Carbapenems are derivatives of thienamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. [1]. In the 1990s, Enterobacteriaceae.spp developed resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum beta-lactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more [2]. In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Health-Care Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems [3].

Cephalosporins or carbapenems have a similar mechanism of action at the PBP but can shield their beta-lactam ring from beta-lactamases with R groups on the adjacent thiazolidine ring without hindering the beta-lactam function. Bacterial beta-lactamases have evolved to circumvent the carbapenem R group shield rendering the antibiotic susceptible to degradation [4] of important, gram-negative bacterial resistance to antibiotics has decreased the physician’s ability to combat infection. Carbapenems are the most potent beta-lactam antibiotics, and unfortunately the resistance to carbapenems has emerged, so it needs a professional healthcare team to evaluate, treat and manage the carbapenem-resistant infections [5].

While carbapenem antibiotics can retain most of the potency against the chromosomal cephalosporinases and extended-spectrum beta-lactamases that are found in many gram-negative pathogens, they are unfortunately susceptible to carbapenemases enzymes [6].  Carbapenemases are beta-lactamases with versatile hydrolytic capacities that also have the tendencies to hydrolyze monobactams which clinically cause high mortality related infections in most scenarios [7]. This resistant mechanism in Carbapenemase Producing Enterobacteriaceae (CPE) is distinct from porins mutation resistant mechanism in ESBL producing bacteria. Both are carbapenems resistant (CRE) but with a much higher in MIC for CPE compared to CRE [8].

Since CRE have developed resistance to preferred antibiotics, second-line therapies are necessary. In addition to Non-β-lactam β-lactamase’s Inhibitors/β-lactam antibiotics, repurported old approved antibiotics, including Tigecycline, Colistin, Fosfomycin, and in some cases the Aminoglycosides are among the remaining treatment options for clinicians to battle these difficult-to-treat infections [9]. Combination therapy with multiple unrelated antimicrobial agents has been shown to decrease mortality in the setting of high-risk infections where death is a likely outcome. Combination regimens involving extended Carbapenems infusion with Colistin or high-dose Tigecycline or Fosfomycin or Aminoglycoside or even triple combinations for CRE infections, which have MICs< 16 mg/l, seem to confer a major clinical outcomes advantage [10]. Colonization with CRE was associated with at least a two-fold increased risk of infection by the colonizing strain amongst ICU patients [11]. The aim of this study is to investigate the clinical impacts of the CRE related VAP among mechanically ventilated COVID-19 infected.

This study was retrospectively conducted in a specialized COVID-19 isolation center at Queen Alia Military Hospital of the Royal Medical Services (RMS) in Jordan.  Admitted COVID-19 infected patient’s data were retrospectively retrieved from our electronic medical record system (Hakeem) over 19 months between Mar 2020 and Sep 2021. Studied patients who were below 18 years, whose hospital length of stay (LOS) didn’t exceed 7 days, and whose studied variables were totally or partially missed were excluded from our study. Owing to our study’s retrospective design, a signed consent form was waived. All eligible admitted mechanically ventilated SARS-CoV-2 infected patients were included in this study. The retrieved retrospective collected data were analyzed using IBM SPSS statistics 22.0, after they are divided into two comparative groups: Non-CRE related VAP infection cohort (Cohort I) and CRE related VAP infection cohort (Cohort II). An Independent and One-Sample T Tests, and Chi Square Test were used to analyze the parametric and non-parametric outcomes’ data, respectively.

The study included a total number of 932 mechanically ventilated SARS-CoV-2 infected patients, 46.24% of them were in Cohort I (N = 431) and 53.76% in Cohort II (N = 501). The mean age of the whole studied 51.41±16.44 years. Non-CRE cohort patients were significantly younger than CRE cohort patients (47.89±16.69 years versus 54.44±15.62 years, respectively, p-Value = 0.00). Male patients were distributed in the study in approximately 3:1 ratio to female patients [699 (75.0%) versus 233 (25.0%), respectively, p-value = 0.021] in which 71.5% (308 Men) and 28.5% (123 Women) belonged to Cohort I compared to 78.0% (391 Men) and 22.0% (110 Women) in Cohort II. The odd ratio for females compared to male patients in our study was 1.42 (95% CI; 1.05-1.91). 

The overall 28-day ICU mortality was detected in 526 in Mechanically Ventilated SARS-CoV-2 infected patients with an overall incidence rate of 56.44% during an average of 19.89±5.55 days and 12.93±4.18 days of ICU and overall hospital admission days, respectively. Cohort I patients compared to Cohort II patients, had an overall 28-day ICU mortality, ICU stay days, and overall hospital admission days of 175 (40.6%),16.19±4.09 days and 22.23±5.63 days compared to 351 (70.06%), 10.13±1.08 days, and 17.88±4.62 days, respectively (p-Value = 0.00). 

Although ALB levels were statistically significantly higher in Cohort I compared to Cohort II at admission and during 1st 3 days of admission (2.311±0.431 g/dl vs 2.017±0.035 g/dl and 2.189.542 g/dl vs 2.017±0.035 g/dl, respectively, p-Value = 0.00), ALB level were insignificantly lower on 4th-5th admitted in Cohort I compared to Cohort II (2.149±0.630 g/dl vs 2.197±0.035 g/dl, respectively, p-Value = 0.096) despite the significantly higher H.ALB inputs in Cohort II compared to Cohort I (30.00±0.00 g//day vs 10.84±8.826 g/day, respectively, p-Value).

Hemodynamically, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP) were all statistically significant higher in Cohort I compared to Cohort II (98.81±4.092 mmHg, 54.78±4.995 mmHg, and 69.41±4.4 mmHg vs 89.71±2.628 mmHg, 47.19±2.245 mmHg, and 61.40±2.065 mmHg, respectively, p-Value = 0.00). Oppositely, changes in heart rate percentage (%∆HR) and norepinephrine rate (NE) were significantly lower in Cohort I compared to Cohort II (19.393%±7.445% and 6.248±7.302 mcg/min vs 28.469%±0.299% and 17.190±3.218 mcg/min, respectively, p-Value = 0.00). 

Scorically, Shock Index (SI) and its derived version (mSI) in addition to Sequential Organ Failure Assessment 

Table 1: Comparatively Studied Variables Between the Non-Carbapenem Resistant Enterobacteriaceae Cohort (Cohort I) and the Carbapenem Resistant Enterobacteriaceae Cohort (Cohort II) Among the Admitted VAP Affected Mechanically Ventilated Critically Ill SARS-Cov-2 Infected Patient at Queen Alia Military Hospital of the Royal Medical Services (RMS) in Jordan

Data results of the comparative variables between the two tested cohorts were statistically analyzed by independent and One-Sample T-Tests, and were expressed as either Mean±SD or as Mean difference±SEM (at p-value<0.05). Cohort I: Critically ill patients who were infected by Non-Carbapenem Resistant Enterobacteriaceae. Cohort II: Critically ill patients who were infected by Carbapenem Resistant Enterobacteriaceae. N: Number of the studied critically ill patients. *: Statistically significant. Yrs: Years. ICU: Intensive Care Unit. ALB: Serum albumin level. H.ALB: Human albumin. SBP: Systolic blood pressure. DBP: Diastolic blood pressure. MAP: Mean arterial pressure. HR: Heart rate. NE: Norepinephrine. 0: baseline. 1: after at least 3 days from baseline. ∆: Changes. SI: Shock Index indicator. mSI: Modified version of Shock Index indicator. SOFA: Sequential Organ Failure Assessment. K: Potassium. Mg: Magnesium. cMg: Corrected magnesium level based on corresponding albumin level (cMg = Mg+0.08*(4-ALB).

Table 2: Continued Comparatively Studied Variables Between the Non-Carbapenem Resistant Enterobacteriaceae Cohort (Cohort I) and the Carbapenem Resistant Enterobacteriaceae Cohort (Cohort II) Among the Admitted VAP Affected Mechanically Ventilated Critically Ill SARS-Cov-2 Infected Patient at Queen Alia Military Hospital of the Royal Medical Services (RMS) In Jordan.

Data results of the comparative variables between the 2 tested cohorts were statistically analyzed by Chi Square Test (at p-value< 0.05) and expressed as Number (Percentage). Cohort I: Critically ill patients who were infected by Non-Carbapenem Resistant Enterobacteriaceae. Cohort II: Critically ill patients who were infected by Carbapenem Resistant Enterobacteriaceae. *: Significant (p-Value <0.05). N: Number of study’s critically ill patients. F: Female. M: Male. Med: Medical. Sur: Surgical. HLOS: Hospital length of stay. ∆: Changes. ICU: Intensive Care Unit. CCI: Charlson Comorbidities Index. Surv: Survivors.

changes (∆SOFA) were also significantly higher in Cohort II compared to Cohort I (1.305±0.080 bpm/mmHg, 1.909±0.135 bpm/mmHg, and 5.00±0.00 vs 1.028±0.132 bpm/mmHg, 1.472±0.231 bpm/mmHg, 2.26±2.207, respectively, p-Value = 0.00).     Dichotomously,   SI,    mSI, ∆SOFA, and new onset prolonged sinus tachycardia (NOPST) had significantly higher distributions in Cohort II compared to Cohort I with an OD ratio of [(<1/≥1) 2.44 (95% CI; 2.25-2.64), (<1.4/≥1.4) 3.67 (95% CI; 3.24-4.14), (No/Yes) 14.48 (95% CI; 9.96-21.07)], respectively.

Biochemically, corrected magnesium levels (Mg), potassium levels, and calculated creatinine clearance values were also significantly higher in Cohort I compared to Cohort II (3.361±0.262 mEq/l, 2.676±0.217 mg/dl, and 56.278±18.241ml/min vs 2.788±0.164 mEq/l, 2.150±0.159 mg/dl, and 30.565±15.619 ml/min, respectively, p-Value = 0.00). Table 1-4 shows comparatively studied variables between the Non-Carbapenem Resistant Enterobacteriaceae Cohort (Cohort I) and the Carbapenem Resistant Enterobacteriaceae Cohort (Cohort II) among the admitted VAP affected mechanically ventilated critically ill SARS-CoV-2 infected patient at Queen Alia Military Hospital of the Royal Medical Services (RMS) in Jordan.

Table3: Continued Comparatively Studied Variables Between the Non-Carbapenem Resistant Enterobacteriaceae Cohort (Cohort I) and the Carbapenem Resistant Enterobacteriaceae Cohort (Cohort II) Among the Admitted VAP Affected Mechanically Ventilated Critically Ill SARS-Cov-2 Infected Patient at Queen Alia Military Hospital of the Royal Medical Services (RMS) in Jordan

Data results of the comparative variables between the 2 tested cohorts were statistically analyzed by Chi Square Test (at p-value< 0.05) and expressed as Number (Percentage). Cohort I: Critically ill patients who were infected by Non-Carbapenem Resistant Enterobacteriaceae. Cohort II: Critically ill patients who were infected by Carbapenem Resistant Enterobacteriaceae*: Significant (p-Value <0.05). N: Number of study’s critically ill patients. SOFA: Sequential Organ Failure Assessment. NOPST: New Onset Prolonged Sinus Tachycardia. SI: Shock Index. mSI: Modified Shock Index. ∆: Changes. ICU: Intensive Care Unit. CrCl: Creatinine clearance.

Table4: Continued Comparatively Studied Variables Between the Non-Carbapenem Resistant Enterobacteriaceae Cohort (Cohort I) and the Carbapenem Resistant Enterobacteriaceae Cohort (Cohort II) Among the Admitted VAP Affected Mechanically Ventilated Critically Ill SARS-Cov-2 Infected Patient at Queen Alia Military Hospital of  the Royal Medical Services (RMS) in Jordan

Data results of the comparative variables between the 2 tested cohorts were statistically analyzed by analyzed by independent and One-Sample T-Tests, and were expressed as either Mean±SD or as Mean difference±SEM. Also, non-parametric data were statistically analyzed by Chi Square Test and expressed as Number (Percentage). (At p-value< 0.05). Chi Square Test (at p-value<0.05) and expressed as Number (Percentage). Cohort I: Critically ill patients who were infected by Non-Carbapenem Resistant Enterobacteriaceae. Cohort II: Critically ill patients who were infected by Carbapenem Resistant Enterobacteriaceae. *: Significant (p-Value<0.05). N: Number of study’s critically ill patients. CRE: Carbapenem Resistant Enterobacteriaceae. ESBL: Extended Spectrum Beta-Lactamases. ABs: Antibiotics. E.spp: Enterobacteriaceae. Species. FQ: Fluoroquinolones.

In this study we compared between Non-Carbapenem Resistant Enterobacteriaceae Cohort (Cohort I) and the Carbapenem Resistant Enterobacteriaceae Cohort (Cohort II) among the admitted VAP affected mechanically ventilated critically ill SARS-CoV-2 infected patient at Queen Alia Military Hospital of the Royal Medical Services (RMS) in Jordan. Our study included 932 critically ill patients, 53.76% of them were with an isolated Carbapenem Resistant Enterobacteriaceae and 46.24% were with an isolated Non-Carbapenem Resistant Enterobacteriaceae. 

According to our results overall 28-day mortality rate was 526 (56.44%), the mortality rate was higher in Carbapenem Resistant Enterobacteriaceae group 461 (92.0%) compared with Non-Carbapenem Resistant Enterobacteriaceae 191 (44.3%). The overall length stays in hospital and overall ICU stay days were lower in In Carbapenem Resistant Enterobacteriaceae group compared with Non-Carbapenem Resistant Enterobacteriaceae, due to the aggressiveness state of Carbapenem Resistant infections.

There are many factors and cofactors affect the mortality among the admitted critically ill patient, such as baseline SOFA score, SI, CrCl, appropriateness of antibiotics. Although The average amount of albumin that was given in Cohort II triple the average amount given in Cohort I, (30 g/day versus 10 g/das), the albumin level in 2nd -3rd day was  lower in Cohort II  (2.017±0.035 g/dl) compared in Cohort I (2.1890.542 g/dl). The difference was statistically insignificant in the 4th-5th day and this may be partially explained by the significantly higher SI, mSI, and ∆SOFA. Regarding the higher incidences of NOPST in Cohort II vs Cohort I, the significantly higher NE rate in Cohort II compared to Cohort I may explained this higher NOPST risk. Indeed, our study results may be biased to Cohort II in overall major clinical outcomes. For example, we assessed that the administered antibiotics dose deficit percentages (%ABs Dose Deficit) were significant higher in Cohort II compared to Cohort I for Piperacillin/Tazobactam and Imipenem/Cilastatin antibiotics (-29.0%±4.2% and -37.9%±9.1% vs -25.7%±2.4% and -29.2%±5.2%, p-Value = 0.00) with Mean differences±SEM of +3.3%±0.6% and +8.7%±1.1%, respectively.

Carbapenem Resistant Enterobacteriaceae associated ventilation associated pneumoniae in mechanically ventilated critically ill SARS-CoV-2 infected patients have at least higher mortality rate and longer overall hospital length of stay compared with patients infected with Non-Carbapenem Resistant Enterobacteriaceae. This study is limited by its retrospective design. A larger, multisite, and prospective study is needed to control for multiple confounders.

1. Perez, Federico and David Van Duin. “Carbapenem-resistant Enterobacteriaceae: A menace to our most vulnerable patients.” Cleveland Clinic Journal of Medicine, vol. 80, no. 4, 2013, pp. 225–233. doi:10.3949/ccjm.80a.12182.

2. Rahal, J.J. et al. “Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella.” JAMA, vol. 280, no. 10, 1998, pp. 1233–1237.

3. Sievert, D.M. et al. “Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010.” Infect Control Hosp Epidemiol, vol. 34, no. 1, 2013, pp. 1–14.

4. Smith, H.Z. and B. Kendall. “Carbapenem resistant Enterobacteriaceae.” StatPearls [Internet], StatPearls Publishing, January 2021. https://www.ncbi.nlm.nih.gov/ books/NBK551704/

5. Papp-Wallace, K.M. et al. “Carbapenems: past, present, and future.” Antimicrobial Agents and Chemotherapy, vol. 55, no. 11, 2011, pp. 4943–4960. doi:10.1128/AAC.00296-11.

6. Jacoby, G.A. and L.S. Munoz-Price. “The new beta-lactamases.” New England Journal of Medicine, vol. 352, no. 4, 2005, pp. 380–391. doi:10.1056/NEJMra041359.

7. Queenan, A.M. and K. Bush. “Carbapenemases: the versatile beta-lactamases.” Clinical Microbiology Reviews, vol. 20, no. 3, 2007, pp. 440–458. doi:10.1128/CMR.00001-07.

8. Meletis, G. “Carbapenem resistance: overview of the problem and future perspectives.” Therapeutic Advances in Infectious Disease, vol. 3, no. 1, 2016, pp. 15–21. Doi: 10.1177/2049936115621709.

9. Paterson, D.L. and Y. Doi. “A step closer to extreme drug resistance (XDR) in gram-negative bacilli.” Clinical Infectious Diseases, vol. 45, no. 9, 2007, pp. 1179–1181. Doi: 10.1086/522287.

10. Rafailidis, P.I. and M.E. Falagas. “Options for treating carbapenem-resistant Enterobacteriaceae.” Current Opinion in Infectious Diseases, vol. 27, no. 6, 2014, pp. 479–483. doi:10.1097/QCO.0000000000000109.

11. Dickstein, Y. et al. “Carbapenem-resistant Enterobacteriaceae colonization and infection in critically ill patients: a retrospective matched cohort comparison with non-carriers.” Journal of Hospital Infection, vol. 94, no. 1, 2016, pp. 54–59. doi:10.1016/j.jhin.2016.05.018.