens
1	Legionnella + Corynebacterium striatum
2	Mucor
3	Pneumocystis jirovecii
4	Baumanii + Staphylococcus epidermidis
5	Pneumocystis jirovecii + Cytomegalovirus
6	Pneumocystis jirovecii
7	Haemophilus parainfluenzae + Mycoplasma
8	Acinetobacter + Coronavirus
9	Acinetobacter
10	Aspergillus

After treatment with carrimycin, the disease in seven patients significantly improved, the course of disease was significantly shortened, fever was quickly controlled, chest computed tomography was significantly improved (Figure 1), and oxygenation was significantly improved. Finally, all anti-infective drugs were gradually discontinued, and the patients were discharged after treatment. One patient died from ARDS, and two patients discontinued treatment (Table 4).

Figure 1 Chest computed tomography images before and after treatment with carrimycin. A: Chest computed tomography (CT) images before treatment with carrimycin; B: Chest CT images after treatment with carrimycin.

Table 4 Outcomes of 10 patients with severe pneumonia after solid organ transplantation.

Recipient	Outcome of transplants	Clinical outcomes
1	Remove	Abandoning treatment
2	Normal	Cure
3	Normal	Death
4	Normal	Cure
5	Normal	Cure
6	Normal	Abandoning treatment
7	Normal	Cure
8	Normal	Cure
9	Normal	Cure
10	Normal	Cure

DISCUSSION

After transplantation, patients require immunosuppressants for anti-rejection therapy. Immunosuppressants include cyclosporine, tacrolimus, prednisone, and mycophenolate mofetil, which can prevent rejection by inhibiting cellular and humoral immunity; however, long-term use of immunosuppressants weakens the immunity of patients. Compared to the general population, infections in SOT recipients are far more complicated and prone to opportunistic infections, mixed infections, rare bacterial infections, and severe infections, making diagnosis more difficult. Delayed diagnosis leads to delayed treatment and poor prognosis[18,19].

Pneumonia is a major threat in renal allograft recipients[20]. According to various studies, pneumonia rates range from 4.5% to 20%[21-28], and pneumonia accounts for 8%–70.3% of all infectious complications[29-32] following kidney transplantation. SP can lead to cellular immune disorders and pro- and anti-inflammatory cytokine imbalances[33]. SP is characterized by occult onset, rapid progress, difficulty in identifying pathogens, and poor treatment effects, and can develop into respiratory failure and even systemic failure in a short time. SP easily develops into ARDS, which is the most direct cause of death in patients with pulmonary infection after renal transplantation[34]. Bacteria are the most common pathogens causing infections after SOT, particularly in the early post-transplantation period[35,36]. In addition to bacterial infections, many other pathogens, such as viruses, fungi, Mycoplasma, and Pneumocystis jirovecii, can also cause pneumonia. With the application of next generation sequencing technology, bronchoalveolar lavage, and other technologies, the technology for identifying pathogens is improving; however, some patients are still unable to identify pathogens in a short time, resulting in disease progression and even death.

In terms of treatment, we generally use high-efficiency broad-spectrum antibiotics after admission, combined with antiviral, anti-Pneumocystis yersinia, and antifungal drugs. However, multiple previous hospitalizations, invasive interventions, and prior antibiotic use make SOT recipients susceptible to colonization by nosocomial and antibiotic-resistant pathogens, including Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and resistant gram-negative bacilli[37-39]. Patients with SP often exhibit anorexia, and the body is in a highly decomposed state, resulting in malnutrition and a further reduction in immune function. Therefore, conventional drugs typically have poor efficacy. When patients are infected, many inflammatory mediators and cytokines released during the inflammatory reaction cause acute lung injury, which can cause ARDS and even lead to systemic inflammatory response syndrome and MODS[40]. Although various treatment measures have been adopted, the condition of some patients cannot be effectively controlled. Therefore, there is an urgent need to identify drugs with good antibacterial activity and low biotoxicity.

Carrimycin is a new class I drug developed by the Institute of Pharmaceutical Biotechnology of the Chinese Academy of Medical Sciences. Shenyang Tonglian Group Co., Ltd. Carrimycin was approved for listing in June 2019. It is a new drug with independent intellectual property rights in China. Carrimycin is a genetically engineered drug developed using synthetic biological technology and belongs to the macrolide class of antibiotics. The main components of carrimycin were isovalerylspiramycin III, II, and I (Figure 2), with minor components consisting of butyrylspiramycin III, propionylspiramycin III, acetylspiramycin III, butyrylspiramycin II, propionylspiramycin II, acetylspiramycin II[41-44]. Compared with acylspiramycin, the longer alkyl chains at position 4’’ render carrimycin increased antibacterial potency, especially in vivo, because of its higher lipophilicity[45,46].

Figure 2 Molecular structure of three main components of carrimycin. Isovaleryl spiramycin I: R = H, molecular formula: C48H82N2O15, molecular weight: 926; Isovaleryl spiramycin II: R = COCH3, molecular formula: C50H84N2O16, molecular weight: 968; Isovaleryl spiramycin III: R = COCH2COCH3, molecular formula: C51H86N2O16, molecular weight: 982.

The China Food and Drug Administration approved carrimycin for the treatment of acute tracheal bronchitis caused by Haemophilus influenzae, Streptococcus pneumoniae and acute sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Moraxella catarrhalis, and Staphylococcus. Carrimycin can inhibit bacterial protein synthesis by blocking the activity of peptidyl transferase in the 50s ribosome, which can directly inhibit bacterial growth. Carrimycin can combine with peroxide-scavenging enzymes to induce peroxide and destroy biological macromolecules such as DNA to achieve sterilization (Table 5). In vivo, carrimycin can promote neutrophils to migrate to inflammatory sites to destroy and phagocytize bacteria and damaged cells and enhance the phagocytosis of macrophages to regulate immunity and enhance resistance. In addition, capreomycin also plays a certain role in inhibiting inflammation and improving inflammation and edema of important organs such as the heart and lungs. A pharmacokinetic study of carrimycin confirmed that its half-life was longer than that of spiramycin, and some metabolites of carrimycin maintained antibacterial activity. The tissue permeability of carrimycin is enhanced, and it has a marked post-antibiotic effect^[46]. Carrimycin has broad prospects in clinical applications, but there has been no research on the application of carrimycin in SP following SOT.

Table 5 Antibacterial spectrum of carrimycin found so far.

Pathogens	Antimicrobial spectrum
Gram-positive bacterium	Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus digestae, Other Streptococcus, Staphylococcus aureus, Legionella pneumophila
Gram-negative bacterium	Haemophilus influenzae, Moraxella catarrh, Neisseria gonorrhoeae
Anaerobe	Digestococcus, Bacteroid, Clostridium, Prevotella, Propionibacterium
Atypical pathogens	Mycoplasma pneumoniae, Ureaplasma urealyticum, Chlamydia trachomatis, Chlamydia pneumonia

Based on our previous observations, we found that the use of carrimycin in patients with low immune function often achieved unexpected results. The specific mechanism is unclear, which may be related to clindamycin improving T lymphocyte function and repairing immune damage. Therefore, we administered carrimycin to patients receiving long-term oral immunosuppressants after organ transplantation. The ten patients in this study were treated with carrimycin following poor response to other drugs. Carrimycin treatment was found to be effective. It is speculated that this is related to the direct bactericidal and bacteriostatic effects of carrimycin, which may also be related to the effects of carrimycin in improving immune function and repairing tissue damage. Our center will further study the specific mechanisms of action of carrimycin in improving the immune function of patients.

In addition, among the ten patients treated with carrimycin, case 5 was complicated by cytomegalovirus infection, and case 8 was complicated by coronavirus infection. After treatment with carrimycin, these patients showed positive effects, suggesting that carrimycin may have antiviral effects. Our results are consistent with those of previous studies, which have found that the main active component of carrimycin strongly binds the angiotensin-converting enzyme type 2 receptor protein and can also bind to the 3-chymotrypsin-like protease binding site; therefore, it has great potential value and unique therapeutic advantages in anti-Severe acute respiratory syndrome coronavirus 2 infection[13]. However, further studies are required to confirm the antiviral effects of carrimycin.

This study has some limitations. As our study had only a comparatively small number of samples from a single center, more studies need to verify the general applicability of our research conclusions. In addition, more research is needed on the timing, course of treatment, and antibacterial spectrum of carrimycin for treating pulmonary infections in SOT recipients. Our center will continue to collect clinical data on carrimycin in treating SP in SOT recipients to make a more reliable evidence-based evaluation of its efficacy and safety and provide new medication options for treating SP in SOT recipients.

CONCLUSION

This study found that carrimycin is safe and effective for treating SP in SOT recipients. Because carrimycin is a newly developed drug in China, many current experimental studies are based on basic and animal trials. The efficacy and safety of carrimycin in clinical treatment require further confirmation of clinical data.