MEAGAN ADAMSICK, PHARMD*

Bacteriophages are viruses that lead to the exponential lysis of bacterial cells by infecting specific bacterial hosts, and although bacteriophage therapy (BT) for the treatment of multidrug resistant (MDR) infections seems novel to most people, the concept of phages far precedes the antibiotic era. Phages were initially described in the 1920s and 1930s for the treatment of dysentery, urinary tract infections, and upper respiratory tract infections. However, the introduction of penicillin in the 1940s shifted focus away from BT to antibiotics for the management of infections. As we progress through the antibiotic era and see the increasing emergence of infections caused by pandrug-resistant pathogens, clinicians are again turning to phages as a potential treatment option.

Aslam et al are members of the Center for Innovative Phage Applications and Therapeutics (IPATH) at the University of California, San Diego, which serves as the United States’ largest group dedicated to the clinical use of BT for antibiotic-refractory infections. In their recent publication, this team of clinicians describes their process for reviewing requests for BT, shares data collected since the creation of the IPATH program, and provides a detailed report of 10 BT cases.

Between June 1, 2018, and April 30, 2020, IPATH received 785 requests for BT from clinicians in the United States and overseas. The number of patients excluded was vast, mostly due to IPATH’s decision that BT was not indicated (n = 525). A hunt for susceptible phages was only recommended in 119 cases (18.5%). Subsequent exclusions were due to no susceptible phages being identified (n = 31) and death of the patient before completion of the phage hunt (n = 10), among others (n = 11). Ultimately, 47 cases had susceptible phages identified and 17 patients were treated with BT.

The process from request to administration is lengthy and serves as a critical barrier to BT in some patients. The range of days between phage request and BT administration was 28 to 386 (median, 170.5 days), underscoring the importance of appropriate patient selection. Patients in septic shock or with a limited life expectancy may not be the best candidates, given the need to allow for a phage hunt and satisfy regulatory requirements. Due to the investigational nature of BT, each case requires a single-use investigational new drug (IND) application to the FDA and approval by the local Institutional Review Board. The IND application requires evidence of clinical need, proof of in vitro bacterial susceptibility to the phage, characterization of genes with known mechanisms of resistance, lack of lysogenic activity, proof of sterility of the product, and minimal exotoxin concentration. All the requirements can be time consuming and generate a significant lag time from phage identification to administration of therapy to the patient.

Seven of the 10 patients discussed in the study achieved clinical success via concurrent BT and systemic antibacterial therapy. Pathogens the investigators identified included 

Pseudomonas aeruginosa, Acinetobacter baumannii, 

The authors include the breakdown of pathogens for all requests made to IPATH, and the subset of patients that received BT is shown in the 

. All patients received intravenous (IV) BT, and 1 patient received nebulized BT in conjunction with IV BT.

The authors also described the development of phage resistance while on therapy in 3 of the 10 cases. Fortunately, they were able to identify alternative phages to overcome the new resistance, but additional experience is needed to determine the best methods at preventing the development of phage resistance. The concept of synergy between antibiotics and phage therapy is also not well studied but is of great interest to aid clinicians in developing optimal treatment regimens.

Identifying the appropriate time and place in therapy for phages is the most challenging aspect. Patients with limited antibiotic options for chronic MDR infections, with a life expectancy longer than the median time to administration of BT, seem to be the best candidates. Clinicians considering BT for patients should make a request to IPATH early in the patient’s chronic infection course to help mitigate some of the delays to administration shared by the authors. Although most patients received IV, hospital-administered BT alongside systemic antibiotic therapy, additional experience will be necessary to confirm the safety of both nebulized and self-administered BT given the limited numbers for each in the study’s 10 cases, although current experience suggests feasibility and safety.

 Aslam S, Lampley E, Wooten D, et al. Lessons learned from the first 10 consecutive cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections at a single center in the United States. 

. 2020;7(9):ofaa389. doi:10.1093/ofid/ofaa389

Meagan Adamsick is a Clinical Pharmacist in Infectious Diseases and Internal Medicine at Massachusetts General Hospital.

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Entering the Phase of Phage: A Closer Look at Bacteriophage Therapy

Early infectious disease outpatient follow-up of outpatient parenteral antimicrobial therapy patients reduces 30-day readmission. 

. 2019;69(5):865-868. doi: 10.1093/cid/ciz073. 

Outpatient parenteral antimicrobial therapy (OPAT) programs offer support for patients who require prolonged intravenous antibiotic therapy outside of an acute care setting. These programs aim to reduce hospital readmissions and allow patients to safely complete antibiotic therapy at home or in a skilled nursing facility. The 2004 Infectious Diseases Society of America OPAT guidelines recommend weekly follow-up with an infectious diseases (ID) provider as best practice.

 Despite this recommendation, most programs report less frequent patient follow-up.

 Readmission rates for patients receiving OPAT are reported to be as high as 20%, mostly due to catheter-related problems, adverse drug reactions, or worsening of the primary infection.

Recently, Saini et al aimed to determine the impact of early outpatient ID follow-up on all-cause 30-day hospital readmission rates for patients enrolled in the PennState Health OPAT program.

 Patients were included if they were enrolled in the OPAT program between January 2012 and December 2014, then pair-matched in a case-control manner relative to 30-day readmission. Patients were excluded from the study if the OPAT course was never started, if OPAT was managed primarily by providers at the patient’s facility, or if the OPAT course included only oral agents. Case (ie, readmission occurred)—control (ie, readmission did not occur) pairs were matched based on age, sex, discharge year, and discharge diagnosis category. Both bivariable and multivariable conditional logistic regression analyses were performed. Patients were followed weekly, with laboratory tests dependent on the antimicrobial regimen. 

During the study period, 1102 patients were enrolled in the OPAT program and 201 (18%) were readmitted within 30 days of discharge. A total of 388 patients (194 case—control pairs) were included in the study. The Table shows patient demographics and indications for OPAT. The average age was 59.6 years; past medical histories of diabetes, renal failure, and immune compromise were present in 32.2%, 10%, and 12.1%, respectively. The most commonly administered antibiotic was vancomycin (36% of the case group and 29% of the control group). Antifungal use (9% vs 2%), fluoroquinolone use (17% vs 10%), and metronidazole use (13% vs 6%) were more common in the case compared with the control group, respectively. More case patients received 3 or more antimicrobials relative to their control counterparts (21% vs 7%). 

Approximately 40% of the readmissions occurred within 7 days of discharge and 97 of 201 (46%) of readmissions were attributed to OPAT-related issues, including worsening infection and acute kidney injury. Of the patients who were readmitted, 13% were seen by an ID provider within 14 days of discharge, compared with 33% of patients in the control group (P = .0001). This finding suggests that early outpatient ID follow-up may reduce the risk of 30-day readmission. On multivariable analysis, immunosuppression was significantly more common in the case group (17% vs 6%; P = .0015; OR, 2.79; 95% CI, 1.17-6.64). Ceftriaxone use, however, was more common in the control group (11% vs 20%; P = .02; OR, 0.49; 95% CI, 0.26-0.92). 

This study has some notable limitations, including that microbiologic data were not assessed. Specific pathogens, such as Staphylococcus aureus, may have further stratified complex patients who may have benefited from early ID follow-up. Additionally, a limited number of patient comorbidities were characterized, preventing identification of any other patient-specific factors that may be associated with readmission. 

Although not the central focus of the study, these findings reinforce the challenges surrounding early OPAT follow-up. Patients in this study were intended to be assessed weekly, which was not achieved in many cases. Delays in care seemingly increased risk of hospital readmission. OPAT programs can use these findings to identify potentially high-risk patients, such as those on 3 or more agents or with immune compromise, to prioritize them for early ID follow-up to help prevent readmission. However, patients on well-tolerated antibiotics, like ceftriaxone, may not require early follow-up. Additional research on risk factors associated with readmission in patients on OPAT is necessary to further stratify which individuals would most benefit from early ID follow-up. Furthermore, programs with an interdisciplinary approach (eg, inclusion of nurses, pharmacists) may be able to optimize safe OPAT based on the reasons for readmission in this study. 

Adamsick and Bidell are clinical pharmacists in infectious diseases and internal medicine at Massachusetts General Hospital.

* indicates active members of the Society of Infectious Diseases Pharmacists.

Tice AD, Rehm SJ, Dalovisio JR, et al; Infectious Diseases Society of America. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. 

Chary A, Tice AD, Martinelli LP, Liedtke LA, Plantenga MS, Strausbaugh LJ; Infectious Diseases Society of America Emerging Infections Network. Experience of infectious diseases consultants with outpatient parenteral antimicrobial therapy: results of an emerging infections network survey. 

Huck D, Ginsberg JP, Gordon SM, Nowacki AS, Rehm SJ, Shrestha NK. Association of laboratory test result availability and rehospitalizations in an outpatient parenteral antimicrobial therapy programme. 

2014;69(1):228-233. doi: 10.1093/jac/dkt303. 

Lee B, Tam I, Weigel B 4th, et al. Comparative outcomes of β-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches. 

. 2015;70(8):2389-2396. doi: 10.1093/jac/dkv130.

Saini E, Ali M, Du P, Crook T, Zurlo J. Early infectious disease outpatient follow-up of outpatient parenteral antimicrobial therapy patients reduces 30-day readmission. 

. 2019;69(5):865-868. doi: 10.1093/cid/ciz073.

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Readmission rates for patients receiving OPAT are reported to be as high as 20%, mostly due to catheter-related problems, adverse drug reactions, or worsening of the primary infection.

MEAGAN ADAMSICK, PHARMD*

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