By Carol A. Kemper, MD, FACP
Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center
A Reservoir of Pharyngeal GC
SOURCES: Barbee LA, Soge OO, Khosropour CM, et al. The duration of pharyngeal gonorrhea: A natural history study. Clin Infect Dis 2021;73: 575-582.
Adamson PC, Klausner JD. The staying power of pharyngeal gonorrhea: Implications for public health and antimicrobial resistance. Clin Infect Dis 2021;73:583-585.
One hundred forty men who have sex with men (MSM) living in Seattle were recruited for a longitudinal cohort study of pharyngeal gonorrhea (GC)/chlamydia infection. The men were asked to self-collect weekly pharyngeal and rectal swabs and complete a survey every week for 48 weeks, and specimens were tested for nucleic acid (NAAT) for GC/chlamydia. Pharyngeal and rectal specimens were collected at baseline, and those who were positive for GC waited two weeks and those who were positive for chlamydia waited three weeks following treatment before participating. Infection was defined as two consecutive positive tests, and clearance was defined as two consecutive negative tests. Participants were asked to wait for treatment so the true duration of infection could be determined.
Twenty percent failed to collect any specimens and were excluded. Nineteen of 112 MSM (16.9%) had 21 episodes of pharyngeal GC infection. The estimated median duration of infection was 16.3 weeks (95% confidence interval, 5.1-19.7 weeks) (incidence 31.7/100 person years). Sore throat was reported in only six cases (26%), and that was only during the first one to two weeks of infection. The duration of infection was not associated with human immunodeficiency virus (HIV) status, smoking history, or a prior history of gonorrhea. Three men (15%) reported only kissing or oral-anal contact, and four men reported no oral sexual exposure at all, suggesting their infections were either passively acquired by nonsexual or environmental means, or the men misreported/forgot what they had been doing.
In addition, 22 men had single positive specimens a median of seven days after their last negative test. If these men were included in the analysis, the estimated duration of infection was closer to 10 weeks.
Previously, pharyngeal GC was believed to be a transient infection, lasting one to six weeks, seldom resulting in symptoms or significant morbidity. This study suggests the natural duration of pharyngeal GC infection may be much longer — perhaps out to four months. This implies that pharyngeal GC may serve as a much more important reservoir for community infection than previously estimated. Since it is much harder to clear pharyngeal GC with antibiotics, and antibiotic levels in the oropharynx may be sub-optimal, pharyngeal GC organisms are more likely to experience selective pressure and risk antibiotic resistance, as well as risk acquiring bits of genetic material from other organisms in the oropharynx. It is possible that serial NAAT testing overestimated the duration of infection in this study, since 5% to 10% of infections may have detectable nucleic acid tests one to two weeks following treatment (and I have observed out to four weeks).
Screening MSM for pharyngeal GC on a regular basis, even in the absence of symptoms, is an important public health measure. Performing test of cure two weeks following treatment is important to detect treatment failures.
Difficult-to-Treat vs. Standard Multidrug Resistance
SOURCES: Karlowsky JA, Lob SH, Raddatz J, et al. In vitro activity of imipenem/relebactam and ceftolozane/tazobactam against clinical isolates of gram-negative bacilli with difficult-to-treat resistance and multidrug-resistance phenotypes — Study for monitoring antimicrobial resistance trends, Untied States 2015-2017. Clin Infect Dis 2021;72:2112-2120.
Al-Hasan MN. Gram-negative bacteria with difficult-to-treat resistance: A moving target. Clin Infect Dis 2012;72:2121-2123.
Authors in the first article sought a comparison of Clinical and Laboratory Standards Institute (CLSI)-defined in vitro activities of imipenem/relebactam and ceftolozane/tazobactam against urinary/respiratory/intra-abdominal gram-negative isolates collected in United States hospitals from 2015-2017 in 18 states. In a unique approach, Enterobacterales isolates (10,516) and Pseudomonas aeruginosa isolates (2,732) were assigned to the usually defined multidrug-resistance (MDR) grouping or a novel grouping called difficult-to-treat resistance (DTR).
From an infection control standpoint, MDR has been defined as nonsusceptibility to three classes of antimicrobial agents. That distinction presumes that different types of resistance have similar therapeutic and institutional implications, and that different classes of antimicrobials have similar value in treatment, which is not the case, e.g., aminoglycosides are seldom used as first-line therapy or as a single agent for sepsis, and therefore, their “weight” in the assessment of MDR is distorted. Instead, certain types and patterns of resistance are more clinically relevant, and the introduction of newer treatment options has altered the playing field.
For example, extended-spectrum beta-lactamase (ESBL) containing-organisms are automatically considered MDR according to current criteria, but carbapenems have provided effective therapy against these isolates for more than a decade. Further, certain carbapenem-resistant isolates have limited treatment options, whereas other do not. Take most carbapenem-resistant P. aeruginosa (PsA): Many still are sensitive to cefepime, ceftazidime, Zosyn, and even fluoroquinolones (FQ). In contrast, carbapenem-resistant Enterobacterales often are extensively drug resistant, with fewer treatment options.
Therefore, it is more relevant and useful to consider isolates that are clinically DTR and which pose a threat to your hospital environment (NMD, VIM, etc.). DTR then is defined as dose-limiting resistance to first-line therapeutic agents, including several newer agents, carbapenems, and FQs. Step-wise loss of susceptibility to one, two, or three first-line agents is associated more clearly with increasing treatment failure and mortality than MDR status. In one study, 43% of patients with bloodstream infection with DTR with nonsusceptibility to three first-line therapeutic agents died during the index hospitalization.
Fortunately, the availability of newer agents for gram-negative treatment is driving the re-assessment of our current concepts of MDR. In this study, among Enterobacterales, imipenem/relebactam inhibited 95.4% of all isolates, and specifically 99.4% of Klebsiella pneumoniae and 99.9% of Escherichia coli. Only Morganella appeared more susceptible to ertapenem and meropenem because Morganellaceae are intrinsically less susceptible to imipenem (and not because of carbapenemase production, so the addition of relebactam does not provide additional activity). Among Enterobacterales, 1% were considered DTR and 15.6% were MDR. Of these, imipenem/relebactam inhibited 82.4% of DTR and 92.1% of MDR (using a breakpoint minimal inhibitory concentration [MIC] ≤ 1 mcg/mL). In contrast, ceftolozane/tazobactam inhibited only 1.5% of DTR and 65.8% of MDR Enterobacterales.
Among all PsA, imipenem/relebactam and ceftolozane/tazobactam inhibited 93.9% and 94.7% of isolates, respectively (using a breakpoint MIC of ≤ 2 mcg/mL and ≤ 4 mcg/mL, respectively). Among PsA, 8.4% were considered DTR and 32.4% were MDR. Of these, imipenem/relebactam inhibited 62.2% of DTR PsA and 82.2% of MDR PsA. Further, ceftolozan/tazobactam inhibited 67.5% of DTR PsA and 84% of MDR PsA. Against all isolates of PsA, susceptibility to imipenem/relebactam was 22% points higher than to imipenem alone — suggesting that many newer strains of PsA are resistant not from constitutive resistance but because of newer beta-lactamases.
As anticipated, resistance was more common in respiratory isolates than in intra-abdominal or urinary isolates, as well as isolates collected in the intensive care unit. In U.S. hospitals, DTR PsA is more common than DTR Enterobacterales (8.4% vs. 1%), but labeling these organisms as MDR overstated the frequency of treatment-limiting options. Both imipenem/relebactam and ceftolozane/tazobactam offer effective treatment options for most MDR and DTR strains of PsA, and imipenem/relebactam provides effective treatment against most MDR and DTR Enterobacterales.