New Antibiotics for Abdominal Infections: What Can We Expect?

Recently a number of new antibiotics or combinations for complicated ‏intra-abdominal infections have been introduced. Here we ‏review the currently available data of these new drugs and discuss ‏how they can be used in critically ill patients with complicated intraabdominal ‏infections.

Complicated intra-abdominal infections ‏(cIAI) remain one of the most challenging ‏infections in the intensive care ‏unit (ICU). Compared to patients with other ‏infections, patients with cIAI typically will ‏develop multiple organ dysfunction syndrome ‏(MODS) more often and have a higher risk of ‏mortality; often they have a protracted stay in ‏the ICU and in the hospital (De Waele et al. ‏2014). The management of these patients can ‏be challenging. This includes evaluating the ‏need for source control as well as effectively ‏getting the source of infection controlled, but ‏also selecting the appropriate antibiotic in times ‏of changing susceptibility patterns and the rise ‏of antimicrobial resistance (AMR).

The role of source control is more relevant in ‏cIAI than in most other commonly encountered ‏infections in the ICU. At times difficult choices ‏have to be made (Leppäniemi et al. 2015). The ‏role of surgery in this context is changing, new ‏techniques are being introduced, and, increasingly, ‏percutaneous drainage is being used as ‏a primary strategy. Despite the prominent role ‏of source control, administering appropriate ‏antibiotics is equally important. Although there ‏are fewer limitations in correctly diagnosing ‏abdominal infections compared to e.g. respiratory ‏tract infections, both timing and spectrum ‏of empirical antibiotic therapy are critical. ‏Antibiotics should be administered when the ‏diagnosis is made and not postponed until ‏intraoperative cultures are obtained.

Antibiotic resistance is also increasingly ‏described in cIAI. In particular the spread of ‏extended spectrum beta-lactamase (ESBL)- ‏producing Enterobacteriaceae in community-acquired ‏cIAI is striking, and may limit the use of many ‏currently available antibiotics. This in turn may ‏put an inappropriate strain on the carbapenem ‏antibiotics with the risk of increasing resistance ‏to this class of antibiotics. The need for new ‏antibiotics in this context is urgent.

Options for appropriate empirical therapy ‏are becoming limited in some situations, and ‏every attempt should be made to choose the ‏correct antibiotic for the patient with cIAI. It ‏should also be remembered that cIAI are typically ‏polymicrobial infections with both aerobic ‏and anaerobic bacteria present in most situations, ‏and will typically require antibiotics that ‏cover both Gram-positive and Gram-negative ‏pathogens.

See Also: Biomarker Guided Antibiotic Therapy: What’s New?

Rise of Multidrug Resistance in cIAI

As in other types of infections, AMR is a pressing ‏issue in cIAI. Patients with cIAI may be ‏at increased risk of AMR as they are often ‏exposed to antibiotics for prolonged periods ‏of time, and source control plays a crucial role. ‏Particularly when source control is inadequate ‏or even impossible, the inoculum persists. As ‏bacteria are exposed to antibiotics during that ‏time, AMR is bound to develop. This has been ‏documented in severe abdominal infections ‏including peritonitis and pancreatitis (De Waele ‏2016; Montravers et al. 2016).

As typically more than one pathogen is ‏involved, the risk of encountering antibiotic ‏resistance is also increased. For the same reason ‏the extensive coverage needed to cover all ‏pathogens (often with multiple antibiotics) ‏may fuel AMR, as bacteria are exposed to more ‏than one antibiotic at the same time. Whereas ‏AMR was only relevant in nosocomial infections ‏until recently, it is now also posing problems ‏in community-acquired disease.

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Overall, AMR is a concern mostly with Gramnegative ‏pathogens. ESBL-producing bacteria ‏are a primary worry worldwide (Sartelli et ‏al. 2015), even more so in some areas, e.g. in ‏Asia. Even then important regional differences ‏are present.

The prevalence of ESBL in E. Coli, K. pneumonia, ‏K. oxytoca and P. Mirabilis has increased dramatically ‏from 2002 to 2011 in cIAI in Asia and the ‏Middle East, where up to 40% of these pathogens ‏isolated from cIAI produce ESBLs (Morrissey et ‏al. 2013). It is unclear if this trend has changed ‏in more recent years as epidemiological studies ‏on AMR after 2013-2014 are lacking. Regional ‏differences are important, and extrapolating data ‏from other parts of the world to develop local ‏empirical therapy guidelines should be avoided.

Carbapenemase-producing Klebsiella pneumonia ‏(KPC) has been posing particular problems in ‏nosocomial infections in some parts of the ‏world. cIAI have not been exempt from KPC ‏involvement, but this appears to be a regional ‏problem mostly at this point.

Although the problem of AMR in cIAI is ‏most relevant for Gram-negative pathogens, ‏trends in Gram-positive infections should not be ‏ignored. Enterococci are considered to be more ‏pathogenic in nosocomial cIAI, and typically are ‏involved in patients who have been exposed to ‏antibiotics that do not cover enterococci, e.g. ‏cephalosporins or fluoroquinolones. Apart from ‏their different appreciation in nosocomial cIAI, resistance in enterococci is increasing as well; E. ‏faecium is typically non-susceptible to penicillin ‏antibiotics, but in E. faecalis ampicillin resistance is ‏also rising. Infection with vancomycin-resistant ‏enterococci is also increasingly described

New Antibiotics for cIAI

Recently a number of new antibiotics or antibiotic ‏combinations have been studied in patients ‏with cIAI. Antibiotics recently introduced or ‏coming soon for the treatment of cIAI include ‏ceftolozane/tazobactam, ceftazidime/avibactam ‏and eravacycline. Although several other new ‏antibiotics may have activity against pathogens ‏typically associated with cIAI, none of them is ‏currently under investigation for this indication, ‏and will not be discussed.

Ceftolozane Plus Tazobactam

Ceftolozane is a new fifth-generation cephalosporin ‏antibiotic that has been marketed in ‏combination with a well-known beta-lactamase ‏inhibitor (BLI), tazobactam, in a fixed 2:1 ‏ratio. It is active against a wide range of Gramnegative ‏bacteria, including Pseudomonas aeruginosa ‏and many ESBL-producing Enterobacteriaceae. It ‏has been approved by the United States Food ‏and Drug Administration for the treatment ‏of complicated urinary tract infections and ‏cIAI (combined with metronidazole for the ‏latter). Dosing for patients with normal renal ‏function is 1000mg ceftolozane plus 500mg ‏tazobactam TID.

Three clinical trials have been performed in ‏patients with cIAI. In a phase 2 study, 121 patients ‏with cIAI requiring surgery were randomised ‏to receive either meropenem or ceftolozane/ ‏tazobactam with metronidazole (Lucasti et al. ‏2014). Clinical cure rates were 83.6% and 96% ‏for ceftolozane and meropenem respectively, ‏on the basis of which the noninferiority of ‏the drug was concluded. The Assessment of the ‏Safety Profile and Efficacy of Ceftolozane/Tazobactam in ‏Complicated Intra-abdominal Infections (ASPECT-cIAI) ‏programme, reporting on two identical phase ‏3 studies with a similar setup to the phase 2 ‏study, and using the same comparator, included ‏993 patients, 806 of which were analysed in ‏the modified intention to treat (MITT) group ‏(Solomkin et al. 2015). For the primary endpoint ‏clinical cure rates were 83% with ceftolozane/ ‏tazobactam plus metronidazole vs. 87.3% with ‏meropenem in the MITT population. In both ‏studies the incidence of adverse effects reported ‏was similar in both groups. Based on these ‏studies, ceftolozane/tazobactam was approved ‏for the indication of cIAI at the end of 2014.

In a recent substudy investigating the ‏outcomes of patients with Pseudomonas aeruginosa, ‏the strong in vitro activity of ceftolozane against ‏these pathogens was confirmed, with high ‏clinical cure rates in the subgroup of patients ‏with Pseudomonas infections (Miller et al. 2016). ‏

Ceftazidime Plus Avibactam

Avibactam is a novel BLI that restores the activity ‏of beta-lactam antibiotics such as ceftazidime ‏against ESBL-producing pathogens. ‏

In a phase 2 study the combination of ceftazidime/ ‏avibactam (2000mg/500mg TID) with ‏metronidazole 500mg TID was compared with ‏meropenem in 204 patients with cIAI (Lucasti ‏et al. 2013). Clinical cure was 91.2% and 93.4% ‏for ceftazidime/avibactam co-administered with ‏metronidazole and meropenem respectively. ‏Adverse events were comparable in both groups.

In two large phase 3 studies with an identical ‏setup 1066 patients with cIAI requiring surgery ‏of percutaneous drainage were randomised to ‏receive ceftazidime/tazobactam plus metronidazole ‏and the combination was found to ‏be noninferior to meropenem (Mazuski et al. ‏2016). In the microbiologically MITT group, ‏clinical cure at test of cure was statistically ‏not different in the ceftazidime/tazobactam ‏plus metronidazole group (81.6% vs. 85.1% ‏respectively), and at other time points outcome ‏was comparable. Safety evaluation did not ‏demonstrate any differences between the groups.

Eravacycline

Eravacycline is a novel antibiotic in the tetracycline ‏class, structurally comparable with tigecycline. ‏It inhibits bacterial protein synthesis through ‏binding to the 30S ribosomal subunit and has ‏broad-spectrum antimicrobial activity against ‏Gram-positive, Gram-negative and anaerobic ‏bacteria with the exception of Pseudomonas aeruginosa, ‏but including MDR pathogens such as ‏methicillin-resistant Staphylococcus aureus (MRSA) ‏and some carbapenem-resistant Gram-negative ‏bacteria. In a phase 2 study the efficacy and ‏safety of two dose regimens of eravacycline ‏was compared with ertapenem in adult hospitalised ‏patients with cIAI requiring surgical or ‏percutaneous intervention: 1.5 mg/kg of body ‏weight every 24 hours (q24h), or 1.0 mg/ ‏kg every 12 h (q12h) (Mazuski et al. 2016). ‏In the microbiologically evaluable population ‏the clinical cure was 92.9% and 100% in the ‏groups receiving eravacycline at 1.5 and 1.0 ‏mg/kg respectively, and 92.3% in the ertapenem group. Another large phase 3 study comparing ‏eravacycline with ertapenem has been finalised ‏but not yet published (IGNITE 1)—the ‏manufacturer has reported that noninferiority ‏was demonstrated but full analysis is not yet ‏available (Tetraphase Pharmaceuticals 2014).

Caveats for Critical Care

Shortcomings of Recent cIAI Studies From a Critical ‏Care Perspective ‏

Although these antibiotics represent new therapeutic ‏options in the management of cIAI, there ‏are some things to consider from a critical care ‏perspective. This is primarily related to the ‏type of patients in the studies with these new ‏antibiotics, and with the type of patients not ‏included due to an often long list with exclusion ‏criteria. Overall the patients in these studies ‏are mild to moderately ill only, with a high ‏prevalence of infections that are typically not ‏encountered in the ICU, such as appendicitis.

In the studies investigating ceftolozane, ‏it was not reported how many patients were ‏diagnosed with severe sepsis or septic shock, or ‏were admitted to an ICU. In the first study more ‏than half of the patients were treated because ‏of appendicitis, and median Acute Physiology ‏and Chronic Health Evaluation (APACHE)-II ‏score was 6 and 7 respectively (Lucasti et al. ‏2014). Similarly, in the ASPECT-cIAI programme, ‏APACHE-II scores were 6 and 6.2 in the study ‏groups and degree of organ dysfunction was not ‏reported (Solomkin et al. 2015). Both studies ‏excluded patients with thrombocytopenia or ‏abnormal renal function.

The studies investigating avibactam in combination ‏with metronidazole excluded severely ‏ill patients; exclusion criteria in the phase 2 ‏study included APACHE-II score of 26 or higher, ‏abnormal renal function and fluid-unresponsive ‏septic shock (Lucasti et al. 2013). Only 1 out ‏of 6 patients had an APACHE-II score between ‏10 and 25, and the appendix and stomach ‏were the most frequent sites of the primary ‏infection. The phase 3 study included mainly ‏patients with low to moderate disease severity ‏as exemplified by the APACHE-II score that ‏was 10 or lower in about 85% of the patients ‏(Mazuski et al. 2016). That study also excluded ‏patients with septic shock or who were receiving ‏haemodialysis. The fact that patients could ‏not be treated with an antifungal agent may ‏have precluded including patients with more ‏severe disease in the study. ‏

‏One particular finding in the phase 3 study ‏was the worse outcome in patients with moderate renal impairment, defined as a creatinine ‏clearance of 30-50ml/min. This may have been ‏caused by the rapid changes in renal function ‏in the subsequent days when patients still ‏received renal function adjusted doses of the ‏drug, although the effect should be present in ‏both the interventional and comparator group ‏(Mazuski et al. 2016).

The study investigating eravacycline excluded ‏more critically ill patients such as patients with ‏septic shock or an APACHE-II score of 25 or ‏higher. Effectively, APACHE-II score was 6 and ‏8.2 in the study groups, and appendicitis was ‏the source of infection in more than 50% of the ‏patients. The use of ertapenem as a comparator ‏can also limit the number of critically ill patients ‏included, as this drug is not recommended ‏for the treatment of severe cIAIs (Solomkin ‏et al. 2010). ‏

Implications for Critically Ill Patients With cIAI

So how does this translate to the use of these ‏new agents in the critically ill? Although it is ‏clear that the in vitro activity of these drugs ‏against a wide range of pathogens is similar or ‏better than many of the antibiotics that we are ‏using now, the changes in physiology of the ‏critically ill may be profound and lead to lower ‏concentrations than expected. This phenomenon ‏has been demonstrated for many antibiotics ‏(Roberts et al. 2014) and is now an integral ‏part of most drug development programmes.

‏In this context it is remarkable that an ongoing ‏study comparing ceftolozane/tazobactam to ‏meropenem for hospital-acquired pneumonia ‏(Safety and efficacy study of ceftolozane/tazobactam to ‏treat ventilated nosocomial pneumonia (MK-7625A-008) ‏(ASPECT-NP), NCT02070757) uses a dose ‏that is double what was used in the cIAI study ‏(clinicaltrials.gov/ct2/show/NCT02070757). It is ‏unclear if this is solely because of the different ‏infection focus. Future pharmacokinetic studies ‏of these new antibiotics in more severely ill ‏patients should answer these concerns.

The exact place of these new agents in ‏our current armamentarium will need to be ‏discussed primarily considering the local ecology. ‏This is where antibiotic stewardship teams ‏should jointly define the indications as well as ‏consider restriction in the use of these powerful ‏agents. Apart from treating the infections ‏adequately, new agents should be cherished ‏and used only where they have a clearly added ‏value – whether this is in empirical therapy ‏in one country or directed therapy for highly ‏resistant pathogens in another. ‏

 
Conclusions

Antibiotic therapy of cIAI is becoming increasingly ‏challenging due to the changes in susceptibility ‏of pathogens involved. Although our ‏current armamentarium may be effective in the ‏treatment of many patients, new therapeutic ‏options are highly desirable. The development ‏of ceftolozane/tazobactam, ceftazidime/avibactam ‏and eravacycline offers an opportunity to ‏effectively treat MDR pathogens and avoid more ‏toxic regimens. The exact place of these agents ‏in the treatment of cIAI should be defined by ‏local antibiotic stewardship teams, considering ‏local ecology and other available options.

Conflict of Interest

Jan De Waele declares Consultancy for AtoxBio, ‏Bayer Healthcare, Cubist, Fresenius, Merck. He is ‏Infection section Chair at the European Society ‏of Intensive Care Medicine, President of the ‏Belgian Society of Intensive Care Medicine, Past ‏President of WSACS - the Abdominal Compartment ‏Society and Senior Clinical Investigator at ‏the Flanders Research Foundation.

Abbreviations

AMR antimicrobial resistance

APACHE Acute Physiology and Chronic Health Evaluation

ASPECT-cIAI Assessment of the Safety Profile and

Efficacy of Ceftolozane/Tazobactam in Complicated

Intra-abdominal Infections

BLI Beta-lactamase inhibitor

cIAI complicated intra-abdominal infections

ESBL extended spectrum beta-lactamase

ICU intensive care unit

KPC Klebsiella pneumonia

MDR multi-drug resistance

MITT modified intention to treat

MODS multiple organ dysfunction syndrome