Ampicillin–Sulbactam for Carbapenem-Susceptible Acinetobacter baumannii Pneumonia: A Case for High-Dose,Continuous Infusion Dosing Strategy in the Trauma ICU

Abstract

Background

: The optimal ampicillin–sulbactam dosing regimen for carbapenem-susceptible Acinetobacter baumannii isolates in critically ill trauma patients has not been clearly defined. One strategy to provide the adequate sulbactam dose includes high-dose continuous infusion.

Case(s) Description:

We present three cases of critically ill trauma patients with augmented renal clearance treated with high-dose ampicillin–sulbactam through an intravenous continuous infusion for ventilator-associated pneumonia. All A. baumannii isolates were susceptible to sulbactam with low minimum inhibitory concentrations. All achieved clinical cure at the end of therapy and no recurrent pneumonia was noted. No clinically substantial adverse effect attributable to ampicillin–sulbactam therapy occurred.

Discussion:

There is limited evidence to endorse high-dose, continuous infusion ampicillin–sulbactam for treatment of infections caused by carbapenem-susceptible A. baumannii. This report presents three critically ill trauma patients with augmented renal clearance that achieved positive clinical outcomes with higher doses of ampicillin–sulbactam administered through a continuous infusion.

Background

High-dose ampicillin–sulbactam is recommended for use in multi-drug resistant Acinetobacter baumannii infections, including carbapenem-resistant A. baumannii (CRAB) isolates where limited alternative therapeutic agents exist.¹ In this combination, sulbactam is the active component and targets A. baumannii through saturation of penicillin-binding proteins (PBP) 1a, 1b and 3.¹ Ampicillin–sulbactam is available as a fixed combination product containing a 2:1 ratio of ampicillin to sulbactam and a total daily dose of 6–9 g of sulbactam is recommended in the management of infections caused by CRAB.¹ Strategies to provide the adequate sulbactam dose for these infections include using high daily doses of ampicillin–sulbactam (up to 27 g/day) administered as an extended infusion (over 4 h) or continuous infusion over 24 h (i.e., 9 g ampicillin–sulbactam IV every 8 h over 8 h).^1,2 The optimal dosing regimen has not been clearly defined for carbapenem-susceptible A. baumannii isolates, and given the virulence of this pathogen, clinicians may choose to use higherdoses in an effort to optimize outcomes. This tactic may also be preferred for critically ill patients at risk for pharmacokinetic alterations, which may be associated with reduced sulbactam concentrations, such as augmented renal clearance (ARC).

Critically ill trauma patients frequently experience ARC, which can lead to underdosing of renally excreted medications, including β-lactam antimicrobials; however, there is a lack of data to guide ampicillin–sulbactam dosing in this setting.^3,4 The aims of this case series are to describe the clinical course of critically ill adult trauma patients with ARC receiving high-dose continuous infusion ampicillin–sulbactam therapy for carbapenem-susceptible A. baumannii pneumonia and to present the clinical outcomes of this treatment.

Description of Cases

All patients included in this cohort were adult trauma patients who received ampicillin–sulbactam for at least 72 h for ventilator-associated pneumonia (VAP) in the trauma intensive care unit (ICU). The diagnosis of pneumonia was defined as positive respiratory culture with at least one organism with ≥ 10⁴ colony-forming units (CFU)/mL obtained through quantitative bronchoalveolar lavage (BAL).⁵ The patients were ≤ 35 years of age, two males and one female, and all had injury severity scores (ISS) ≥ 15. Body mass index reflects one overweight patient and two patients with obesity weighing >100 kg. Augmented renal clearance in trauma intensive care (ARCTIC) scores were 9 for the two male patients and 7 for the female patient, indicating all patients met criteria for ARC.⁶ In addition, the ARC predictor scores were above the threshold probability of 0.2.⁷ Finally, calculated creatinine clearance (CrCl) using Cockcroft-Gault equation was >130 mL/min for all patients while on ampicillin–sulbactam therapy.⁸ A detailed injury list, criteria for ARCTIC scores, ARC predictor scores, and CrCl values are described in Table 1.

Table 1.

Patient Cases with Details on Augmented Renal Clearance, Microbiology, and Ampicillin–Sulbactam Therapy

Patient characteristics	Injury list	Calculated CrCl,ARCTIC score and ARC predictor score on therapy	BAL^a culture (organisms and ampicillin–sulbactam MIC)	Ampicillin–sulbactam daily dose and method of administration	Other antibiotic therapy/comments
Patient 1 25 y/o female BMI 34 kg/m²	Bilateral pneumothorax and rib fractures Left tibial fracture Right medial femoral condyle fracture, tibial head fracture, tibial plafond fracture Left humeral fracture Left comminuted fracture of the olecranon process of the ulna Right comminuted oblique fracture of the medial malleolus Acute aortic injury Grade I liver injury Grade II right kidney injury Right fracture superior obturator ring Nondisplaced sacral fracture Right avulsion fracture to medial patella Left orbital injury and eyelid laceration Left and right knee avulsion	CrCl: 198 mL/min ARCTIC: 7 Age <56 (4 points) SCr <0.7 mg/dL (3 points) ARC Predictor: 83.89%	80,000 CFU/mL A. baumannii, no other organism MIC ≤ 2/1 mcg/mL (sulbactam MIC ≤ 1 mcg/mL)	18 g through continuous infusion (9 g infusion over 12 h every 12 h/6 g sulbactam/day)	Broadened to cefepime, metronidazole, and vancomycin after 6 d of ampicillin–sulbactam for empirical treatment of abdominal wall infection. Diagnostic imaging did not reveal infection and antimicrobials were discontinued with negative cultures.
Patient 2 35 y/o male BMI 33 kg/m²	TBI^b with left occipital condyle fracture C3-T4 vertebral body fractures Grade I vertebral artery injury Sternal fracture Left rib fractures 1–8, right rib fractures 2–9 Right hemothorax, small left pneumothorax L1-L2 transverse process fractures	CrCl: 227 mL/min ARCTIC: 9 Age <56 (4 points) Male (2 points) SCr <0.7 mg/dL (3 points) ARC Predictor: 68.43%	30,000 CFU /mL A. baumannii, 10,000 CFU/mL MSSA, and >100,000 CFU/mL normal flora MIC ≤ 2/1 mcg/mL (sulbactam MIC ≤ 1 mcg/mL)	18 g through continuous infusion (9 g infusion over 12 h every 12 h/6 g sulbactam/day)	Cefepime started empirically for two days before changing to ampicillin—sulbactam monotherapy
Patient 3 20 y/o male BMI 27 kg/m²	Severe TBI^b with herniation and hematoma evacuation Facial fractures: frontal sinus, temporal bone, left LeFort II, right LeFort III fracture, bilateral orbital fractures Right pneumothorax and left upper lobe pulmonary contusions Soft tissue density around the celiac trunk Right olecranon fracture	CrCl: 179 mL/min ARCTIC: 9 Age <56 (4 points) Male (2 points) SCr <0.7 mg/dL (3 points) ARC Predictor: 80.33%	>100,000 CFU/mL A. baumannii, >100,000 CFU/mL Stenotrophomonas maltophilia MIC ≤ 2/1 mcg/mL (sulbactam MIC ≤ 1 mcg/mL)	18 g through continuous infusion (6 g infusion over 8 h every 8 h/6 g sulbactam/day)	Levofloxacin replaced ampicillin–sulbactam after 7 d of therapy for treatment of Stenotrophomonas maltophilia

BAL, bronchoalveolar lavage.

TBI, traumatic brain injury.

ARC, augmented renal clearance; A. baumannii, Acinetobacter baumannii; CFU, colony-forming units; CrCl, calculated creatinine clearance; MIC, minimum inhibitory concentration; SCr, serum creatinine; MSSA: Methicillin-susceptible Staphylococcus aureus.

BAL cultures revealed multiple organisms in 2/3 patients; therefore, other active antimicrobial therapy was used before and after ampicillin–sulbactam on the basis of the patient’s clinical scenario. Details regarding the dosing and administration of ampicillin–sulbactam as a continuous infusion and the use of other agents are included in Table 1. The duration of ampicillin–sulbactam and all antimicrobial therapy for pneumonia, ranging from 6–10 days in total, is available in Table 2. Two patients had isolation of A. baumannii in BAL cultures early (within 5 d) in hospital admission, whereas the remaining patient had late VAP, diagnosed 7 days after admission. Ampicillin–sulbactam minimum inhibitory concentration (MIC) of ≤ 2/1 mcg/mL (i.e., sulbactam MIC ≤ 1 mcg/mL) was reported for all A. baumannii isolates. Clinical cure was defined as the resolution of infection-related symptoms at the end of therapy without change or addition of antibiotic therapy, and noninitiation of a new antibiotic for pneumonia within 48 h of discontinuation of therapy. Patients were also surveilled for recurrent pneumonia up to 30 days after therapy was completed or until inpatient discharge. Recurrent pneumonia was defined as an additional antibiotic course for either hospital-acquired pneumonia or VAP defined as at least 5 additional days of antibiotics, which could not be attributed to another cause. Clinical cure was achieved in all patients, and no patient had recurrent pneumonia. Patient 1 received an additional 10 days of antimicrobials >72 h after VAP treatment was completed for left lower extremity cellulitis.

Table 2.

Clinical Outcomes Associated with Patient Cases

	Patient 1	Patient 2	Patient 3
Ampicillin–sulbactam Duration (days)	6	4	7
Total Antibiotic Duration (days)	9	6	10
Time Spent on Ventilator (days)	10	6	30
ICU Length of Stay (LOS) (days)	20	8	42
Hospital LOS (days)	30	11	42
Liver function tests, change from baseline^a		Not available
AST (IU/mL)	346 to 42		65 to 66
ALT (IU/mL)	203 to 70		68 to 103
ALP (IU/mL)	34 to 250		104 to 232

AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.

Other outcomes assessed included presence of sepsis or septic shock, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and ampicillin–sulbactam adverse effects. None of the patients met criteria for sepsis or septic shock at the time of VAP diagnosis or during the treatment of VAP through laboratory and vital signs monitoring and/or a standard provider screening note. Patient 2 required mechanical ventilation for less than one week and was discharged from the ICU and hospital in less than two weeks, whereas the remaining patients were in the hospital for at least 30 days because of other traumatic injuries and disposition challenges. These outcomes for each patient are displayed in Table 2. Finally, patients were reviewed for safety of high-dose ampicillin–sulbactam by monitoring liver function tests: Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Patients 1 and 3 had these laboratory values available before and after therapy. Changes from baseline to end of therapy are described in Table 2. Evaluation of liver function tests did not raise safety concerns for any patient related to the use of high-dose, continuous infusion ampicillin–sulbactam. Approval was obtained from the institutional review board for this case series.

Discussion

This case series adds data to an area of clinical interest with limited evidence. These three critically ill trauma patients with ARC, as defined by ARCTIC scores >6 and ARC predictor scores above 0.2, were able to achieve positive clinical outcomes with higher doses of ampicillin–sulbactam administered through a continuous intravenous infusion.

A systematic review of treatment regimens for extensively resistant A. baumannii points to improved efficacy of higher doses of ampicillin–sulbactam (at least 18 g/day of ampicillin–sulbactam, corresponding to 6 g/day of sulbactam), in combination with other treatments.⁹ High-dose ampicillin–sulbactam can also provide clinical cure with ampicillin–sulbactam monotherapy with a low incidence of adverse events compared to monotherapy with nephrotoxic agents, such as colistin.¹⁰ The high-dose tactic has been associated with a substantial increase in ALT; however, similar to this study, these conclusions are limited to retrospective studies with missing data.¹¹

Despite this endorsement for higher dosing, pharmacokinetic studies have focused on patients with renal impairment, as opposed to patients at risk for underdosing.¹² Perhaps one reason for this limited evidence is a lack of availability of therapeutic drug monitoring for the vital sulbactam component in clinical practice. Carbapenem-susceptible A. baumannii isolates are associated with lower sulbactam MICs compared with carbapenem-resistant isolates, and optimal target attainment may not require a high-dose, continuous infusion. Using MIC₅₀ and MIC₉₀ from a surveillance study of 4 and 32 mcg/mL, respectively, greater than 90% probability of target attainment (using target of 25% free time above MIC) has been demonstrated for A. baumannii isolates with sulbactam MICs ≤ 4 mcg/mL using sulbactam doses as low as 4 g/day administered through intermittent intravenous infusion.¹³ However, sulbactam doses as high as 9 g/day will only attain 90% probability of target attainment (using target of 25% free time above MIC) for A. baumannii isolates with MICs up to 16 mcg/mL.^14–16 Sulbactam–durlobactam is a beta-lactam/beta-lactamase inhibitor combination that was recently approved for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex in adult patients.¹⁷ Future clinical evidence will also likely inform the choice of sulbactam–durlobactam versus ampicillin–sulbactam as optimal agents in the setting of different resistance patterns.¹⁸

Although sulbactam therapeutic drug monitoring is not widely available for clinical use, utilization of a high-dose tactic to optimize the sulbactam component is standard at our institution. Furthermore, we were able to ensure stability of continuous infusion with the administration of 9 g IV ampicillin–sulbactam over 12 h every 12 h (Patient Case 1 and 3) or 6 g IV ampicillin–sulbactam over 8 h every 8 h (Patient Case 2). The use of calculated CrCl to describe ARC has its limitations; however, the ARCTIC score and ARC predictor score for trauma patients show strong predictability and are suggested as a screen for antimicrobial dosing adjustments.^6,7 Evidence for increased clearance of piperacillin and tazobactam has been demonstrated in trauma patients with elevated ARC scores.¹⁹ Tertiary resources label ARC dosing for ampicillin–sulbactam as 6–18 g/day, given as an intermittent infusion on the basis of expert opinion.²⁰ With recent guidance recommending ampicillin–sulbactam combined doses of 18 g/day as a minimum dose for CRAB, it is clear more evidence on efficacy and safety is warranted.¹

Conclusion

Although these results are hypothesis generating, they represent an important clinical dilemma facing clinicians in the trauma ICU. Organisms, especially those identified in early VAP, may not display multi-drug resistance, and the use of more narrow, targeted antimicrobials should be optimized to prevent recurrence and relapse. Although the use of extended and continuous intravenous infusions of antimicrobials are generally recommended in the setting of ARC, more evidence is needed to determine an optimal dosing strategy of ampicillin–sulbactam in this patient population for VAP attributable to carbapenem-susceptible A. baumannii.

Footnotes

Authors’ Contributions

B.R.S.: Conceptualization, methodology, validation, investigation, data curation, and writing—original draft; B.A.S.: Conceptualization, writing—original draft, and writing—reviewing and editing; V.V.: Writing—original draft and writing—reviewing and editing; K.M.A.: Conceptualization, methodology, validation, writing—original draft, writing—reviewing and editing, and supervision.

Authors Disclosure Statement

No author has any disclosure to report for this study.

Funding Information

There is no funding to report for this study.

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