Background

Commensal bacterial flora in the conjunctival sac is a potential risk factor for infection after intraocular surgeries [1, 2]. A broad range of commensal bacteria have been identified at the ocular surface of patients with infectious eye disease and have been reported to contribute to the occurrence of endophthalmitis after cataract surgery [2,3,4]. According to the study of Durand [5], Coagulase-negative Staphylococci (70% of cases), Staphylococcus aureus (10%), and Streptococcus spp. (9%) are the major pathogens responsible for endophthalmitis cases after cataract surgery. Without effective preoperative examination and prevention, the bacteria mentioned above may lead to endophthalmitis, a devastating eye infection which can cause irreversible blindness in the infected eye within hours or days of symptom onset [5].

The use of antibiotics is an effective strategy to significantly decrease the incidence of ocular bacterial infections (positive swabs). Among all kinds of antibiotics, levofloxacin (which belongs to quinolones and fluoroquinolones) has been proved to have well-established efficacy and tolerability in the treatment of external ocular infections caused by both Gram-positive and Gram-negative bacteria [6,7,8,9,10,11,12,13]. However, with the widespread use of antibiotics, the resistance rate of bacteria towards antibiotics (including levofloxacin) has gradually increased, which has become a severe threat to public health [14,15,16,17,18]. It becomes even worse with a concomitant decline in the development of novel antibiotics and the emergence of multidrug-resistant strains [19, 20]. Moreover, patient-related risk factors such as older age, sex (male), the presence of hypertension and/or diabetes mellitus (DM), and a history of hospital-based surgery may be associated with increasing bacterial load and the emergence of multidrug-resistant bacteria [1]. However, the species and characteristics of multidrug-resistant bacteria in human conjunctival sac have not been systematically summarized.

According to The Food and Drug Administration (FDA), real-world data (RWD) is defined as all data relating to patient health status and/or the delivery of health care, routinely collected from a variety of sources. Moreover, real-world evidence (RWE) is the clinical evidence regarding the usage and potential benefits or risks of a medical product, derived from the analysis of RWD [21]. By studying RWE, clinicians can optimize currently available therapies or develop new prophylactic strategies [22]. It provides support for us to further study the characteristics of levofloxacin resistant bacteria in conjunctival sac.

In the current study, we searched the related literature and reviewed the results of conjunctival sac bacterial cultures of patients that had used Cravit (levofloxacin eye drops, Santen Pharmaceutical Co., Ltd) for antibiotic prophylactic therapy before cataract surgery. With the exception of data from the literature, all RWD were collected in Peking University Third Hospital from 2016 to 2019. By calculating the positive rate, analyzing positive strains and their drug sensitivity, as well as classifying results by clinical factors that may affect the positive rate of cultures, we revealed the association between different clinical factors and the conjunctival sac bacterial load. Further, by analyzing the results we confirmed the necessity for antibiotic use before cataract surgeries and offered prophylaxis suggestions and references.

Methods

Ethical approval and consent to participate

All participants provided written informed consent, consistent with the tenets of the Declaration of Helsinki. Peking University Third Hospital Medical Ethics Committee approved all procedures carried out in this study, including the procedure of accessing the clinical/personal patient data used in our research (approval number: M2019432).

Data screening and selection

We included all medical records and related literature data and obtained RWD including basic patient information and conjunctival sac bacterial culture information of patients that had used Cravit (levofloxacin eye drops 5 mL: 24.4 mg, Santen Pharmaceutical Co., Ltd) for antibiotic prophylactic therapy before cataract surgeries. Literature on prophylactic therapy using other antibiotics or povidone-iodine (PVI) was also reviewed and summarized for comparison. For medical records, we restricted the inclusion criteria to patients with cataracts that had visited Peking University Third Hospital from 2016 to 2019. For published literature, the keywords used were “antibiotics”, “prophylactic therapy”, and “cataract surgery”. We restricted the inclusion criteria to observational cohort studies only. The timing of publication was restricted to the last 10 years (2009–2019). Any study published prior to the last 10 years was considered as outdated and was excluded. Moreover, studies that lacked information regarding age, sex, and previous medical history of patients and were not focused on the conjunctival sac bacterial culture of patients undergoing antibiotic prophylactic therapy were excluded. Publications were also excluded if the concentration of levofloxacin used was different from that in the current study. All relevant literature not included were summarized and compared with our study on the clinical effects of antibiotics and bacterial resistance to them.

Data extraction

After screening medical records and publications, we extracted detailed data including the preoperative conjunctival sac bacterial culture of patients using Cravit, patient sex, presence of hypertension and/or DM, and history of hospital-based surgeries. All conjunctival sac bacterial culture samples were only collected and isolated from patients who had come for cataract surgery and had used Cravit preoperatively, 4 times a day for 3 days, from 2016 to 2019. For patients who underwent bilateral operations, we only conducted the cataract surgery on one eye at a time. The interval between the left eye operation and right eye operation of each patient was more than one month. The medical records of the first-eye surgeries were retrieved. Patients were asked to only use topical antibiotics on the eyes that were to be operated. The isolates were all collected from the conjunctival sac of patients just before the operation and were identified using the Vitek-2 automated systems (bioMerieux, France). Antimicrobial susceptibility testing (AST) for tobramycin, ceftriaxone, erythromycin, vancomycin, leveofloxacin, ofloxacin, and rifampin was performed using the Kirby-Bauer (K-B) disk diffusion method according to the Clinical and Laboratory Standards Institute (CLSI) guideline.

Data analysis

Data of patient basic information, results of conjunctival sac bacterial culture, and antimicrobial susceptibility testing were collected and recorded using Excel (Microsoft Office 2019; Microsoft Corporation, Redmond, WA, USA). All statistical analyses were conducted using SPSS 24.0 (International Business Machines Corp.). Considering the data frame, distribution and sample sizes of our results, multiple statistical approaches were applied in our studies. Comparison of the incidence of each clinical factor between culture-positive groups and culture-negative groups was performed using the chi-square test. Binary logistic regression analysis was also used to explore the association between clinical factors and the positive culture of conjunctival sac bacteria. The Kruskal–Wallis H test was conducted to analyze the results of K-B test. Due to the small sample sizes for some strains, the Kruskal–Wallis H test was only conducted on strains of 6 or more isolated samples with K-B test results. Culture-positive patients were divided into two groups according to the clinical factors that were associated with culture results. The presence of various bacteria and their AST results were compared using the chi-square test and Mann–Whitney U test. It was notable that since we involved multiple factors without clear pre-defined hypothesis, multiple testing correction were considered into the final P value threshold (P < 0.001). Statistical significance of other tests was defined as P < 0.05.

Results

Overall results

Patients and clinical factors

RWD of 15,415 cases, including conjunctival sac bacterial cultures, were retrieved. Because the concentration of levofloxacin used in the published literature was different from that in the medical records of our study, and there was a lack of information regarding age, sex, and previous medical history of patients, all RWD were retrieved from the medical records of patients from Peking University Third Hospital. Clinical factors that may affect conjunctival sac bacterial load of patients before cataract surgery are shown in Table 1. Among the total cases, there were 5,866 (38.1%) males and 9,549 (61.9%) females. There were 5,960 (38.7%) patients with a history of hypertension and 3,493 (22.7%) patients with a history of DM. The number of patients with a history of one or more hospital-based operations was 7,555 (49.0%). There were 169 (1.1%) patients who had undergone bilateral operations and only the medical records of the first-eye surgeries were retrieved.

Table 1 Clinical factors related to conjunctival sac bacterial load in patients before cataract surgery
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There were 274 culture samples that were positive, suggesting that these patients had a greater conjunctival sac bacterial load. The positive rate was 1.8%. Among them, there were 37 samples that led to postoperative endophthalmitis eventually (0.2% of all samples). Male patients (n = 137, 2.3%) and patients with a history of hypertension (n = 149, 2.5%) or DM (n = 88, 2.5%) were at an increased risk of having positive bacterial cultures (P < 0.05), but the history of hospital-based surgeries may have had no influence (P > 0.05). Besides, the results of binary logistic regression analysis was shown in Table 2 and the logistic model was statistically significant (χ2(4) = 52.686, P < 0.001). Among the 4 independent variables included in the model, sex, presence of hypertension and DM were statistically significant (P < 0.05). The risk of positive culture of conjunctival sac bacteria in male was 1.677 times higher than that in female. The risk in patients with hypertension was 1.844 times higher than that in patients without hypertension. The risk in diabetic patients was 1.385 times higher than that in non-diabetic patients. There were only three patients who had undergone bilateral operations, and the interval between the left eye operation and right eye operation of each patient, as previously stated, was more than one month (Table 3).

Table 2 Binary logistic regression analysis of positive conjunctival sac bacterial culture in patients before cataract surgery based on clinical factors
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Table 3 Summary of conjunctival sac bacteria of the patients who had undergone bilateral operations
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Culture identification

The top 10 species of culture-positive samples and the number of culture-positive samples of each species were shown in the Fig. 1A. Of all the 274 positive culture samples, Staphylococcus epidermidis (n = 56, 20.4%), Kocuria rosea (n = 37, 13.5%), and Micrococcus luteus (n = 32, 11.7%) were the three most frequently isolated strains, accounting for 45.6% of culture-confirmed cases. Furthermore, there were 19 positive samples in total that led to postoperative endophthalmitis for the three most common isolates (10 Staphylococcus epidermidis samples, 6 Kocuria rosea samples and 3 Micrococcus luteus samples). The percentage of postoperative endophthalmitis for the three most common isolates were shown as pie graphs in Fig. 1B.

Fig. 1
figure 1

A Number of culture-positive samples for the top 10 identified bacterial strains. B Pie graphs showing the percentage of postoperative endophthalmitis for the three most common isolates

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Antimicrobial susceptibility testing

Among the 274 culture-positive samples, information on antimicrobial susceptibility testing using the K-B test was recorded for 234 (85.4%) samples and is summarized in Table 4. For Staphylococcus epidermidis, Kocuria rosea, Kocuria kristinae, Kocuria varians, Micrococcus luteus, Micrococcus lylae, Moraxella spp., Brevundimonas diminuta, inactive biochemical spectra, and unidentifiable bacterial groups, there were statistically significant differences in resistance to different antimicrobial agents (P < 0.05). The zone diameters of rifampin in the K-B test were the largest, which means all these bacteria were most sensitive to rifampin.

Table 4 Number of isolated bacteria and K-B test results
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Of the 234 identified cases with K-B test results, Staphylococcus epidermidis (n = 40, 17.1%) was the predominant organism. The results were retrieved and summarized in Table 5. According to the CLSI guideline, among 40 Staphylococcus epidermidis isolates, 100.0% were sensitive to vancomycin, 95.0% (38 of 40 isolates) to rifampin, 47.5% (19 of 40 isolates) to ceftriaxone, 37.5% (15 of 40 isolates) to tobramycin, 22.5% (9 of 40 isolates) to erythromycin, and 12.5% (5 of 40 isolates) to levofloxacin and ofloxacin.

Table 5 Results of K-B test of Staphylococcus spp
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It should be noted that the majority of Staphylococcus epidermidis (33 of 40 isolates, 82.5%) isolated samples had multidrug resistance to 3 kinds of antimicrobial agents or more. Further, 22.5% (9 of 40 isolates) were resistant to 3 kinds, 40.0% (16 of 40 isolates) to 4 kinds, and 20.0% (8 of 40 isolates) to 5 kinds. The Upsetview of multidrug resistance of Staphylococcus epidermidis is shown in Fig. 2.

Fig. 2
figure 2

Upsetview of multidrug resistance of Staphylococcus epidermidis

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Subgroup classified by clinical factors

Sex

Among the 274 culture-positive samples, 50.0% (n = 137) were from male patients, and the rest (n = 137) were from females. For male culture-positive patients, Staphylococcus epidermidis (n = 31, 22.6%), Kocuria rosea (n = 18, 13.1%), Kocuria kristinae (n = 13, 9.5%), Micrococcus luteus (n = 11, 8.0%), and Kocuria varians (n = 7, 5.1%) were the 5 strains with the highest positive rates, accounting for 58.4% of culture-confirmed cases. For female culture-positive samples, Staphylococcus epidermidis (n = 25, 18.2%) was still the most prevalent culture-positive strain, followed by Micrococcus luteus (n = 21, 15.3%) and Kocuria rosea (n = 18, 13.1%). These 3 strains accounted for 46.7% of the culture-confirmed cases. It should be noted that the number of Staphylococcus epidermidis-positive isolates in the male patient group (n = 31, 22.6%) was more than that in the female patient group (n = 25, 18.2%), and there was significant difference between the two groups (χ2 = 7.139, P < 0.05). There was no significant difference in K-B results for various antimicrobial agents between the male and female patients.

Hypertension

Patients with hypertension had more positive culture results than those without hypertension (P < 0.05). Among culture-positive patients with hypertension, there were 18.1% (n = 27) with Staphylococcus epidermidis, 14.1% (n = 21) with Micrococcus luteus, and 12.1% (n = 18) with Kocuria rosea. For culture-positive patients without hypertension, Staphylococcus epidermidis (n = 29, 23.2%), Kocuria rosea (n = 19, 15.2%), and Kocuria kristinae (n = 11, 8.8%) were the 3 most prevalent strains. Compared to the hypertension patient group (n = 21, 14.1%), Micrococcus luteus (n = 11, 8.8%) was less frequently found in patients without hypertension. There was statistically significant difference between the two groups (χ2 = 9.829, P < 0.05).

As for K-B test results, the median zone diameter of Staphylococcus epidermidis for ofloxacin in the hypertension group (0 mm) was smaller than that in the non-hypertension group (9 mm), and there was a significant difference between two groups (P < 0.05). However, this could be related to use of levofloxacin preoperatively and requires careful analysis.

Diabetes mellitus

The 4 strains with the highest positive culture rates in the DM group were the same as the strains in the non-DM group, namely Staphylococcus epidermidis (n = 22, 25.0% of patients with DM; n = 34, 18.3% of patients without DM), Kocuria rosea (n = 12, 13.6% of patients with DM; n = 25, 13.4% of patients without DM), Micrococcus luteus (n = 12, 13.6% of patients with DM; n = 25, 13.4% of patients without DM), and Kocuria kristinae (n = 5, 5.7% of patients with DM; n = 14, 7.5% of patients without DM). The number of Staphylococcus epidermidis-positive samples of non-diabetic patients (n = 34, 18.3%) was greater than the number among diabetic patient samples (n = 22, 25.0%), and there was a significant difference between the two groups (χ2 = 8.865, P < 0.05). The information of K-B test results was also retrieved, and there was no significant difference between the diabetes group and non-diabetes group.

Comprehensive analysis of related clinical factors

After comprehensive analysis of all related clinical factors, we identified 27 (9.9% of all positive samples) male patients with both hypertension and diabetes mellitus. Staphylococcus epidermidis was the most detected strain (n = 9, 33.3%). The proportion of Staphylococcus epidermidis was highest in the male group (22.6%), the hypertension group (18.1%), and the DM group (25.0%). There were significant differences for various antimicrobial agents in the K-B test (P < 0.05), and the zone diameters of rifampin were largest of all the antimicrobial agents (median zone diameter was 32 mm). As shown in the Fig. 3, the median zone diameter of rifampin in samples from males with hypertension and DM (32 mm) was larger than that in the male group (28 mm), hypertension group (30 mm), and DM group (29 mm). There were no significant differences between groups (P > 0.05).

Fig. 3
figure 3

Violin plot of K-B test of Staphylococcus epidermidis against Rifampin. Each red line represents the median of each subgroup

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Discussion

This study systematically retrieved RWD of 15,415 cases of patients that had used levofloxacin eye drops preoperatively. Data was retrieved from published literature from the last 10 years and from patients that had come to Peking University Third Hospital from 2016 to 2019. As we searched, there were several studies on conjunctival swab culture in cataract patients preoperatively without using antibiotic drops in the eyes (Table 6). According to the results, the positive rate of bacterial cultures of the conjunctival sac in cataract patients preoperatively without using antibiotic drops ranged from 48.3% to 74.0% [23,24,25]. Through 36 16S rRNA gene libraries from 45 samples of preoperative cataract patients, Deepthi et al. indicated that among all the 211 detected isolates in human conjunctival sacs, the most often detected genera were Corynebacterium spp. (n = 30, 14.93%), Staphylococcus spp. (n = 26, 12.94%), and Cutibacterium spp. (n = 23, 11.44%), followed by Escherichia spp. (n = 13, 6.47%) and Acinetobacter spp. (n = 12, 5.97%) [26]. In the current study, the results revealed that after topically applying levofloxacin preoperatively, the positive rate of bacterial cultures from the conjunctival sac were 1.8%, which was indicative of the strong antimicrobial effect of levofloxacin in application before cataract surgery. However, it should be noted that even if levofloxacin had been used four times a day for 3 days, the possibility of a positive conjunctival sac bacterial culture still remained. Due to residual bacteria in the conjunctival sac, culture-positive patients were still at risk of endophthalmitis and other infectious diseases. Historically, the incidence of post-cataract surgery endophthalmitis ranges from 0.03% to 0.70% which could lead to serious consequences [27, 28]. As shown in Table 7, there are several major pathogens isolated from conjunctival sac of patients with post-cataract surgery endophthalmitis [5, 18, 29,30,31,32,33,34,35,36,37,38]. Among them, Gram-positive bacteria is the major pathogen and Coagulase-negative Staphylococci is the most frequently isolated strain [5, 18, 32, 33, 36,37,38]. According to Egrilmez et al., Coagulase-negative Staphylococci shows resistance rates of more than 30% for fluoroquinolone and methicillin [39]. In addition to endophthalmitis, it can also lead to other infectious diseases including bacterial keratitis. Without effective antibiotic prophylactic therapy, patient may be at risk of potentially vision-threatening infection.

Table 6 Summary of studies on conjunctival swab culture in cataract patients preoperatively without using antibiotic drops in the eyes
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Table 7 Summary of major pathogens involved in post-cataract surgery endophthalmitis
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According to our results, Staphylococcus epidermidis, Kocuria rosea, and Micrococcus luteus were the 3 strains with the highest culture-positive rates after usage of levofloxacin eye drops for 3 days preoperatively. All of these bacteria belong to the Micrococcaceae family and are commensals, which can be found on human skin, mucous membranes, and the conjunctival sac [40, 41]. They can cause opportunistic infections, requiring considerable attention [42]. Staphylococcus epidermidis is considered non-pathogenic. However, patients with a compromised immune system are often at risk of being infected. Characteristically, infections caused by Staphylococcus epidermidis are often chronic, which contrasts the acute infections caused by Staphylococcus aureus [43]. The pathogenesis of Staphylococcus epidermidis infection usually involves the formation of biofilms and phenol-soluble modulins which can kill human red and white blood cells [44,45,46]. It has been reported that Staphylococcus epidermidis cause biofilm growth on intravenous catheters and medical prostheses [47]. Thus, patients with Staphylococcus epidermidis are at risk of infection after implantation of intraocular lenses during cataract surgery. Besides, Kocuria rosea and Micrococcus luteus can also cause infectious disease in immunocompromised hosts. It has been reported that Kocuria rosea can cause meningitis, canaliculitis, endocarditis, and descending necrotizing mediastinitis [48,49,50,51,52,53,54]. As an opportunistic pathogen, Micrococcus luteus can also cause serious infections, such as endocarditis and brain abscess [55, 56]. Our study shows that patients with certain clinical factors (male, the presence of hypertension or diabetes mellitus) are at risk of having a greater conjunctival sac bacterial load, which has been confirmed in previous studies [57,58,59,60]. These factors are often present in patients, which may lead to immunocompromised hosts and resulting ocular opportunistic infections caused by the above-mentioned bacteria[1]. It is therefore suggested that ophthalmologists pay more attention to patients with any of these three clinical factors. As for the antibiotic resistance of conjunctival sac bacteria, we found that the resistance of Staphylococcus epidermidis against ofloxacin in the hypertension group was stronger than in the non-hypertension group (P < 0.05). However, the result cannot explain a direct relationship between hypertension and antibiotic resistance of bacteria and how these relate to the preoperative use of levofloxacin. Levofloxacin, a fluoroquinolone, is an isomer of ofloxacin [61]. By using levofloxacin preoperatively, ofloxacin-sensitive bacteria were widely eliminated in patients, and the ratio of ofloxacin-resistant bacteria in patient conjunctival sacs was relatively increased. This may have influenced the results of the current study.

The fact that there still were culture-positive samples after three days of antibiotic prophylactic treatment with levofloxacin shows that, in addition to a high conjunctival sac bacterial load, another possible reason could be the drug resistance of these bacteria. With the widespread use of antibiotics, antimicrobial resistance rates have gradually increased [19, 20]. In the current study, several kinds of bacterial strains were reported as resistant to antimicrobial agents, especially to levofloxacin and ofloxacin. Among them, several Staphylococcus epidermidis isolates had multidrug resistance to antimicrobial agents. It is commonly believed that antimicrobial resistance is higher in Staphylococcus epidermidis than in other Coagulase-negative Staphylococcus spp. [62]. The resistance of these bacterial strains against levofloxacin has been confirmed in several studies and has raised questions regarding the use of particular antimicrobial agents for routine prophylaxis [14,15,16,17,18].

In order to further decrease the conjunctival sac bacterial load through antibiotic prophylactic therapy, we need to carefully consider combinations of other effective antimicrobial agents. Our study suggests that rifampin would be a good choice for better topical prophylactic therapy, since most bacteria were sensitive to that agent. Rifampin belongs to rifamycins and has activity against several types of bacteria. Rubio et al. pointed out that 83.9% of conjunctival sac bacteria were sensitive to rifampin. Rifampin was the most effective for the eradication of the whole, predominantly Gram-positive, flora [63]. According to Chojnacki et al., the rifampin plus polymyxin B-trimethoprim combination demonstrated synergistic antimicrobial activity towards ocular clinical Staphylococcus aureus and Pseudomonas aeruginosa isolates, a low spontaneous resistance frequency, and in vitro bactericidal kinetics and antibiofilm activities equal to or exceeding those of moxifloxacin [64]. Compared to literature on the clinical effects of other antibiotics (Table 8), our study revealed a higher sensitivity of conjunctival sac bacteria towards rifampin[7, 65,66,67,68,69,70,71,72,73,74,75]. Further, there was not enough evidence for side effects of the topical application of rifampin at low concentrations.

Table 8 Summary of antibiotic studies
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Although rifampin is a good choice for combination therapy, it may lead to multidrug resistance and more severe consequences, including fever, headache, orange tears, skin redness or rash (allergic reaction) and other symptoms. Usage of multiple antimicrobial agents can effectively reduce bacterial load in the conjunctival sac. However, more resistant strains can also develop as a result of combined treatment. Therefore, simply adding more antimicrobial agents is an unsustainable strategy for improving antibiotic prophylactic therapy. Furthermore, patients may be at a greater risk of infectious diseases, and the proportion of antibiotic abuse may be higher due to clinical factors. The bacterial flora of the ocular surface may have already been multidrug-resistant in these patients. Thus, local application of multiple antibiotics may aggravate the risk of multidrug resistance.

Alternatively, we advocate a variety of other methods for decreasing the conjunctival sac bacterial load without using more antibiotics. Usage of povidone iodine (PVI) for irrigation during operation can reduce the bacterial burden in the conjunctival sac and has been proven as effective [76]. According to available literature (Table 9), the irrigation with high concentrations of PVI (5%-10%) can effectively decrease the conjunctival bacterial flora. PVI (5%) solution does not increase antimicrobial resistance and has no adverse effects. Low-concentration PVI (0.05%) irrigation of the conjunctival sac for 30 s can achieve a low bacterial contamination rate and reduce damage to the ocular surface. Levofloxacin can enhance the effectiveness of conjunctival sac irrigation with PVI solution [9, 77,78,79,80,81,82,83,84,85,86,87,88]. Compared to the preoperative use of topical antibiotics, the use of PVI can achieve the same degree of elimination of conjunctival sac bacteria. However, appropriate PVI concentration and irrigation duration should be precisely controlled, or it may cause damage to the ocular surface. Preoperative topical antibiotic treatment could be used as an additional method for further elimination of conjunctival sac bacteria.

Table 9 Summary of povidone-iodine studies (PVI)
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We must admit that our study still has limitations. Due to a lack of information, some statistical analyses could not be conducted and we may not provide unexpected results. Not all clinical factors related to conjunctival sac bacterial load were analyzed in our study due to missing data, including age, history of cancer, and screening for infectious diseases. These factors cannot be ignored and would have to be investigated in a follow-up study. However, this limited result can still arouse our attention to the drug-resistance of conjunctival sac bacteria and provide suggestions for preventive treatment.

Conclusions

Male and the presence of hypertension and diabetes mellitus are clinical risk factors for a greater conjunctival sac bacterial load. In order to decrease the conjunctival sac bacterial load for the prevention of possible infections, we offer a prophylaxis suggestion based on RWD, namely the combined use of levofloxacin and rifampin. However, such combined therapy but may aggravate the risk of multidrug resistance. Therefore, alternative ways should be suggested.