With the widespread use of antibiotics, the problem of bacterial drug resistance is becoming more and more serious. Among them, the susceptibility of inactive bacilli to antibiotics has changed dramatically, and multi-drug resistant strains (MDR) have emerged, and because they exhibit a high degree of resistance, we may be faced with a situation where there is no drug to treat, so this problem has attracted widespread attention. In this article, we will only discuss the development trend of drug resistance, treatment options and problems faced.
Development trend of drug resistance in Bacillus spp.
It is widely distributed in hospital settings and can cause serious infections in high-risk populations. It is widely distributed in hospital settings and can cause serious infections in high-risk populations. At the same time, the drug resistance mechanism of A. baumannii is complex and prone to multi-drug resistance, and because of its high viability, it can colonize hospitals for a long time and cause outbreaks of infections, so there is more concern about the drug resistance trend and infections caused by this bacterium.
Since the first outbreak of multi-drug resistant Acinetobacter baumannii (MDR-Ab) infection in New York in 1991, the resistance of the organism has become increasingly serious. 2000, a survey from SENTRY showed that the resistance rate of the organism to the first-line drugs carbapenems increased from 2% to 46-54% [1]. This event became a global landmark event. Since then the resistance of the bacterium is still progressing rapidly, and in 1998, the National University Hospital in Taiwan isolated an immobile bacterium that is fully resistant to the currently routinely tested drugs, called pan-drug resistant bacterium (PDR-Ab). Since then this strain has been rapidly increasing worldwide.
The drug resistance of this bacterium is not accidental; it is consistent with the general trend of bacterial drug resistance evolution. Current studies suggest that the risk factors for acquiring MDR-Ab infection are mainly related to the severity of the patient’s disease, intensity of therapeutic interventions, immunity, underlying cardiopulmonary function, receipt of multiple invasive operations, mechanical ventilation, and broad-spectrum antibiotic use, which determine its distribution in the hospital with a prevalence in ICU, hematology, transplantation, and burn wards. It mainly causes hospital-acquired pneumonia, especially ventilator-associated pneumonia, bacteremia, urinary tract infections, and meningitis, among which lower respiratory tract infections caused in mechanically ventilated patients have become of increasing clinical concern.
The significance of the evolution of drug resistance in this bacterium is that resistance to carbapenems would imply resistance to multiple antibiotics at the same time. In addition, the emergence of PDR-Ab has the potential to push us to the point where we are truly drug-free, so there has been a surge of interest in recent years to address this serious challenge.
Multi-drug resistant strains are strains that are resistant to at least five of the seven classes of antibiotics commonly used against Pseudomonas (including: pseudomonas-resistant penicillins, cephalosporins, aminoglycosides, quinolones, carbapenems, tetracyclines, and sulfonamides). Pan-drug resistant strains (PDR), on the other hand, are strains that are fully resistant to all of the above 7 classes of antibiotics, and they are a special type of MDR.
Treatment of MDR-Ab – sulbactam-containing preparations
MDR-Ab, especially carbapenem-resistant Clostridium perfringens (CR-Ab), is often sensitive to sulbactam-containing agents, which is related to the resistance mechanism of the bacteria. As its production of multiple hydrolytic enzymes is the main mechanism, in response to this, sulbactam, unlike most β-lactams, can act directly on the bacterial penicillin-binding protein PBP2, thus showing its unique bactericidal effect on Fusobacterium. It also inhibits a variety of β-lactamases (TEM1, TEM2, SHV1, etc.) and most ultra broad-spectrum β-lactamases (ESBLs) produced by bacteria as a response to multiple hydrolytic enzyme resistance.
The significance of the evolution of resistance in B. immortalis is that resistance to carbapenems would imply simultaneous resistance to multiple antibiotics. Not only that, but with the emergence of pan-drug resistant bacteria, there is the potential to push us to a point where we are truly drug-free.
Not only is this theoretical, but a series of clinical studies since 1996 have confirmed the therapeutic effect of sulbactam-containing preparations against MDR-Ab (and especially against CR-Ab). Satisfactory results were received for both wound, respiratory and urinary tract infections, as well as for severe bacteremia and meningitis, with an overall cure rate of >80%, and no difference between the use of sulbactam alone and in combination formulations, thus establishing the key role of sulbactam in the treatment of this bacterium. Sulbactam compounding is now recommended for MDR-Ab empirically. In particular, the empirical choice of ampicillin/sulbactam can significantly reduce mortality in critically ill patients and in regions with a high prevalence of this strain.
Treatment of PDR-Ab
1. New use of old drugs and new drug development
The key point of the above treatment for MDR-Ab is that there are still in vitro sensitive drugs, but for PDR-Ab, how should we treat it?
The current useful exploration is mainly for the low permeability and pumping mechanism in drug resistance mechanism. On the one hand, the traditional polymyxin E (Colistin) and minocyclines have been chosen, because they mainly act on bacterial cell membranes, have strong drug permeability, and can produce slow-acting bactericidal effects; on the other hand, the newly developed new tetracycline, tigecycline, is effective in drug resistance caused by reduced antibiotic intake, because it can overcome all pump-out mechanisms. in antibiotic resistance caused by reduced intake.
The relevant studies seem to give us a ray of hope, but it is easy to find after careful analysis: the application of mucormycin class has high side effects and the incidence of renal failure is 27% in those with normal renal function and 58% in those with pre-existing renal insufficiency, limiting clinical use. In addition, its effectiveness in pneumonia is significantly lower than that in urinary tract and bloodstream infections (25% vs. 80%), and pneumonia is the most common site of infection, so the drug is not satisfactory in terms of efficacy or side effects. Tetracyclines and their derivatives, despite their good efficacy, have been studied in small sample sizes and need further confirmation; tigecycline, a new drug, seems to have the most potential [14], but again, the small sample size and the fact that it is not yet available limit its use, but, with widespread use, it will inevitably face the emergence of resistance again. Therefore, for pan-drug-resistant strains, we need to continue to accumulate experience in the use of doxycyclines and tigecycline on the one hand, and it is more urgent to find a breakthrough point by choosing reasonable combination drugs and appropriate doses from the existing drugs with the help of a deeper understanding of the resistance mechanism.
2.The exploration of PDR-Ab treatment
With the in-depth research on the drug resistance mechanism of PDR-Ab, it is believed that the production of various hydrolases is the main drug resistance mechanism of PDR-Ab, followed by the change of PBP target and affinity, the decrease of outer membrane permeability and the absence of permeability protein, and the pump-out mechanism, etc. In this regard, we can explore the value of existing drugs.
(1) Targeting PBP binding targets and enzyme-producing resistance – the advantages of sulbactam
The unique role of sulbactam in MDR-Ab has been pointed out above to establish its therapeutic role in MDR-Ab. But can it continue to be useful for a strain that is resistant in in vitro drug sensitivity testing? Analyzing the current PDR-Ab, we will find a significant proportion of sulbactam-containing preparations as mediators in full resistance. Recent studies have concluded that the endogenous antibacterial activity of sulbactam is directly related to the concentration [15]. In the literature, the choice of relatively high doses of sulbactam (4-6 g/d) was reported to be effective for PDR-Ab. These useful attempts suggest that for pan-resistant strains, if an intermediary drug is available, it is not necessarily ineffective in vivo if used at adequate doses.
②Decreased outer membrane permeability and pump-out mechanisms – the basis for combination therapy
Studies in Pseudomonas aeruginosa have shown that synergistic combinations can overcome mainly low levels of impermeability or pump-out resistance, and since this is one of the mechanisms of resistance in P. aeruginosa, it suggests that combination therapy may be effective. However, the combination is not blind and arbitrary, and the minimum inhibitory concentration (MIC) of the drug should be taken into account. Studies on Pseudomonas aeruginosa point out that the maximum and safe dose may be effective when the MIC of both ceftazidime and amikacin is 16 mg/L, but is no longer considered when the MICs of both are 256 mg/L and 64 mg/L, respectively.
Studies on the pharmacokinetics and clinical efficacy of combination therapy with PDR-Ab are limited and controversial in the limited number of studies.
First of all some in vitro or animal studies do not support combination therapy. Spanish authors compared the pharmacokinetics and pharmacodynamics of Teneren alone or in combination with amikacin in a guinea pig model of Bacillus immobilis pneumonia. The results showed a decrease in maximum plasma concentration (Cmax) and area under the curve (AUC) and an increase in lung tissue bacterial concentrations after the combination of Tylenol with amikacin, with consistent findings for both Tylenol-susceptible and drug-resistant strains. This suggests that the combination of drugs may diminish the antibacterial effect.
However, HsuehPR et al. synergistic combination experiments concluded differently, suggesting that imipenem in combination with sulbactam or in combination with amikacin showed a synergistic effect, while imipenem in combination with quinolones or quinolones in combination with sulbactam showed no synergistic effect. At the same time, the authors point out that although the synergistic effect resulted in a lower MIC value, this value still exceeds the plasma level that can be achieved with conventional doses of antibiotics, suggesting that the therapeutic potential of this combination may be limited. At the same time, however, they do not deny that some patients have also been successfully treated with high doses of imipenem (3 g/d) in combination with sulbactam. It is evident that for this resistant strain, there may be differences in pharmacokinetics in vivo and in vitro, and we need to further investigate the significance of combination pharmacokinetic tests and the differences in pharmacokinetic/pharmacodynamic effects in vivo and in vitro in depth to provide clinical assistance.
Recent in vitro pharmacokinetic studies have compared the effects of combinations between non-traditional therapeutic agents. The study showed that the susceptibility of doxycycline, mucormycin, and rifampicin alone was 92%, 100%, and 64%, respectively, against B. immobilis. The combination of doxycycline and mucormycin had synergistic effects on all strains, while mucormycin combined with rifampicin had synergistic effects on only 20% of strains and mucormycin combined with meropenem had synergistic effects on 12% of strains. It is suggested that the combination of doxycycline and mucomycin may be the best choice. However, clinical operability and true efficacy have not been reported.
In recent years, various combination models of antibiotics have been proposed, such as: cefoperazone/sulbactam or other cephalosporins combined with amikacin, imipenem combined with amikacin, cefoperazone/sulbactam combined with amikacin and imipenem, β-lactams combined with fluoroquinolones or rifampicin Since they are all reported in small samples, it is difficult for us to evaluate the advantages and disadvantages of their effects.
With the progress of research on drug resistance mechanism, a series of special enzymes were found, and an article pointed out that 96.4% of the OXA-23 carbapenem hydrolase PCR was positive in the A. baumannii strain isolated in 2004 in China, and related studies showed that this strain was only sensitive to polymyxin B, minocycline (doxycycline) and cefoperazone/sulbactam as intermediates. This suggests that by mastering the epidemiological characteristics of local drug-resistant bacteria and drawing on relevant studies, it is possible to select drugs empirically, even if we cannot perform resistance gene analysis on a case-by-case basis. In our unit, we empirically selected adequate amounts of cefoperazone/sulbactam combined with minocyclines over a period of time in response to this epidemiological feature and achieved good results.
In conclusion, when choosing a combination regimen, we should take into account the MIC values of the drugs on the one hand, and on the other hand, we should learn as much as possible about the major local drug resistance phenotypes to facilitate rational combination of drugs for different drug resistance mechanisms.
Problems in the clinic
1. How to select drugs for non-multi-drug resistant Bacteroides fumigatus
The problem we often face is when the bacteria are sensitive to multiple antibiotics, including carbapenems, whether to prefer the traditional first-line drugs carbapenems or try to avoid them. Because of the increasing severity of bacterial resistance, we need to consider not only the efficacy of the drug, but also the induction of resistance and its impact on the overall resistance trend. As mentioned earlier, bacterial resistance is closely related to the widespread use of antibiotics, and Bacteroides immobilis is no exception. A large number of current studies point to the application of carbapenems as an independent risk factor for the development of MDR-Ab. Therefore, we must take into account the bacterial resistance caused by antibiotics while treating infections, and choose effective and low-inducing resistance drugs as much as possible.
2.Whether sulbactam single agent can be selected for the treatment of immobile bacillus infection
There are more and more studies pointing out that sulbactam is the component that really works on B. immobilis, and clinical studies also support that there is no significant difference between the overall efficacy of sulbactam single dose and compounded dose, so theoretically it is possible. However, a careful analysis of the relevant studies shows that the efficacy of the same drug in the treatment of different sites of infection is different. For meningitis and bacteremia the efficiency is around 80%, while for pneumonia the efficiency is only 20% to 50%, or even lower. Why is there this difference? This is our third common clinical problem.
3. The clinical complexity of treating drug-resistant bacterial infections
The risk factors for acquiring multi-drug resistant bacteria are mentioned at the beginning of the text, and these make clinical decision making more complicated. This part of the patient is hospitalized for a long time, applying multiple antibiotics, and there are often multiple resistant bacteria colonized in the body. Before making decisions, it is important to distinguish between colonization and infection, however, it is difficult to draw a strict clinical line because of the continuity between the two, so it is particularly important to decide on the timing of treatment, which will directly affect the outcome of treatment. At the same time such patients have a prolonged disease, diverse pathogenic bacteria, mainly mixed infections, clinical sometimes difficult to determine whether the immobile bacilli at this time is the only pathogenic bacteria, especially for pulmonary infections, this may be an important reason for the reported application of sulbactam single agent treatment of immobile bacillus pneumonia is less effective than meningitis, bacteremia.
We must take into account the bacterial resistance caused by antibiotics while treating infections and choose drugs that are effective and low inducing resistance whenever possible. In conclusion, in clinical practice we are faced with a complex set of problems not only in terms of which drugs should be selected for the resistant bacteria themselves, but also in terms of differentiating infection from colonization, determining the optimal timing of treatment, differences in response to treatment at different sites of infection, and the impact of treatment on overall resistance trends.
In summary
Although there is no optimal treatment plan for multi-drug resistant strains, especially for pan-drug resistant strains, there is still hope to find practical treatment options by increasing the dose, extending the infusion time, and even changing the route of administration (e.g., inhalation) to achieve optimal pharmacokinetics and pharmacokinetics by improving the understanding of the resistance mechanism and combining pharmacokinetic and pharmacological studies.
At present, it is believed that the choice of intermediary drugs is not necessarily ineffective in vivo when given in adequate doses and in reasonable combinations; the role of non-traditional antibacterial drugs (doxycycline, mucilage, rifampicin, etc.) needs to be further evaluated. Meanwhile, for drug-resistant bacteria, it is more important to adopt a comprehensive treatment strategy, such as cutting off the transmission route and actively treating the primary disease, and to fully consider the clinical complexity when selecting drugs, as well as to develop a reasonable antibiotic use strategy to delay drug resistance.