Significant Publications on Infectious Diseases Pharmacotherapy in 2019

Introduction

Each year, several significant infectious diseases (ID) publications are released in a multitude of journals. With the increasing threat of antimicrobial resistance and multi-drug resistant (MDR) organisms, continuously publishing research and clinical experience has become an important part of ensuring that patients receive the best care possible. The number of publications indexed in PubMed in 2019 with the keywords “infectious diseases” and “HIV” were 33,294 and 16,580, respectively. Additionally, the search terms “multi-drug resistance” and “antimicrobial stewardship” resulted in 7060 and 1224 articles, respectively, representing growing areas of interest in ID literature. ID practitioners encounter a significant challenge in trying to remain well versed with the current literature and trends with such a large quantity of literature published each year.

To help alleviate this task, the Houston Infectious Diseases Network (HIDN) summarizes annually the prior year’s most significant ID publications.^1-12 HIDN consists of ID clinicians from the Texas Medical Center in Houston, TX, and includes physicians, pharmacists, microbiologists, and researchers from over 15 institutions. The network regularly meets throughout the year to discuss collaborative efforts in best practices, education, research, and stewardship. HIDN members also serve as mentors for fellows, residents, and students that are interested in ID. Since 2007, HIDN members have compiled significant ID pharmacotherapy articles in order to select and review the top 10 publications each year, involving over 70 different clinical pharmacists and trainees. In the thirteenth edition of this paper, HIDN members were asked to nominate articles, not of their authorship, that they felt had the most influence on ID pharmacotherapy practice.

Once the nomination period closed, nominations were compiled and an electronic survey with these options was sent via e-mail in January 2020 to the members of the Society of Infectious Diseases Pharmacists (SIDP) to vote on the 10 general ID articles and one HIV article that they felt made the most significant impact on clinical practice. A voting option of “other” was available for voting members to write in any additional article nomination(s) not included, each of which counted as a single vote. Members were also given the opportunity to opt out of voting in either of the 2 article categories. The final rankings were assembled based on total survey responses.

From the SIDP membership, 156 and 54 participants voted on articles in general ID and HIV, respectively. Overall rankings for both the general ID and HIV articles can be found in Tables 1 and 2, respectively.^13-38 A total of 48 general ID articles were nominated; the 20 receiving the most votes are included in Table 1. Six HIV articles were nominated, all of which are included in Table 2. Below are the summaries of the 11 papers that received the most total votes by the end of the voting period, arranged alphabetically by the first author’s last name.

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Table 1.

Top 20 Significant 2019 General Infectious Diseases Publications Ranking Based on Total Votes.

Rank	Reference	Article	Number (%) individuals ranking article in top 10 (n = 156)
1	13	Li HK, Rombach I, Zambellas R, et al. Oral versus intravenous antibiotics for bone and joint infection.	106 (67.9)
2	14	Tamma PD, Conley AT, Cosgrove SE, et al. Association of 30-day mortality with oral step-down vs continued intravenous therapy in patients hospitalized with Enterobacteriaceae bacteremia.	89 (57.1)
3	15	Al-Hasan MN, Rac H. Transition from intravenous to oral antimicrobial therapy in patients with uncomplicated and complicated bloodstream infection.	82 (52.6)
4	16	Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America.	76 (48.7)
5	17	Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America.	73 (46.8)
6	18	Geriak M, Haddad F, Rizvi K, et al. Clinical data on daptomycin plus ceftaroline versus standard of care monotherapy in the treatment of methicillin-resistant Staphylococcus aureus bacteremia.	71 (45.5)
7	19	Pogue JM, Kaye KS, Veve MP, et al. Ceftolozane/tazobactam vs polymyxin or aminoglycoside-based regimens for the treatment of drug-resistant Pseudomonas aeruginosa.	67 (42.9)
8	20	Punjabi C, Tien V, Meng L, et al. Oral fluoroquinolone or trimethoprim-sulfamethoxazole vs β-lactams as step-down therapy for Enterobacteriaceae bacteremia: systematic review and meta-analysis.	67 (42.9)
9	21	Crass RL, Rodvold KA, Mueller BA, et al. Renal dosing of antibiotics: Are we jumping the gun?	65 (41.7)
10	22	Tsuji BT, Pogue JM, Zavascki AP, et al. International consensus guidelines for the optimal use of the polymyxins: endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP).	55 (35.3)
11	23	Kollef MH, Nováček M, Kivistik Ü, et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial.	54 (34.6)
12	24	Mergenhagen KA, Starr KE, Wattengel BA, et al. Determining the utility of methicillin-resistant Staphylococcus aureus nares screening in antimicrobial stewardship.	52 (33.3)
13	25	Branch-Elliman W, O’Brien W, Strymish J, et al. Association of duration and type of surgical prophylaxis with antimicrobial-associated adverse events.	50 (32.1)
14	26	Cranendonk DR, Opmeer BC, van Agtmael MA, et al. Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial.	50 (32.1)
15	27	Fabre V, Amoah J, Cosgrove SE, et al. Antibiotic therapy for Pseudomonas aeruginosa bloodstream infections: How long is long enough?	49 (31.4)
16	28	Lodise TP, Rosenkranz SL, Finnemeyer M, et al. The emperor’s new clothes: prospective observational evaluation of the association between initial vancomycin exposure and failure rates among adult hospitalized patients with MRSA bloodstream infections (PROVIDE).	46 (29.5)
17	29	Meng L, Wong T, Huang S, et al. Conversion from vancomycin trough concentration-guided dosing to area under the curve-guided dosing using 2 sample measurements in adults: implementation at an academic medical center.	45 (28.8)
18	30	Teshome BF, Vouri SM, Hampton N, et al. Duration of exposure to antipseudomonal β-lactam antibiotics in the critically ill and development of new resistance.	39 (25.0)
19	31	Benkabouche M, Racloz G, Spechbach H, et al. Four versus 6 weeks of antibiotic therapy for osteoarticular infections after implant removal: a randomized trial.	34 (21.8)
20	32	Grillo S, Cuervo G, Carratalá J, et al. Impact of β-lactam and daptomycin combination therapy on clinical outcomes in methicillin-susceptible Staphylococcus aureus bacteremia: A propensity score-matched analysis.	34 (21.8)

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Table 2.

Significant 2019 HIV/AIDS Publications Ranking Based on Total Votes.

Rank	Reference	Article	Number (%) of individuals ranking article as top 1 (n = 54)
1	33	Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana.	26 (48.1)
2	34	Braun DL, Turk T, Tschumi F, et al. Noninferiority of simplified dolutegravir monotherapy compared to continued combination antiretroviral therapy that was initiated during primary Human Immunodeficiency Virus infection: a randomized, controlled, multistate, open-label, noninferiority trial.	8 (14.8)
3	35	Hocqueloux L, Raffi F, Prazuck T, et al. Dolutegravir monotherapy versus dolutegravir/abacavir/lamivudine for virologically suppressed people living with chronic Human Immunodeficiency Virus infection: the randomized noninferiority monotherapy of Tivicay trial.	8 (14.8)
4	36	Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus 2 different prodrugs of tenofovir to treat HIV.	6 (11.1)
5	37	Rhein J, Huppler Hullsiek K, Tugume L, et al. Adjunctive sertraline for HIV-associated cryptococcal meningitis: A randomised, placebo-controlled, double-blind phase 3 trial.	4 (7.4)
6	38	Gupta A, Montepiedra G, Aaron L, et al. Isoniazid preventive therapy in HIV-infected pregnant and postpartum women.	2 (3.7)

Al-Hasan et al. Transition From Intravenous to Oral Antimicrobial Therapy in Patients With Uncomplicated and Complicated Bloodstream Infection. ¹⁵

Although transitioning from intravenous (IV) to oral antibiotics in stable patients with bloodstream infections (BSI) is becoming a more popular practice, several patient and provider barriers exist prohibiting its widespread acceptance. In order to better provide clinicians with confidence in oral antimicrobial regimens and support efforts to improve patient adherence, Al-Hasan et al. authored a narrative review summarizing select evidence for adult patients with BSI who were transitioned from IV to oral antibiotics or those that compared effectiveness of different oral agents for this purpose. The authors included English-language articles from MEDLINE since inception and abstracts from scientific meetings since 2017.

In uncomplicated gram-positive BSI, most studies investigating oral switch therapy are for Staphylococcus aureus and data for other gram-positive BSIs is lacking. Early evidence discouraged oral antibiotic use by demonstrating inferiority of trimethoprim-sulfamethoxazole to vancomycin in serious S. aureus infections. ³⁹ However, new interest has emerged with the introduction of linezolid and several studies have shown success transitioning from IV to oral therapy with linezolid in uncomplicated S. aureus BSI.^40,41 There are currently no data supporting early transition to oral β-lactams in methicillin-susceptible S. aureus (MSSA) BSI. The SABATO trial may provide additional data in this area when completed. ⁴²

In complicated gram-positive BSI, most data comes from the use of oral antibiotics in right-sided S. aureus endocarditis, where the combination of fluoroquinolones and rifampin has been studied with positive outcomes.^43-45 The POET trial also supports oral switch therapy in left-sided endocarditis for a number of gram-positive organisms. ⁴⁶ Although many studies have investigated oral antibiotics for osteomyelitis, many patients that were included did not have BSI. Oral linezolid has been used for the treatment of osteomyelitis due to gram-positive bacteremia and is considered an alternative for vertebral osteomyelitis due to S. aureus and Enterococcus species.^47,48

In uncomplicated gram-negative BSI, the option to transition to oral therapy increased with the development of fluoroquinolones, which remains the most common choice due to high bioavailability and supporting literature.^49-53 Other agents included in these studies, such as trimethoprim-sulfamethoxazole and β-lactams, have been used in too few patients to draw meaningful conclusions on their effectiveness.^54-57 In gram-negative BSI complicated by bone and joint infections, oral fluoroquinolones are also a first-line choice due to their high bone penetration. ⁵⁸

In BSI due to Candida species, studies have demonstrated that it is safe and effective to transition to oral azole therapy once patients meet criteria established from randomized controlled trials, such as bloodstream clearance, clinical improvement, and documented susceptibility to fluconazole or another azole.^59-62

It is important to note that this was not a systematic review, so definitions of uncomplicated versus complicated BSI were not consistent across all studies, and author bias may have been present in the articles selected for inclusion. In some patients with BSI due to gram-negative or Candida species, early transition to oral antimicrobials is likely appropriate. Considerations in selecting patients for oral treatment include patient stability, source control, oral agent bioavailability, dosing regimens, adverse effect profiles, and supporting clinical literature for that patient population and infection type. Ultimately more data is needed to clearly define appropriate patient population(s), timing of IV to PO switch, therapy duration and optimal agents for oral therapy.

Crass RL et al. Renal Dosing of Antibiotics: Are We Jumping the Gun? ²¹

Many antibiotics undergo renal elimination and therefore are dose-adjusted in patients with renal dysfunction to decrease toxicity while maintaining efficacy. However, labeled dose adjustments are often determined in small, phase 1, pharmacokinetic trials that enroll uninfected patients with chronic kidney disease (CKD). ⁶³ Consequently, these dosing recommendations may not be applicable to acutely infected, critically ill populations with acute kidney injury (AKI). Additionally, several studies have demonstrated that administration of adequate antibiotic therapy within 48 hours improves survival in severe infections.^64-69 Adequate antibiotic therapy includes not only activity against infecting organisms but also adequate dosing and administration to achieve pharmacodynamic targets. Crass et al. hypothesized that many patients admitted with infections and renal impairment suffer from AKI and experience renal recovery within 48 hours of hospital admission, increasing the risk for suboptimal antibiotic dosing and poorer outcomes.

To test their hypothesis, Crass et al. conducted a retrospective review of patients admitted with selected infectious diagnoses between January 2006 and April 2018. Infectious diagnoses included patients with ICD-9 and ICD-10 codes for admitting, primary, or present-on-admission complicated urinary tract (UTI), complicated intraabdominal (IAI), bacterial pneumonia, or skin and soft tissue infections (ABSSSI). Patients with more than one infection, CKD stage ≥4, incomplete records, or fewer than 3 serum creatinine (SCr) levels were excluded. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines were used to define AKI as well as impute baseline SCr. ⁷⁰ Renal function was measured with the Cockcroft-Gault, MDRD, and CKD Epidemiology Collaboration equations. Moderate renal impairment was defined as a creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR) of 30-50 mL/min[/1.73 m²]. Transient AKI was defined as a resolution of KDIGO criteria by 48 hours.

A total of 18,650 unique encounters were included, with the majority of patients being older (mean 61 years), white (85%) males (51%) with normal renal function on admission (mean CrCl/eGFR 100 mL/min[/1.73 m²]). The most common admissions involved UTI (41%), followed by ABSSSI (32%), IAI (16%), and pneumonia (11%). Approximately 18% of patients experienced an AKI on admission, with a 2 times higher rate observed in patients with an admission CrCl/eGFR <60 mL/min[/1.73 m²]. In patients with AKI, resolution of renal impairment was observed in 57% of patients by 48 hours after admission. In patients with moderate renal impairment on admission, up to 46% demonstrated renal recovery (>50 mL/min[/1.73 m²]) by 48 hours.

A limitation of this study is it did not evaluate antibiotic dosing to strengthen the link between dose, transient AKI, and outcomes. However, these data suggest antibiotic dose reduction in transient AKI may worsen patient outcomes and may explain the decreased clinical response observed with antibiotics, such as what has been observed with ceftolozane/tazobactam and ceftazidime/avibactam in patients with CrCl 30-50 mL/min.^71-74 Deferred renal dose adjustment of wide therapeutic index antibiotics, such as for 48 hours, may be a useful strategy to improve outcomes in patients with infections and acute renal impairment.

Geriak M et al. Clinical Data on Daptomycin Plus Ceftaroline Versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia. ¹⁸

Initial treatment failure of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia occurs in up to 50% of cases and is associated with poor outcomes, including increased mortality.^75-77 In vitro studies have demonstrated the addition of an antistaphylococcal penicillin to daptomycin (DAP) provides a synergistic effect against MRSA, and a combination of daptomycin and ceftaroline (DAP+CPT) has shown high clinical response rates as salvage therapy for persistent MRSA bacteremia.^78-82 However, studies evaluating the use of DAP+CPT for the initial treatment of MRSA bacteremia are lacking.

Geriak et al. conducted a prospective, unblinded trial comparing DAP+CPT with standard-of-care initial therapy for MRSA bacteremia. Patients aged ≥18 years from 3 hospitals in the United States were prospectively randomized to receive DAP+CPT or DAP or vancomycin (VAN/DAP) monotherapy within 72 hours of initial positive MRSA blood culture collection. Patients were allowed to have received standard antibiotics for <72 hours before randomization, including DAP, CPT, and VAN. MRSA was identified using the Nanosphere Verigene® Gram-Positive Blood Culture Nucleic Acid Test (Luminex, Madison, WI) and was confirmed by standard microbiology testing with MicroScan (Beckman Coulter, Brea, CA). The intended primary study outcome was bacteremia duration.

The study was stopped early due to an unexpected mortality difference between arms, and the investigators were underpowered to analyze bacteremia duration as initially designed. A total of 40 patients were enrolled over 18 months, with 17 patients receiving DAP+CPT and 23 patients receiving VAN (n = 21) or DAP (n = 2). Sources of infection and foci of infection were similar between both groups, with secondary tissue (skin, bone/joint, pulmonary, or urine) being the most common source of bacteremia (53% DAP+CPT vs. 52% VAN/DAP) followed by endovascular (47% DAP+CPT vs. 35% VAN/DAP). Median DAP doses were similar between the cohorts (8.6 mg/kg for DAP+CPT vs. 8.0 mg/kg in DAP monotherapy) and the median (IQR) initial vancomycin trough was 16.2 mg/L (10.7-19.8 mg/L) for those receiving VAN monotherapy. In both groups the median time from bacteremia onset to randomization was 2 days. The median duration of randomized therapy was 8 days for DAP+CPT (median total duration = 38 days) and 12 days for VAN/DAP monotherapy (median total duration = 26 days). The median bacteremia duration was 3 days in each group (p = 0.56). In-hospital mortality occurred in 0% of the DAP+CPT arm and 26% (n = 6) of the monotherapy arm (p = 0.02). No patients receiving DAP+CPT died in the 90-day follow-up period, versus 26% (p = 0.02) and 30% (p = 0.03) of the VAN/DAP arm in 30- and 90-days, respectively. All deaths occurred in patients with endovascular sources of bacteremia.

Notable limitations of the study include its open-label design, low number of patients receiving daptomycin monotherapy, limited sample size, and lack of independent data safety and monitoring board to evaluate the trial stoppage. Cost concerns regarding DAP+CPT may limit applicability on a larger scale, though larger, blinded, prospective trials appear to be warranted to analyze outcomes associated with combination vs. monotherapy in MRSA bacteremia.

Li HK et al. Oral Versus Intravenous Antibiotics for Bone and Joint Infection. ¹³

The standard treatment of bone and joint infections requires surgical intervention followed by a prolonged course of IV antibiotics.^83,84 However, a 2013 meta-analysis revealed that IV treatment of complex bone and joint infections lacked additional benefit compared to oral therapy, calling for a larger, randomized, controlled trial to validate these findings. ⁸⁵

Li et al. conducted an open-label, parallel-group, randomized, controlled, non-inferiority trial to determine the utility of oral antibiotics compared to IV therapy for the treatment of complex bone and/or joint infection warranting antimicrobial therapy for ≥6 weeks. These included osteomyelitis of the extra-axial skeleton, vertebral osteomyelitis, native joint infection needing excision arthroplasty, prosthetic joint infection, or infection of an orthopedic fixation device. Pertinent exclusion criteria included patients with concomitant infections needing extended IV antibiotic therapy or those with infections without an oral treatment option.

The primary endpoint was definite treatment failure within 1 year after randomization, meeting at least 1 clinical (draining sinus tract arising from or frank pus adjacent to bone or prosthesis), microbiologic (phenotypically identical pathogen isolated from >1 deep tissue sample or pathogen isolated from closed aspirate or biopsy), or histological (presence of inflammatory infiltrates or microorganisms) criteria. The non-inferiority margin was set at 7.5%. Notable secondary outcomes included possible or probable treatment failure, early treatment discontinuation, Clostridioides difficile infection, and serious adverse events.

A total of 1054 patients were recruited across 26 sites in the U.K., with 527 patients assigned to the IV group and the oral study groups. Approximately 60% of patients had metalware-related infections and 7.6% of patients were treated without surgical intervention. The most common causative organism identified was Staphylococcus aureus, accounting for 35-40% of infections in each study arm. About 10% of the oral group received up to 5 days of concomitant IV therapy for an unrelated infection. Antimicrobial therapy was continued >6 weeks in 76.7% of patients, with median durations (IQR) of 78 days (42-99) and 71 days (43-94) in the IV and oral groups, respectively (p = 0.63). Definite treatment failure occurred in 14.6% (74/506) of the IV group and 13.2% (67/509) of the oral group. This accounted for a −1.4% risk difference between the oral and IV groups (95% CI, −5.6 to 2.9), meeting the non-inferiority margin after missing endpoint data was computed (3.7% of patients). The IV group had a higher rate of early treatment discontinuation (18.9% vs 12.8%, p = 0.006) and a higher median hospital length of stay (14 vs 11 days, p < 0.001) compared to the oral group. Even though the planned use of rifampin was higher in the oral (51.5%) than IV group (15.5%), actual use after randomization was more similar (31.4% and 22.9%, respectively) and was unlikely to have affected overall outcome. The authors additionally conducted a “worst case” sensitivity analysis in which all missing endpoints for the IV group were considered a failure, and results were consistent with the primary analysis findings of non-inferiority. The rates of secondary outcomes were similar between groups.

Study limitations include an open-label design without blinding, lack of comparison between specific antibiotics, and the inability to have a true matched placebo group. However, the study was purposefully inclusive with regard to infecting organism, which strengthens its external validity. In conclusion, oral therapy was found to be non-inferior to intravenous therapy assessed at 1 year, when oral antibiotics were used for the first 6 weeks in patients with complicated bone or joint infections.

Metlay et al. Diagnosis and Treatment of Adults With Community-Acquired Pneumonia: An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. ¹⁷

It has been over 10 years since the last American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) community-acquired pneumonia (CAP) guideline was released in 2007. ⁸⁶ The 2019 updated guideline reflects changes in available clinical evidence by focusing on 16 questions related to CAP diagnosis and treatment.

Healthcare-associated pneumonia (HCAP), a term introduced in 2005 to identify patients at risk for resistant bacteria, has been removed.^87,88 The 2019 guideline instead recommends additional empiric methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa coverage only in patients with a prior history of MRSA or P. aeruginosa respiratory infection, locally validated risk factors for antibiotic-resistant bacteria, or in severe CAP if they have received parenteral antibiotics within the last 90 days, regardless of residence prior to admission. The Pneumonia Severity Index (PSI) is preferentially recommended over the CURB-65 tool to guide inpatient versus outpatient treatment designation, and severe CAP is defined using the same criteria as recommended in the 2007 guideline.

Shifting microbiologic diagnostic trends are reflected in the 2019 guideline as well. Sputum culture and Gram stain, which are low yield in detecting CAP causative organisms, is only recommended in patients with severe CAP or who have MRSA or P. aeruginosa risk factors, defined as prior MRSA- or P. aeruginosa-positive respiratory cultures or hospitalization and receipt of parenteral antibiotics in the prior 90 days. It is also suggested these patients have pretreatment blood cultures drawn. Testing for pneumococcal and Legionella urinary antigens is only recommended for patients with severe CAP, or in cases indicated by epidemiologic risk factors. Similarly, testing respiratory samples for influenza is suggested during periods of high influenza activity.

Influenza-positive patients are recommended to initially receive antivirals and antibiotics, regardless of treatment setting. Empiric antibiotics may be discontinued after 48-72 hours in those with early clinical stability, and without evidence of a bacterial pathogen, such as a low procalcitonin value. Inpatients diagnosed with influenza should be started on oseltamivir, regardless of symptom duration.

Treatment recommendations for outpatients has changed as amoxicillin is now recommended as a first-line agent, instead of doxycycline which now holds a conditional recommendation, for outpatients without comorbidities (chronic heart, lung, liver, or renal disease, diabetes mellitus, alcoholism, malignancy, or asplenia) or risk factors for MRSA or P. aeruginosa. Macrolide monotherapy is only recommended in areas with macrolide-resistant S. pneumoniae rates <25%. Outpatients with comorbidities should receive a β-lactam in combination with a macrolide or doxycycline, or respiratory fluoroquinolone monotherapy.

Inpatients without risk factors for MRSA or P. aeruginosa are recommended to receive empiric therapy with a β-lactam/macrolide combination or a respiratory fluoroquinolone (with added β-lactam if severe). Ceftaroline was added as a recommended β-lactam option on the basis of their Phase 3 trial data. ⁸⁹ In patients with P. aeruginosa risk factors, the recommendation for empiric dual coverage was removed in favor of using one antipseudomonal β-lactam. Additionally, routine use of anaerobic coverage in aspiration pneumonia is not recommended unless an empyema or lung abscess is present.

Antibiotic duration should be guided on an individual basis by clinical stability, which includes resolution of vital sign abnormalities, normal mental status, and good appetite, for a minimum of 5-days for both inpatients and outpatients. In concordance previously published pneumonia guidelines, it is recommended that patients with CAP due to MRSA or P. aeruginosa receive a minimum of 7 days of therapy. ⁸⁸ Serum procalcitonin levels are not recommended to determine antibiotic initiation.

Although this guideline provides a much-needed update, further evidence is needed to adequately answer many of the clinical questions raised. Future research focuses should include diagnostics that can differentiate between viral and bacterial causes, and the role of newly-indicated antimicrobials, such as lefamulin and omadacycline.

Nicolle et al. Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America. ¹⁶

Asymptomatic bacteriuria (ASB), defined as the presence of bacteria in the urine, with or without pyuria, in the absence of signs or symptoms of a urinary tract infection (UTI), is both a challenge and an opportunity for antimicrobial stewardship programs and ID clinicians. The ASB guidelines, first published in 2005 and now updated in 2019, provides recommendations regarding the screening for and treatment of ASB. ⁹⁰ The 2019 update provides expanded recommendations for special populations, including children and neutropenic patients.

In concordance with the 2005 guidelines, the 2019 guidelines recommend that only pregnant women and individuals preparing to undergo urologic surgery be screened and treated for ASB. Similarly, screening and treatment of ASB is not recommended in most populations discussed in the guidelines, including pediatric patients, non-pregnant women, diabetic adults, patients with spinal cord injury, patients with indwelling catheters (regardless of duration), and patients undergoing non-urologic surgery. The guidelines also recommend against screening and treatment of ASB in older adults, regardless of place of residence, cognitive impairment, or recent falls; in justifying this recommendation, the guidelines cite the well-established risks of antibiotic use in this population and the absence of evidence showing treatment benefit. Importantly, these guidelines stress that screening for and treatment of ASB in kidney transplant patients more than 1 month after transplant is discouraged based on the lack of evidence showing benefit. They also recommend against screening for and treatment of ASB in other solid organ transplant patients, regardless of transplant date. For neutropenic patients and renal transplant patients within one month of transplant, however, no recommendation is made due to insufficient evidence.

The authors note that some subpopulations, such as spinal cord injury patients and diabetic women who have recurrent UTIs, may benefit from treatment of ASB. These subpopulations are highlighted as areas for future research. Other areas for future study include antibiotic prophylaxis in patients with ASB at the time of catheter removal, discovery of specific biomarkers to distinguish between ASB and UTI, optimal perioperative antimicrobial regimens in urologic procedures, and new clinical trials in pregnant women given improvements in prenatal management.

In summary, the 2019 ASB guidelines recommend against screening for and treatment of ASB in most patient populations due to the well-known risks of antibiotic use and a dearth of evidence demonstrating benefit. Given providers’ natural inclination to treat positive urine cultures, these guidelines provide a useful tool for antimicrobial stewardship program initiatives to optimize the utilization of urine cultures and management of ASB.

Pogue et al. Ceftolozane/Tazobactam vs Polymyxin or Aminoglycoside-Based Regimens for the Treatment of Drug-Resistant Pseudomonas aeruginosa. ¹⁹

Treatment options for multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa are limited and historically involved agents including polymyxins and aminoglycosides, which are associated with suboptimal pharmacokinetics, a narrow therapeutic index, high rates of nephrotoxicity, and inferior efficacy compared to first-line options.^91-95 Ceftolozane/tazobactam is a novel cephalosporin/β-lactamase inhibitor combination that often retains activity against MDR P. aeruginosa, but its comparative safety and efficacy versus polymyxins or aminoglycosides remains unknown based on current literature.

Pogue et al. conducted a retrospective, multicenter, observational cohort study across 6 centers from January 2010 through May 2018 to address this question. The study included patients with infections due to MDR or XDR P. aeruginosa who received treatment with ceftolozane/tazobactam or an IV polymyxin or aminoglycoside backbone regimen for at least 48 hours. Patients were excluded if the infecting isolate was resistant to the study drug, if they had a CrCl ≤20 mL/min or required renal replacement therapy at the onset of study drug treatment, or if they received overlapping therapy with ceftolozane/tazobactam and an IV polymyxin or aminoglycoside for >48 hours. Patients with polymicrobial infections or concomitant infections were included if those infections were determined to have been appropriately managed. Clinical cure was defined as resolution of the signs/symptoms of infection with the initial study regimen without need for therapy modification based on failure or toxicity. AKI was defined per the “RIF” components of the RIFLE criteria. ⁹⁶

A total of 200 patients were included: 100 who received ceftolozane/tazobactam and 100 who received a polymyxin or aminoglycoside-based regimen. The population was critically ill overall with 69% admitted to the ICU, 63% mechanically ventilated, and 42% with either severe sepsis or septic shock. The most common infection was ventilator-associated pneumonia (52%) followed by urinary tract infection (14%), and 7% had concurrent bacteremia. Combination therapy was used more commonly in polymyxin/aminoglycoside patients than in those who received ceftolozane/tazobactam (72% vs 15%; p < 0.001).

In patients treated with ceftolozane/tazobactam, clinical cure was demonstrated in 81% of patients vs 61% of patients treated with polymyxin/aminoglycoside therapy (OR, 2.72; 95% CI, 1.43-5.17). After adjusting for age, ID consult, baseline creatinine clearance, duration of therapy, and time to active therapy, treatment with ceftolozane/tazobactam was independently associated with clinical cure (aOR, 2.63; 95% CI, 1.31-5.30). Patients treated with ceftolozane/tazobactam also experienced less AKI (6% vs 34%; aOR, 0.08; 95% CI, 0.03-0.22). In-hospital mortality, length of stay, C. difficile infection rates, and 30-day recurrence or readmission rates were not significantly different between the 2 groups.

Study limitations included the retrospective study design and that a pharmacodynamic evaluation was not done for aminoglycoside/polymyxin treated patients as dosing information and minimum inhibitory concentration (MIC) values were not collected. The study was also underpowered to detect a mortality difference. Despite these limitations, this study supports the use of ceftolozane/tazobactam over polymyxins or aminoglycosides for the treatment of MDR and XDR P. aeruginosa infections where traditional β-lactams are not an option.

Punjabi et al. Oral Fluoroquinolone or Trimethoprim-Sulfamethoxazole vs β-Lactams as Step-Down Therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-Analysis. ²⁰

Transitioning from IV to PO antibiotics in clinically stable patients with gram-negative bacteremia has become an increasingly common practice. Generally, fluoroquinolones (FQs) or trimethoprim-sulfamethoxazole (TMP-SMX) are chosen over β-lactams due to higher bioavailability, but clinical evidence examining this issue is mixed and does not consistently show clear superiority of higher bioavailability agents. Clarity on this issue is clinically important as these agents have different tolerability profiles and susceptibility patterns.

Punjabi et al. conducted a systematic review and meta-analysis aiming to compare outcomes with FQs or TMP-SMX to β-lactams as oral step-down therapies for Enterobacteriaceae bacteremia. Eight retrospective cohort studies were included, comprising 2,289 hospitalized adults in the United States. Six studies included uncomplicated infections from a variety of sources, and 2 exclusively studied urosepsis. One study focused solely on E. coli bacteremia while the others included all Enterobacteriaceae. Most studies reported infection recurrence at the primary site of infection, defined as symptomatic infection with the same organism species with or without bacteremia, but 2 studies looked only at recurrent bacteremia. All studies reported all-cause mortality, with time frames varying from 21 to 90 days. Of the 2,289 patients included in the study, 65% received a FQ, 7.7% TMP-SMX, and 27.2% β-lactams. Average duration of IV therapy ranged from 3 to 5 days and total therapy ranged from 13.6 to 16 days. Treatment duration was not different between the FQ/TMP-SMX and β-lactam groups.

This meta-analysis concluded there was no statistically significant difference in mortality between groups, but an increase in overall recurrence was observed in the β-lactam group (5.5%) versus the FQ/TMP-SMX group (2%) (OR 2.06, 95% CI, 1.18-3.61). Findings were consistent for the FQs versus β-lactam cohort (OR 2.05, 95% CI 1.17–3.61). No difference was seen with TMP-SMX versus β-lactam cohort (OR 0.96, 95% CI 0.30–3.06), however this cohort was limited by a small sample size. Studies that investigated incidence of C. difficile infection (2/8 studies), readmission rates (5/8 studies), and MDR organism emergence (2/8 studies) found no differences between groups. Studies analyzing dosing appropriateness found β-lactams were more frequently under-dosed than FQs or TMP-SMX.

Limitations of this meta-analysis include retrospective study inclusion, population and reported outcome heterogeneity between studies, multiple β-lactam agents included, potential β-lactam under dosing, and small TMP-SMX group size. The results of this meta-analysis suggest patients treated with step-down oral β-lactam therapy have higher recurrence rates compared to oral FQs. However, the reason for this likely extends beyond bioavailability. The authors theorize that differences in recurrence are likely due to a lack of pharmacokinetic/pharmacodynamic optimization of oral β-lactam regimens, while acknowledging that the increased frequency of optimized regimens may worsen compliance and negate the possible benefits. Consequently, the clinical outcomes of optimally-dosed β-lactams compared to FQs remains unclear.

Tamma et al. Association of 30-Day Mortality With Oral Step-Down vs Continued Intravenous Therapy in Patients Hospitalized With Enterobacteriaceae Bacteremia. ¹⁴

Although increasing amounts of evidence support the safety and efficacy of transitioning from intravenous (IV) to oral antibiotic therapy for Enterobacteriaceae bacteremia, as presented above, clinical questions remain about the applicability of such studies on a wide scale. Two such studies published in 2016 and 2017 included a majority of patients with urinary tract-sourced bacteremias, warranting larger studies with more diverse populations.^52,54

Tamma et al. conducted a multicenter, retrospective cohort study assessing clinical outcomes between patients transitioned to oral step-down therapy versus those continued on IV antibiotics for Enterobacteriaceae bacteremia treatment. The primary outcome of the study was 30-day, all-cause mortality. The study included hospitalized patients who were ≥18 years of age, with monomicrobial Enterobacteriaceae (Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Proteus mirabilis, or Serratia marcescens) bacteremia, adequate source control, and a Pitt bacteremia score of ≤1 by day 5 after initial positive culture. Patients in the oral step-down group must have transitioned to oral therapy by day 5.

A total of 876 patients for the oral step-down group and 1285 patients for the IV group were included, although propensity-score matching resulted in 739 patients analyzed in each arm. Common sources of infection included urinary (40.2%), gastrointestinal (20.1%), catheter-associated (18.4%), biliary (14.2%), pulmonary (3.9%), and skin and soft tissue (2.8%). There was no difference in 30-day mortality between groups, with 97 deaths (13.1%) in the oral step-down group versus 99 (13.4%) in the IV group (HR, 1.03; 95% CI, 0.82-1.30). Six patients (0.8%) in the oral step-down group had recurrent 30-day bacteremia versus 4 (0.5%) in the IV group (HR, 0.82; 95% CI, 0.33-2.01). The median length of hospitalization was 5 (IQR, 3-8) vs 7 (IQR, 4-14) days in the oral step-down and IV groups, respectively (p < 0.001). The median duration of IV antibiotics in the oral step-down group was 3 days (IQR, 2-4 days) vs 14 days (IQR, 11-15 days) in the IV group. In the oral step-down group, 83.5% received high-bioavailability agents (fluoroquinolones or trimethoprim-sulfamethoxazole) and 16.5% received low-bioavailability agents (β-lactams). No difference was seen in 30-day mortality between the high-bioavailability and low-bioavailability groups (11% vs 12.3%; HR, 1.05; 95% CI, 0.67-1.66), although the study was not powered to detect a difference.

Study limitations included the retrospective study design and potential for residual, uncontrolled confounding despite propensity score matching due to the numerous and potentially clinically significant differences in baseline characteristics (notably increased neutropenia, more patients in the ICU on day 1 of therapy, higher Pitt bacteremia score, more combination therapy >48 hours, and fewer urinary sourced infections in the IV therapy cohort) before matching. There is also risk of attrition bias as it is unknown how many in-hospital deaths occurred, or how many patients were lost to follow-up. This study demonstrates oral step-down therapy may be effective and associated with reduced length of stay in patients with Enterobacteriaceae bacteremia with sufficient source control and appropriate initial clinical response. This study adds to the growing body of literature supporting oral step-down therapy for Enterobacteriaceae bacteremia treatment.

Tsuji et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). ²²

Use of the polymyxin antibiotics, colistin and polymyxin B, has become more commonplace with the increasing incidence of infections caused by MDR gram-negative organisms. However, polymyxins have significant toxicities, challenging dosing nomenclature, outdated package labeling, and unreliable susceptibility testing that cause significant confusion for providers. These inaugural polymyxin guidelines aim to provide clarity and guidance to optimize the use of these agents in the treatment of MDR gram-negative bacteria, by thoroughly addressing all aspects of use from an international perspective.

Breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) for colistin, but not polymyxin B, were recommended. For Acinetobacter spp. and P. aeruginosa isolates with a MIC ≤ 2 are considered susceptible. EUCAST, but not CLSI, also recommended that Enterobacteriaceae isolates with a MIC ≤ 2 be considered susceptible. Citing insufficient data, CLSI instead offered epidemiological cutoff values based on MIC distribution data for several Enterobacteriaceae (Klebsiella aerogenes, Enterobacter cloacae, Escherichia coli, K. pneumoniae, and Raoultella ornithinolytica).

Regarding agent selection, institutional access to both agents is recommended by the guidelines, with preferred use of polymyxin B over colistin for most indications except urinary tract infections and intrathecal or intraventricular administration. This weak recommendation is made from low-quality evidence suggesting decreased rates of AKIwith polymyxin B. When either of these agents are used, the guidelines recommend combination therapy for most MDR organisms, except carbapenem-resistant Acinetobacter spp. with no other available active agent. In this instance, the guidelines suggest monotherapy with polymyxins until more data is available. Additionally, intravenous and inhaled polymyxin combination therapy is recommended for treatment of pneumonia. It should be noted that the authors are not recommending polymyxin therapy preferentially for these infections, but intended to address situations when providers have already chosen to utilize a polymyxin-based regimen.

The recommended pharmacokinetic/pharmacodynamics (PK/PD) targets are an area under the plasma concentration curve across 24 hours at steady state (AUC_{ss,24 hr}) of 50 mg·hour/L for colistin and 50-100 mg·hour/L for polymyxin B. This is to be treated as the maximum tolerated dose, as AKI may occur if one exceeds this level. Unfortunately, a readily available method for therapeutic drug monitoring of colistin and polymyxin B is not currently available. To help achieve these PK/PD targets, the guidelines recommend a departure from the weight-based dosing for colistin commonly used in clinical practice. In place of weight based dosing, a loading dose of 300 mg (∼9 million IU) colistin methanesulfonate (CMS) is recommended, with a maintenance dose 12-24 hours later depending upon depending on renal function (300-360 mg/day in 2 divided doses if normal renal function). For polymyxin B, a loading dose of 2-2.5 mg/kg based on total body weight (TBW) is recommended, followed by 1.25-1.5 mg/kg TBW every 12 hours. Though renal adjustments exist for CMS, it is recommended to not adjust polymyxin B for renal dysfunction and renal replacement therapy due to limited renal elimination and lack of clinical pharmacokinetic studies.

The guidelines address additional topics such as susceptibility testing methods, renal dose adjustment, intrathecal and intraventricular dosing, therapeutic drug monitoring and AKI prevention strategies, all of which could not be included in this summary. Several recommendations are limited by low quality evidence. However, the authors provide detailed explanations of the rationale behind each recommendation. Multiple areas for future study are also discussed, including the need for additional studies regarding combination therapy, polymyxin B breakpoints, and validation of recommended dosing regimens.

Zash et al. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. ³³

Current HIV infection guidelines recommend integrase strand transfer inhibitor-based antiretroviral therapy (ART), such as dolutegravir, as a first-line treatment option for HIV management. ⁹⁷ However, the U.S. Food and Drug Administration (FDA) published an alert in 2018 reporting cases of neural tube defects in babies born to women receiving dolutegravir either at the time of conception or early in the first trimester. ⁹⁸ This report was based on preliminary results from an observational study in Botswana that included 4 defects among 426 exposures. ⁹⁹ Subsequent concern for neural-tube defects due to dolutegravir exposure has affected the selection of ART in child-bearing, HIV-positive women. However, data was lacking to confirm the association between dolutegravir and the risk of neural tube defects.

Zash et al. conducted the Tsepamo study, a national birth-outcomes surveillance study in Botswana, which was originally designed to evaluate birth outcomes associated with exposure to efavirenz from conception. Importantly, efavirenz-based ART was the recommended therapy for HIV management in Botswana when the study began in 2014 until the country shifted to dolutegravir-based ART as first-line therapy in 2016. This study aimed to compare the prevalence of neural-tube defects associated with exposure to dolutegravir-based ART versus non-dolutegravir-based ART at conception. ART at conception was defined as maternal ART starting before the calculated date of last menstrual period. Patients’ ART regimens, start dates, and any changes in ART were extracted and reviewed. Neural-tube defects included myelomeningocele, meningocele, encephalocele, anencephaly with or without craniorachischisis, or iniencephaly.

A total of 119,033 deliveries were included between August 2014 and March 2019, and 98 neural-tube defects were identified (0.08% of deliveries). A total of 1683 women were taking dolutegravir-based ART at conception, while 14,792 had exposure to non-dolutegravir ART at conception. Total neural-tube defects included 49 instances of meningocele or myelomeningocele, 33 of anencephaly, 15 of encephalocele, and 1 of iniencephaly. The absolute difference in prevalence between dolutegravir-based and non–dolutegravir-based ART exposure from conception was 0.20% (95% CI, 0.01 to 0.59). Five neural-tube defects were reported in deliveries with dolutegravir exposure (0.30%; 95% CI, 0.13 to 0.69) at conception versus 15 defects from mothers with non-dolutegravir-based ART exposure at conception (0.10%; 95% CI, 0.06 to 0.17). It should be noted that only 2 of the 5 women who experienced neural tube defects while taking dolutegravir were taking folate supplementation (started taking in 3rd month and 6th month of pregnancy).

Study limitations included an observational study design and differences in baseline characteristics, including fewer women in the dolutegravir group receiving pre-conception folate supplementation compared to the non-dolutegravir group, though very few women received pre-conception supplementation overall (0.1% and 0.2% respectively). More women in the dolutegravir group, however, received folate supplementation during pregnancy compared to the non-dolutegravir group (69% vs 52%), though the authors stated this was similar enough to not have likely influences outcomes. The authors concluded that the incidence of neural-tube defects associated with dolutegravir was slightly higher than that of the other ART exposure, although the prevalence is lower than shown in the preliminary data. As of December 2019, restrictions on the use of dolutegravir during the first trimester and in women who are trying to conceive have been removed from the United States Department of Health and Human Services (U.S. DHHS) HIV guidelines. The WHO now recommends dolutegravir as a preferred option for all populations, while the U.S. DHHS guidelines state that dolutegravir is an alternative, rather than a preferred treatment option in women trying to conceive and during pregnancy.^97,100

Conclusion

Although many significant, practice-changing pieces of ID literature were published in 2019, this review is intended to help highlight those thought to be most significant by members of HIDN and SIDP. This year’s review included multiple articles on the use of oral antibiotics as step-down from or in place of intravenous agents for a variety of infectious indications, optimal management of difficult-to-treat infections, and several long-awaited guidelines updates. The continued large number of publications relating to use of oral rather than intravenous antibiotics, as well as the number of these articles voted into our top 2019 publications, emphasizes this as a developing area in ID and stewardship pharmacotherapy. Such publications continue to answer unmet clinical needs and will likely result in an exciting and changing practice environment in 2020 and beyond.